Case files Neurology [Third ed.] 9780071848008, 0071848002

Table of contents :
Cover
Title Page
Copyright Page
Contents
Contributors
Preface
Acknowledgment
Introduction
Listing of Cases
Section I: How to Approach Clinical Problems
Part 1. Approach to the Patient
Part 2. Approach to Clinical Problem-Solving
Part 3. Approach to Reading
Section II: Clinical Cases
Fifty-Four Case Scenarios Movement Disorders (Cases 1-6)
Trauma (Cases 7-8)
Altered Mental Status (Cases 9-10)
Stroke (Cases 11-13)
Seizures (Cases 14-17)
Headache (Cases 18-19)
Dementia (Cases 20-24)
Infection (Cases 25-31)
Cranial Nerve Disorders (Cases 32-37)
Motor Disorders (Cases 38-43)
Pediatric Neurology (Cases 44-51)
Tumors (Cases 52-53)
Miscellaneous (Cases 54)
Section III: Review Questions
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Z

Citation preview

THIRD EDITION

CASE FILES®

Neurology Eugene C. Toy, MD

Pedro Mancias, MD

Assistant Dean for Educational Programs Director, Doctoring Courses Professor and Vice Chair of Medical Education Department of Obstetrics and Gynecology McGovern Medical School at University of   Texas Health Science Center (UTHealth)   at Houston Houston, Texas

Professor Assistant Dean, Diversity and Inclusion Assistant Dean, Student Affairs and Admissions Distinguished Teaching Professor Adriana Blood Professor of Pediatrics McGovern Medical School at University of   Texas Health Science Center (UTHealth)   at Houston Houston, Texas

Ericka Simpson, MD Associate Professor, Neurology Weill-Cornell Medical College, New York Co-Director MDA Neuromuscular Clinics and   Director of ALS Clinical Research Division Methodist Neurological Institute Program Director The Methodist Hospital Neurology Residency   & Neuromuscular Fellowship Houston, Texas

Erin E. Furr-Stimming, MD Associate Professor of Neurology Chief of Neurology, LBJ Hospital Director, Neurology Clerkship Director, Huntington’s Disease Society of   America Center of Excellence McGovern Medical School at University of   Texas Health Science Center (UTHealth)   at Houston Houston, Texas

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

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Copyright © 2018 by the McGraw-Hill Education. 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: 978-0-07-184801-5 MHID: 0-07-184801-0 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-184800-8, MHID: 0-07-184800-2. 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 Education 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 Ues page at www.mhprofessional.com. 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 authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standard accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the editors 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. 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.

DEDICATION

To my fellow Houstonians who braved the devastating flood damage of Hurricane Harvey; To the amazingly courageous and selfless first responders and volunteers who went into harm’s way again and again to rescue the children, men, women, and helpless; To my fellow healthcare professionals, with whom I worked side by side, to help all those who were displaced and in need of medical care; To my fellow Texans who faced the biggest flooding disaster to strike here—today we are submerged, but by uniting, tomorrow, we will emerge stronger and more vibrant. You are each my hero and inspiration. —ECT To my mentor and chair Stanley H. Appel—a living Giant of Neurology who set a standard of excellence for the care and evaluation of the neurology patient. To my husband, Rodney, and our children, Emmanuel, Christian, and Christopher. To my Lord, Jesus Christ, the ultimate physician. —EPS To the late Dr. Frank Yatsu and my mentor and friend Dr. Ian Butler for being excellent role models in practicing clinical neurology. —PM To my amazing husband, Chris, and wonderful sons, Hopson, Eason and Wells. To my parents, my greatest fans, Jim and Jo Furr. Thank you for allowing me to pursue my dreams. —EFS

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CONTENTS

Contributors / vii Preface / xv Acknowledgments / xvii Introduction /xix Listing of Cases / xxi Section I How to Approach Clinical Problems....................................................................1 Part 1. Approach to the Patient.................................................................................................. 3 Part 2. Approach to Clinical Problem-Solving....................................................................... 8 Part 3. Approach to Reading.....................................................................................................10 Section II Clinical Cases.......................................................................................................15 Fifty-Four Case Scenarios  Movement Disorders (Cases 1-6)........................................................................................17   Trauma (Cases 7-8)...................................................................................................................63   Altered Mental Status (Cases 9-10)....................................................................................79   Stroke (Cases 11-13)................................................................................................................95   Seizures (Cases 14-17).......................................................................................................... 117   Headache (Cases 18-19)...................................................................................................... 151   Dementia (Cases 20-24)...................................................................................................... 173   Infection (Cases 25-31)........................................................................................................ 219          

Cranial Nerve Disorders (Cases 32-37)........................................................................... 273 Motor Disorders (Cases 38-43).......................................................................................... 327 Pediatric Neurology (Cases 44-51).................................................................................. 379 Tumors (Cases 52-53)........................................................................................................... 441 Miscellaneous (Cases 54).................................................................................................... 459

Section III Review Questions....................................................................................................................... 465 Index / 473

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CONTRIBUTORS

Shivika Chandra, MD

Fourth Year Resident in Neurology McGovern Medical School at Houston Houston, Texas Essential Tremor Huntington Disease Metastatic Brain Tumor Parkinson Disease Sixth Nerve Palsy

David Chiu, MD

Professor Director, Eddy Scurlock Stroke Center Methodist Neurological Institute Weill-Cornell Medical College Houston, Texas Acute Cerebral Infarction Stroke in Young Person

Nitish Chourasia, MD

Fourth Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Absence and Complex Partial Seizures Stroke in a Young Patient

Shilpa Dass, MD

Third Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Amyotrophic Lateral Sclerosis (Pure Motor Weakness) Foot Drop

John Eatman, MD

Assistant Professor Department of Neurology and Neuromuscular Medicine St. Luke’s Health System Kansas City, Kansas Ataxia, Spinocerebellar Chronic Inflammatory Demyelinating Polyneuropathy Dermatomyositis Guillain-Barre Syndrome Ptosis (Myasthenia Gravis)

Alireza Faridar, MD

Neuroimaging Fellow Department of Neurology Houston Methodist Hospital Houston, Texas Autism Febrile Seizure (Seizures with Fever in Child) New-Onset Childhood Seizure Spinal Cord Injury, Traumatic Tourette Syndrome

vii

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viii

CONTRIBUTORS

Stanley Fisher, MD

Associate Professor, Neurology University of Missouri, Kansas City Co-Director of Saint Luke’s Marion Bloch Neuroscience Institute Kansas City, Missouri Syncope Versus Seizure (Cardiogenic Syncope) Tourette Syndrome

Keely M. Fitzgerald, DO

Fifth Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Cerebral Concussion Duchenne/Becker Muscular Dystrophy

Stuart M. Fraser, MD

First Year Resident in Pediatrics McGovern Medical School at Houston Houston, Texas Infections in Immunocompromised Hosts: Toxoplasmosis

Erin E. Furr-Stimming, MD

Associate Professor of Neurology Chief of Neurology, LBJ Hospital Director, Neurology Clerkship Director, Huntington’s Disease Society of America Center of Excellence McGovern Medical School at University of Texas Health Science Center (UTHealth) at Houston Houston, Texas

Rajan Gadhia, MD

Assistant Professor, Neurology and Vascular Neurology Methodist Neurological Institute Weill-Cornell Medical College Houston, Texas Acute Cerebral Infarct Delirium Epidural/Subdural Hematoma Stroke in a Young Patient Subarachnoid Hemorrhage

Ankita Ghosh, MD

Second Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Meningioma of the Acoustic Nerve Pediatric Headache

Paul Gidley, MD

Professor Department of Head and Neck Surgery The University of Texas MD Anderson Cancer Center Houston, Texas Facial Paralysis Meningioma of the Acoustic Nerve Vertigo

Vansanthi K. Gomathinayagam, MS

Fourth Year Medical Student McGovern Medical School in Houston Houston, Texas Chronic Headache Subacute Combined Degeneration of the Spinal Cord

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CONTRIBUTORS

ix

Mohammad I. Hirzallah, MD

Fourth Year Resident in Neurology McGovern Medical School at Houston Houston, Texas Acute Disseminated Encephalomyelitis Migraine Headache Spinal Cord Injury, Traumatic Tardive Dyskinesia

David H. Hunter, MD

Fifth Year Resident McGovern Medical School at Houston Houston, Texas Alzheimer Dementia Delirium from Head Trauma HIV-Associated Dementia Lewy Body Dementia N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis Sporadic Creutzfeldt-Jakob Disease

Evan Johnson

Fourth Year Medical Student McGovern Medical School at Houston Houston, Texas Adult Onset Seizure Cardiogenic Syncope Psychogenic Non-epileptic Seizures (Pseudoseizure)

Surabhi Kaul, MD

Third Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Autism Tourette Syndrome

Pedro Mancias, MD

Professor Assistant Dean, Diversity and Inclusion Assistant Dean, Student Affairs and Admissions Distinguished Teaching Professor Adriana Blood Professor of Pediatrics McGovern Medical School at University of Texas Health Science Center (UTHealth) at Houston Houston, Texas Dermatomyositis Spinal Muscle Atrophy Type 1/Hypotonia in Infancy

Brooke McQueen, MD

Assistant Professor, Neurology Department of Neurology Houston Methodist Hospital Houston, Texas Benign Rolandic Epilepsy Foot Drop Median Nerve Mononeuropathy (Carpal Tunnel) Psychogenic Non-epileptic Seizures (Pseudoseizure)

Ashkan Mowla, MD

Interventional Neuroradiology Fellow UCLA Los Angeles, California Multiple Sclerosis Optic Neuritis

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x

CONTRIBUTORS

Mohammad Obadah Nakawah, MD Assistant Professor Neurology and Neuroimaging Houston Methodist Hospital Houston, Texas Absence and Complex Partial Seizures Adult Onset Seizure Tardive Dyskinesia

Sherwin Oommen, MD

First Year Resident in Pediatrics McGovern Medical School at Houston Houston, Texas Seizures with Fever in Child Spinal Cord Injury, Traumatic

Henry Ossó-Rivera, MD

Fifth Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Benign Epilepsy with Centrotemporal Spikes (BECTS) Lissencephaly

Dustin Paul, DO

Fourth Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Chronic Inflammatory Demyelinating Polyneuropathy Median Nerve Mononeuropathy (Carpal Tunnel)

Carlos A. Pérez, MD

Third Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Guillain-Barré Syndrome Ptosis (Myasthenia Gravis)

Milvia Pleitez, MD

Neurology Practitioner Houston, Texas Anisocoria Creutzfeldt-Jacob Disease Delirium HIV-Associated Dementia Infant Botulism Infections in Immunocompromised Hosts: Toxoplasmosis Meningitis, viral Neurosyphilis/Tabes Dorsalis

Kavya I. Rao, MD

Second Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Vertigo, Benign Paroxysmal Positional

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CONTRIBUTORS

xi

Jenny K. Riecke

Fourth Year Medical Student McGovern Medical School at Houston Houston, Texas Acute Cerebral Infarct Multiple Sclerosis Optic Neuritis Pseudotumor Cerebri/Idiopathic Intracranial Hypertension Subarachnoid Hemorrhage

Sam N. Russo, MD

First Year Resident in Pediatrics McGovern Medical School at Houston Houston, Texas New Onset Childhood Seizure

Parama Sahoo, MD

Kasturba Medical College Mangalore, India Meningitis, viral

Sheetal Shroff, MD

Assistant Professor, Neurology Department of Neurology Houston Methodist Hospital Houston, Texas HIV-Associated Dementia Infections in Immunocompromised Hosts: Toxoplasmosis Meningioma of the Acoustic Nerve Metastatic Brain Tumor Subacute Combined Degeneration of the Spinal Cord Tabes Dorsalis

Ericka Simpson, MD

Associate Professor Neurology Weill-Cornell Medical College New York, New York Co-Director MDA Neuromuscular Clinics and Director of ALS Clinical Research Division Methodist   Neurological Institute Program Director The Methodist Hospital Neurology Residency and Neuromuscular Fellowship Houston, Texas Acute Disseminated Encephalomyelitis (EDEM) Anisocoria Cerebral Concussion Creutzzfeldt-Jakob Disease Delirium Dystonia HIV-Associated Dementia Infant Botulism Infections in Immunocompromised Hosts: Toxoplasmosis Lissencephaly Meningitis, viral Pediatric Headache Spinal Muscular Atrophy Type 1 Tabes Dorsalis

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xii

CONTRIBUTORS

Stacy Smith, MD

Neurology, Neuro-ophthalmology, Headache Department of Neurology Houston Methodist Hospital Systems Houston, Texas Anisocoria Cerebral Concussion Chronic Headache Migraine Headache Multiple Sclerosis Optic Neuritis Pseudotumor Cerebri/Idiopathic Intracranial Hypertension Sixth Nerve Palsy (Ischemic Mononeuropathy)

Allison L. Toy, RN

Registered Nurse Baylor Scott & White Hillcrest Medical Center Waco, Texas Primary Manuscript Reviewer

Regina Troxell, MD

Fourth Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Ataxia, Spinocerebellar Facial Paralysis

Amit Verma, MD

Associate Professor, Neurology Director, Clinical Neurophysiology Methodist Neurological Institute Weill-Cornell Medical College Houston, Texas Absence and Complex Partial Seizure Adult Onset Seizure Benign Epilepsy with Centrotemporal Spikes New Onset Childhood Seizure Psychogenic Non-epileptic Seizures

John J. Volpi, MD

Assistant Professor, Neurology Co-Director, Vascular Neurology Director, Neurosonology Methodist Neurological Institute Weill-Cornell Medical College Houston, Texas Acute Cerebral Infarct Cardiogenic Syncope Stroke in a Young Patient Subarachnoid Hemorrhage

Alise O. Welsh, FNP, MSN

Nurse Practitioner, Comprehensive Epilepsy Program Texas Children’s Hospital Clinical Instructor, Baylor College of Medicine Houston, Texas Acute Spinal Cord Injury Benign Epilepsy with Centrotemporal Spikes Pediatric Headache Seizures with Fever in Child Spinal Muscular Atrophy Type 1

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CONTRIBUTORS

xiii

Andrea C. Younes, MD

Second Year Resident in Child Neurology McGovern Medical School at Houston Houston, Texas Infantile Botulism

Ashiq Zaman, MD

MHA Candidate University of Oklahoma, College of Public Health Oklahoma City, Oklahoma Cardiogenic Syncope Essential Tremor Facial Nerve Paralysis Parkinson Disease Vertigo, Benign Paroxysmal Positional

Pamela J. Zelnick

Fourth Year Medical Student McGovern Medical School in Houston Houston, Texas Anisocoria Tabes Dorsalis

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PREFACE

We appreciate all the kind remarks and suggestions from the many medical students over the past 3 years. Your positive reception has been an incredible encouragement, especially in light of the short life of the Case Files® series. In this third edition of Case Files®: Neurology, the basic format of the book has been retained. Improvements were made in updating many of the chapters. The new case includes NMDA receptor encephalitis, paraneoplastic effects, and spinal muscular atrophy type 1; a new section of Review Questions at the end of the book has been included. We reviewed the clinical scenarios with the intent of improving them; however, their “real-life” presentations patterned after actual clinical experience were accurate and instructive. The multiple choice questions have been carefully reviewed and rewritten to ensure that they comply with the National Board and USMLE format. Through this third edition, we hope that the reader will continue to enjoy learning diagnosis and management through the simulated clinical cases. It certainly is a privilege to be teachers for so many students, and it is with humility that we present this edition.

xv

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ACKNOWLEDGMENTS

The curriculum that evolved into the ideas for this series was inspired by two talented and forthright students, Philbert Yau and Chuck Rosipal, who have graduated from medical school. It has been a pleasure to work with Dr. Ericka Simpson, a brilliant, compassionate, and dedicated teacher. It has also been an amazing experience expanding our team working with Dr. Pedro Mancias, one of the brightest clinicians and most talented educators I have encountered anywhere in the world, and Dr. Erin Stimming, an excellent physician, teacher, and inspiration. I am greatly indebted to my editor, Bob Boehringer, whose exuberance, experience, and vision helped to shape this series. Likewise, Cindy Yoo has been a dream with whom to collaborate. I appreciate McGraw-Hill’s believing in the concept of teaching through clinical cases. My “family” at McGraw-Hill has been most gracious. I appreciate the support from my encouraging Chair Dr. Sean Blackwell and my educational Vice Dean Dr. Patricia Butler. I appreciate my feline companion Mithril, who is now in cat heaven, who would sit at my desk and purr encouragements while I was editing. Most of all, I appreciate my ever-loving wife Terri; and wonderful children, Andy and his wife Anna, Michael, Allison, and Christina for their patience, encouragement, understanding, and “sharing their father” with my students and writing. Eugene C. Toy

xvii

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INTRODUCTION

Mastering the cognitive knowledge within a field such as neurology is a formidable task. It is even more difficult to draw on that knowledge, procure and filter through the clinical and laboratory data, develop a differential diagnosis, and finally to form a rational treatment plan. To gain these skills, the student often learns best at the bedside, guided and instructed by experienced teachers, and inspired toward selfdirected, diligent reading. Clearly, there is no replacement for education at the bedside. Unfortunately, clinical situations usually do not encompass the breadth of the specialty. Perhaps the best alternative is a carefully crafted patient case designed to stimulate the clinical approach and decision-making. In an attempt to achieve that goal, we have constructed a collection of clinical vignettes to teach diagnostic or therapeutic approaches relevant to the discipline of neurology. Most importantly, the explanations for the cases emphasize the mechanisms and underlying principles, rather than merely rote questions and answers. This book is organized for versatility: it allows the student “in a rush” to go quickly through the scenarios and check the corresponding answers, as well as the student with more time to have thought-provoking explanations. The answers are arranged from simple to complex: a summary of the pertinent points, the bare answers, an analysis of the case, an approach to the topic, a comprehension test at the end for reinforcement and emphasis, and a list of resources for further reading. The clinical vignettes are arranged by system to allow students to integrate the information easier; but beware, patients don’t present to their doctors by “system”! A listing of cases is included in Section III to aid the student who desires to test his or her knowledge of a certain area or to review a topic including basic definitions. Finally, we intentionally did not primarily use a multiple choice question (MCQ) format because clues (or distractions) are not available in the real world. Nevertheless, several MCQs are included at the end of each scenario to reinforce concepts or introduce related topics.

HOW TO GET THE MOST OUT OF THIS BOOK Each case is designed to simulate a patient encounter with open-ended questions. At times, the patient’s complaint is different from the most concerning issue, and sometimes extraneous information is given. The answers are organized with four different parts:

PART I 1. Summary—the salient aspects of the case are identified, filtering out the extraneous information. The student should formulate his or her summary from the case before looking at the answers. A comparison to the summation in the answer will help to improve one’s ability to focus on the important data, while appropriately discarding the irrelevant information, a fundamental skill in clinical problem-solving. 2. A straightforward answer is given to each open-ended question.

xix

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xx

INTRODUC TION

3. The Analysis of the Case, which is comprised of two parts: a. Objectives of the case—A listing of the two or three main principles that are crucial for a practitioner to manage the patient. Again, the student is challenged to make educated “guesses” about the objectives of the case on initial review of the case scenario, which helps to sharpen his or her clinical and analytical skills. b. Considerations—A discussion of the relevant points and brief approach to the specific patient.

PART II Approach to the disease process—This has two distinct parts: a. Definitions or neurophysiology—Terminology or neuroanatomy correlates pertinent to the disease process. b. Clinical approach—A discussion of the approach to the clinical problem in general, including tables, figures, and algorithms.

PART III Comprehension questions—Each case contains several multiple choice questions that reinforce the material or introduce new and related concepts. Questions about material not found in the text will have explanations in the answers.

PART IV Clinical pearls—A listing of several clinically important points is reiterated as a summation of the text and allows for easy review, such as before an examination.

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LISTING OF CASES

LISTING BY CASE NUMBER CASE NO.

DISEASE

  1 Essential Tremor   2 Huntington Disease   3 NMDA Encephalitis   4 Parkinson Disease   5 Ataxia, Spinocerebellar   6 Tardive Dyskinesia   7 Spinal Cord Injury, Traumatic   8 Epidural/Subdural Hematoma   9 Delirium from Hepatic Encephalopathy 10 Cerebral Concussion 11 Acute Cerebral Infarct 12 Subarachnoid Hemorrhage 13 Stroke in a Young Patient (Acute Ischemic) 14 New-Onset Seizure, Adult 15 Absence Versus Complex Partial Seizures 16 Cardiogenic Syncope 17 Psychogenic Nonepileptic Seizure 18 Migraine Headache 19 Chronic Headache 20 Alzheimer Dementia 21 Lewy Body Dementia 22 Subacute Combined Degeneration of the Spinal Cord 23 Optic Neuritis 24 Multiple Sclerosis 25 Acute Disseminated Encephalomyelitis 26 Viral Meningitis 27 Infantile Botulism 28 HIV-Associated Dementia 29 Sporadic Creutzfeldt-Jakob Disease 30 Tabes Dorsalis 31 Intracranial Lesion (Toxoplasmosis) 32 Posterior Communicating Artery Aneurysm 33 Pseudotumor Cerebri/Idiopathic Intracranial Hypertension 34 Sixth Nerve Palsy (Ischemic Mononeuropathy)

CASE PAGE 18 26 34 40 50 58 64 72 80 88 96 104 112 118 126 136 144 152 164 174 184 192 200 210 220 226 236 244 250 258 266 274 286 294 xxi

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LISTING OF CASES

35 Facial Paralysis 36 Ptosis (Myasthenia Gravis) 37 Vertigo, Benign Paroxysmal Positional 38 Chronic Inflammatory Demyelinating Polyneuropathy 39 Guillain-Barré Syndrome 40 Dermatomyositis 41 Amyotrophic Lateral Sclerosis 42 Median Nerve Mononeuropathy 43 Foot Drop 44 New-Onset Seizure, Child 45 Febrile Seizures 46 Pediatric Headache (Migraine Without Aura) 47 Duchenne Muscular Dystrophy 48 Tourette Syndrome 49 Benign Epilepsy with Centrotemporal Spikes 50 Lissencephaly 51 Autism Spectrum Disorder 52 Meningioma of the Acoustic Nerve 53 Metastatic Brain Tumor 54 Spinal Muscular Atrophy Type 1

302 310 320 328 334 342 352 362 372 380 388 396 404 412 420 426 434 442 452 460

LISTING BY DISORDER (ALPHABETICAL) CASE NO.

DISEASE

15 Absence Versus Complex Partial Seizures 11 Acute Cerebral Infarct 25 Acute Disseminated Encephalomyelitis 20 Alzheimer Dementia 41 Amyotrophic Lateral Sclerosis   5 Ataxia, Spinocerebellar 51 Autism Spectrum Disorder 49 Benign Epilepsy with Centrotemporal Spikes 16 Cardiogenic Syncope 10 Cerebral Concussion 19 Chronic Headache 38 Chronic Inflammatory Demyelinating Polyneuropathy   9 Delirium from Hepatic Encephalopathy 40 Dermatomyositis 47 Duchenne Muscular Dystrophy   8 Epidural/Subdural Hematoma   1 Essential Tremor

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CASE PAGE 126 96 220 174 352 50 434 420 136 88 164 328 80 342 404 72 18

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LISTING OF CASES

35 Facial Paralysis 45 Febrile Seizures 43 Foot Drop 39 Guillain-Barré Syndrome 28 HIV-Associated Dementia   2 Huntington Disease 27 Infantile Botulism 31 Intracranial Lesion (Toxoplasmosis) 21 Lewy Body Dementia 50 Lissencephaly 42 Median Nerve Mononeuropathy 52 Meningioma of the Acoustic Nerve 53 Metastatic Brain Tumor 18 Migraine Headache 24 Multiple Sclerosis 14 New-Onset Seizure, Adult 44 New-Onset Seizure, Child   3 NMDA Encephalitis 23 Optic Neuritis   4 Parkinson Disease 46 Pediatric Headache (Migraine Without Aura) 32 Posterior Communicating Artery Aneurysm 33 Pseudotumor Cerebri/Idiopathic Intracranial Hypertension 17 Psychogenic Nonepileptic Seizure 36 Ptosis (Myasthenia Gravis) 34 Sixth Nerve Palsy (Ischemic Mononeuropathy)   7 Spinal Cord Injury, Traumatic 54 Spinal Muscular Atrophy Type 1 29 Sporadic Creutzfeldt-Jakob Disease 13 Stroke in a Young Patient (Acute Ischemic) 22 Subacute Combined Degeneration of the Spinal Cord 12 Subarachnoid Hemorrhage 30 Tabes Dorsalis   6 Tardive Dyskinesia 48 Tourette Syndrome 37 Vertigo, Benign Paroxysmal Positional 26 Viral Meningitis

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302 388 372 334 244 26 236 266 184 426 362 442 452 152 210 118 380 34 200 40 396 274 286 144 310 294 64 460 250 112 192 104 258 58 412 320 226

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SECTION I

How to Approach Clinical Problems Part 1 Approach to the Patient Part 2 Approach to Clinical Problem-Solving Part 3 Approach to Reading

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SECTION I: HOW TO APPROACH CLINICAL PROBLEMS

3

Part 1. Approach to the Patient Applying “book learning” to a specific clinical situation is one of the most challenging tasks in medicine. To do so, the clinician must not only retain information, organize facts, and recall large amounts of data but also apply all of this to the patient. The purpose of this text is to facilitate this process. The first step involves gathering information, also known as establishing the database. This includes taking the history, performing the physical examination, and obtaining selective laboratory values, special studies, and/or imaging tests. Sensitivity and respect should always be exercised during the interview of patients. A good clinician also knows how to ask the same question in several different ways, using different terminology. For example, patients may deny having “tremulousness” but will answer affirmatively to feeling “shaky.”

CLINICAL PEARL »»

The history is usually the single most important tool in obtaining a diagnosis. The art of seeking this information in a nonjudgmental, sensitive, and thorough manner is essential in becoming a good clinician.

HISTORY 1. Basic information: a. Age: Some conditions are more common at certain ages; for instance, forgetfulness is more likely to be caused by dementia in an elderly patient than the same complaint in a teenager. b. Gender: Some disorders, such as cluster headaches, are more common in men. In contrast, women more commonly have migraine headaches. Also, the possibility of pregnancy must be considered in any woman of childbearing age. c. Ethnicity: Some disease processes are more common in certain ethnic groups (such as type 2 diabetes mellitus in Hispanic patients). d. Course: Certain conditions are characterized by a particular clinical course, such as relapsing-remitting, slowly progressive, or acute/subacute, which aids in making a differential diagnosis.

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The discipline of neurology illustrates the importance of understanding how to correlate the neuroanatomic defect to the clinical manifestation.

2. Chief complaint: What is it that brought the patient into the hospital? Has there been a change in a chronic or recurring condition, or is this a completely new problem? The duration and character of the complaint, associated

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symptoms, and exacerbating/relieving factors should be recorded. The chief complaint engenders a differential diagnosis, and the possible etiologies should be explored by further inquiry.

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The first line of any presentation should include age, gender, marital status, handedness, and chief complaint. Example: A 32-year-old married white right-handed man complains of left arm weakness and numbness.

3. History of present illness:  This is the most important part of the history and should include a detailed description of the complaint, including: a. Neurological deficits—motor, sensory, cognitive, coordination. b. Onset and course of the problem. c. If pain, then location of the pain, character, nature, and severity. d. Aggravating and alleviating factors. e. Associated conditions or complaints. f. How the neurological condition affects the patient including disability and limitations in normal activity. g. Treatments or medications that the patient has tried. h. Medical, surgical, family, or environmental conditions that may have an impact on the patient’s condition. i. Patient’s greatest concern. 4. Past medical history: a. Major illnesses such as hypertension, diabetes, reactive airway disease, congestive heart failure, angina, or stroke should be detailed. i. Age of onset, severity, end-organ involvement. ii. Medications taken for any particular illness, including any recent changes to medications and the reason for the change(s). iii. Last evaluation of the condition (eg, when was the last stress test or cardiac catheterization performed in the patient with angina?). iv. Which physician or clinic is following the patient for the disorder? b. Minor illnesses such as recent upper respiratory infections should be noted. c. Hospitalizations, no matter how trivial, should be queried. d. In pediatric patients, pregnancy complications, delivery route and gestational age, developmental history, genetic considerations, or dysmorphisms should be noted. 5. Past surgical history: Note the date and type of procedure performed, indication, and outcome. Surgeon and hospital name/location should be listed. This information should be correlated with the surgical scars on the patient’s body.

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Any complications should be delineated, including anesthetic complications, difficult intubations, and so forth. 6. Allergies: Reactions to medications should be recorded, including severity and temporal relationship to medication. Immediate hypersensitivity should be distinguished from an adverse reaction. 7. Medications: A list of medications, dosage, route of administration, frequency, and duration of use should be developed. Prescription, over-the-counter drugs, herbal remedies, and recreational or illicit drugs are all relevant. If the patient is currently taking antibiotics, it is important to note what type of infection is being treated. 8. Immunization history: Vaccination and prevention of disease is one of the principal goals of the primary care physician; however, recording the immunizations received including dates, age, route, and adverse reactions, if any, is critical in evaluating the neurology patient as well. 9. Social history: Occupation, marital status, family support, and tendencies toward depression or anxiety are important. Use or abuse of illicit drugs, tobacco, or alcohol should also be recorded. 10. Family history: Many major medical problems are genetically transmitted (eg, Huntington disease and muscular dystrophy). In addition, a family history of conditions such as Alzheimer dementia and ischemic heart disease can be a risk factor for the development of these diseases. Social history including marital stressors, sexual dysfunction, and sexual preference are of importance. 11. Review of systems: A systematic review should be performed but focused on life-threatening and more common diseases. For example, in a young man with a testicular mass, trauma to the area, weight loss, and infectious symptoms are important to note. In an elderly woman with generalized weakness, symptoms suggestive of cardiopulmonary disease should be elicited, such as chest pain, shortness of breath, fatigue, or palpitations.

PHYSICAL EXAMINATION 1. General appearance: Note mental status, alert versus obtunded, anxious, in pain, in distress, and the patient’s interaction with other family members and with the examiner. Note any dysmorphic features of the head and body that may be important for many inherited or congenital disorders. 2. Vital signs: Record the temperature, blood pressure, heart rate, and respiratory rate. Oxygen saturation is useful in patients with respiratory symptoms. Height and weight are often placed here with a body mass index (BMI) calculated (BMI = kg/m2 or lb/in2). 3. Head and neck examination: Evidence of trauma, tumors, facial edema, goiter and thyroid nodules, and carotid bruits should be sought. In patients with altered mental status or a head injury, pupillary size, symmetry, and reactivity are important. Mucous membranes should be inspected for pallor, jaundice, and evidence of dehydration. Cervical and supraclavicular nodes should be palpated.

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4. Breast examination: Inspection for symmetry and skin or nipple retraction as well as palpation for masses should be performed. The nipple should be assessed for discharge, and the axillary and supraclavicular regions should be examined. 5. Cardiac examination: The point of maximal intensity (PMI) should be ascertained, and the heart should be auscultated at the apex as well as at the base. It is important to note whether the auscultated rhythm is regular or irregular. Heart sounds (including S3 and S4), murmurs, clicks, and rubs should be characterized. Systolic flow murmurs are fairly common as a result of the increased cardiac output, but significant diastolic murmurs are unusual. 6. Pulmonary examination: The lung fields should be examined systematically and thoroughly. Stridor, wheezes, rales, and rhonchi should be recorded. The clinician should also search for evidence of consolidation (bronchial breath sounds, egophony) and increased work of breathing (retractions, abdominal breathing, accessory muscle use). 7. Abdominal examination: The abdomen should be inspected for scars, distension, masses, and discoloration. For instance, the Grey-Turner sign of bruising at the flank areas can indicate intra-abdominal or retroperitoneal hemorrhage. Auscultation should identify normal versus high-pitched and hyperactive versus hypoactive bowel sounds. The abdomen should be percussed for the presence of shifting dullness (indicating ascites). Then careful palpation should begin away from the area of pain and progress to include the whole abdomen to assess for tenderness, masses, organomegaly (ie, spleen or liver), and peritoneal signs. Guarding and whether it is voluntary or involuntary should be noted. 8. Back and spine examination: The back should be assessed for symmetry, tenderness, or masses. The flank regions particularly are important to assess for pain on percussion that may indicate renal disease. 9. Perform genital examination and rectal examination as indicated by the history and review of systems. 10. Extremities/skin: The presence of joint effusions, tenderness, rashes, edema, and cyanosis should be recorded. It is also important to note capillary refill and peripheral pulses. For rashes, it is important to note the pattern of the rash on the patient’s body and/or face. 11. Neurologic examination: Patients who present with neurologic complaints require a thorough assessment, including mental status, cranial nerves, muscle tone and strength, sensation, reflexes, cerebellar function, and gait to determine where the lesion or problem is located in the nervous system. Locating the lesion is the first step to generating a differential of possible diagnoses and implementing a plan for management. a. Cranial nerves need to be assessed: Ptosis (III), facial droop (VII), hoarse voice (X), speaking and articulation (V, VII, X, XII), eye position (III, IV, VI), pupils (II, III), smell (I); visual acuity and visual fields, pupillary reflexes to light and accommodation; hearing acuity and Weber and Rinne

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test, sensation of three branches of V of face; shoulder shrugging (XI); and protruding the tongue (VII). b. Motor: Observe for involuntary movements, muscle symmetry (right vs left, proximal vs distal), muscle atrophy, and gait. Have patient move against resistance (isolate muscle group, compare one side vs another, and use 0-5 scale). c. Coordination and gait: Rapid alternating movements, point-to-point movements, Romberg test, and gait (walk, heel-to-toe in straight line, walk on toes and heels, rising from squatted position or from sitting) should be assessed. d. Reflexes: Assess biceps (C5,6), triceps (C6,7), brachioradialis (C5,6), patellar (L2-4), ankle (S1-2), and frontal release signs or pathologic reflexes (plantar reflex, palmomental, glabellar, snout), and clonus. e. Sensory: Patient’s eyes should be closed and both sides of the body compared, distal versus proximal; vibratory sense (low-pitched tuning fork); subjective light touch; position sense, dermatome testing, pain, and temperature should also be noted. f. Discrimination: Evaluate graphesthesia (identify number “drawn” on hand), stereognosis (place familiar object in patient’s hand), and two-point discrimination. 12. Mental status examination: A thorough neurologic examination requires a mental status examination. The Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA) are a series of verbal and nonverbal tasks that serves to detect impairments in memory, concentration, language, and spatial orientation. 13. For pediatric patients: A thorough developmental assessment should be performed, including careful evaluation of speech, hearing, socialization, gross and fine motor ability, and gait.

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A thorough understanding of functional anatomy is important to optimally interpret the physical examination findings.

14. Laboratory assessment depends on the circumstances. a. Complete blood count (CBC) can assess for anemia, leukocytosis (infection), and thrombocytopenia. b. Basic metabolic panel: Electrolytes, glucose, blood urea nitrogen (BUN), and creatinine (renal function). c. Urinalysis and/or urine culture to assess for hematuria, pyuria, or bacteruria. A pregnancy test is important in women of childbearing age. d. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and alkaline phosphatase test for liver function; amylase and lipase evaluate the pancreas.

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e. Cardiac markers (creatine kinase myocardial band [CK-MB], troponin, myoglobin) are indicated if coronary artery disease or other cardiac dysfunction is suspected. CK and CK-MB are often elevated in many neuromuscular disorders. Aldolase is more specific for skeletal muscle. f. Drug levels such as antiseizure medication level or acetaminophen level in possible overdoses. Drug screens should be considered in pertinent cases. g. Arterial blood gas measurements give information about oxygenation and also about carbon dioxide and pH readings. 15. Diagnostic adjuncts: a. Electroencephalogram (EEG) should be considered if focal or gross central nervous system pathology is suspected. Evoked potentials (visual, auditory, sensory) should be evaluated if disruption of afferent sensory pathways is suspected. b. Computed tomography (CT) is useful in assessing the brain for masses, bleeding, strokes, and skull fractures. c. Magnetic resonance imaging (MRI) helps to identify soft tissue planes very well. d. Nuclear medicine imaging (positron emission tomography [PET] or singlephoton emission computed tomography [SPECT] scans) may be helpful in some selected instances. e. Tissue analysis of nerves, muscles, or less commonly of the brain is rarely used. f. Lumbar puncture (LP) is indicated to assess any inflammatory, infectious, or neoplastic processes that can affect the brain, spinal cord, or nerve roots. g. Electrodiagnostic testing (electromyography [EMG]/nerve conduction velocity [NCV]) is an extension of the neurologic examination and is used to assess nerve and muscle disorders.

Part 2. Approach to Clinical Problem-Solving CLASSIC CLINICAL PROBLEM-SOLVING There are typically four distinct steps that the neurologist undertakes to systematically solve most clinical problems: 1. Making the diagnosis 2. Assessing the severity of the disease 3. Treating based on the stage of the disease 4. Following the patient’s response to the treatment

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Making the diagnosis: This is achieved by carefully evaluating the patient, analyzing the information, assessing the risk factors, and developing a list of possible diagnoses (the differential). Usually a long list of possible diagnoses can be pared down to a few of the most likely or most serious ones, based on the clinician’s knowledge, experience, and selective testing. For example, a 30-year-old patient who complains of acute onset of right facial weakness and drooling from the right side probably has cranial nerve VII palsy. Yet another individual who is a 60-yearold man with right-sided facial weakness and left arm numbness likely has an ischemic stroke.

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The first step in clinical problem-solving is making the diagnosis.

Assessing the severity of the disease: After establishing the diagnosis, the next step is to characterize the severity of the disease process, in other words, to describe “how bad” the disease is. This can be as simple as determining whether a patient is “sick” or “not sick.” Is the patient with a hemorrhagic stroke comatose or with a “blown pupil”? In other cases, a more formal staging can be used. For example, cancer staging is used for the strict assessment of the extent of malignancy.

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The second step is to establish the severity or stage of the disease. This usually impacts the treatment and/or prognosis.

Treating based on stage: Many illnesses are characterized by the stage or severity because this affects the prognosis and treatment. As an example, a patient with mild lower extremity weakness and areflexia that develops over 2 weeks may be carefully observed; however, once respiratory depression occurs, respiratory support must be given.

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The third step is tailoring the treatment to fit the severity or “stage” of the disease.

Following the response to treatment: The final step in the approach to disease is to follow the patient’s response to the therapy. Some responses are clinical, such as improvement (or lack of improvement) in a patient’s strength. A standardized method of assessment is important. Other responses can be followed by testing (eg, visual field testing). The clinician must be prepared to know what to do if the

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patient does not respond as expected. Is the next step to treat again, to reassess the diagnosis, or to follow up with another more specific test?

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The fourth step is to monitor treatment response or efficacy. This can be measured in different ways—symptomatically or based on physical examination or other testing.

Part 3. Approach to Reading The clinical problem-oriented approach to reading is different from the classic “systematic” research of a disease. Patients rarely present with a clear diagnosis; hence, the student must become skilled at applying textbook information to the clinical scenario. Because reading with a purpose improves the retention of information, the student should read with the goal of answering specific questions. There are several fundamental questions that facilitate clinical thinking. These are as follows: 1. What is the most likely diagnosis? 2. How would you confirm the diagnosis? 3. What should be your next step? 4. What is the likely neuroanatomic defect? 5. What are the risk factors for this condition? 6. What are the complications associated with the disease process? 7. What is the best therapy?

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Reading with the purpose of answering the seven fundamental clinical questions improves retention of information and facilitates the application of “book knowledge” to “clinical knowledge.”

WHAT IS THE MOST LIKELY DIAGNOSIS? The method of establishing the diagnosis has been covered in the previous section. One way of attacking this problem is to develop standard approaches to common clinical problems. It is helpful to understand the most common causes of various presentations (see the Clinical Pearls at the end of each case), such as “the worst headache of the patient’s life is worrisome for a subarachnoid hemorrhage.” The clinical scenario would be something such as the following:

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“A 38-year-old woman is noted to have a 2-day history of a unilateral, throbbing headache and photophobia. What is the most likely diagnosis?” With no other information to go on, the student would note that this woman has a unilateral headache and photophobia. Using the “most common cause” information, the student would make an educated guess that the patient has a migraine headache. If instead the patient is noted to have “the worst headache of her life,” the student would use the clinical pearl: “The worst headache of the patient’s life is worrisome for a subarachnoid hemorrhage.”

CLINICAL PEARL »»

The more common cause of a unilateral, throbbing headache with photophobia is a migraine, but the main concern is subarachnoid hemorrhage. If the patient describes this as “the worst headache of his or her life,” the concern for a subarachnoid bleed is increased.

HOW WOULD YOU CONFIRM THE DIAGNOSIS? In the scenario above, the woman with “the worst headache” is suspected of having a subarachnoid hemorrhage. This diagnosis could be confirmed by a CT scan of the head and/or LP. The student should learn the limitations of various diagnostic tests, especially when used early in a disease process. The LP showing xanthochromia (red blood cells) is the gold standard test for diagnosing subarachnoid hemorrhage, but it can be negative early in the disease course.

WHAT SHOULD BE YOUR NEXT STEP? This question is difficult because the next step has many possibilities; the answer can be to obtain more diagnostic information, stage the illness, or introduce therapy. It is often a more challenging question than “What is the most likely diagnosis?” because there may be insufficient information to make a diagnosis, and the next step may be to pursue more diagnostic information. Another possibility is that there is enough information for a probable diagnosis, and the next step is to stage the disease. Finally, the most appropriate answer may be to treat. Hence, from clinical data, a judgment needs to be rendered regarding how far along one is on the road of the following: 1. Make a diagnosis → 2. Stage the disease → 3. Treat based on stage → 4. Follow response Frequently, the student is taught to “regurgitate” the same information that someone has written about a particular disease but is not skilled at identifying the next step. This talent is learned optimally at the bedside, in a supportive environment, with freedom to take educated guesses and with constructive feedback. A sample scenario can describe a student’s thought process as follows: 1. Make the diagnosis: “Based on the information I have, I believe that Mr. Smith has a left-sided cerebrovascular accident.” 2. Stage the disease: “I don’t believe that this is severe disease because his Glasgow score is 12, and he is alert.”

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3. Treat based on stage: “Therefore, my next step is to treat with oxygenation, monitor his mental status and blood pressure, and obtain a CT scan of the head.” 4. Follow response: “I want to follow the treatment by assessing his weakness, mental status, and speech.”

CLINICAL PEARL »»

Usually, the vague query, “What is your next step?” is the most difficult question because the answer can be diagnostic, staging, or therapeutic.

WHAT IS THE MOST LIKELY NEUROANATOMIC DEFECT? Because the field of neurology seeks to correlate the neuroanatomy with the defect in function, the student of neurology should constantly be learning the function of the various brain centers and the neural conduits to the end organ. Considering the location of the lesion is essential in the differential diagnosis. Conveniently, neurology can be subdivided into compartments such as movement disorders, stroke, tumor, and metabolic disorders for the purpose of reading, yet the patient can have a disease process that affects more than one central nervous function.

WHAT ARE THE RISK FACTORS FOR THIS PROCESS? Understanding the risk factors helps the practitioner to establish a diagnosis and to determine how to interpret tests. For example, understanding risk factor analysis may help in the management of a 55-year-old woman with carotid insufficiency. If the patient has risk factors for a carotid arterial plaque (such as diabetes, hypertension, and hyperlipidemia) and complains of transient episodes of extremity weakness or numbness, she may have either an embolic or thrombotic disease mechanism.

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Being able to assess risk factors helps to guide testing and develop the differential diagnosis.

WHAT ARE THE COMPLICATIONS TO THIS PROCESS? Clinicians must be cognizant of the complications of a disease so that they will understand how to follow and monitor the patient. Sometimes the student will have to make the diagnosis from clinical clues and then apply his or her knowledge of the consequences of the pathologic process. For example, “A 26-year-old man complains of severe throbbing headache with clear nasal drainage.” If the patient has had similar episodes, this is likely a cluster headache. However, if the phrase is added, “The patient is noted to have dilated pupils and tachycardia,” then he is likely a user of cocaine. Understanding the types of consequences also helps the clinician to be aware of the dangers to a patient. Cocaine intoxication has

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far different consequences such as myocardial infarction, stroke, and malignant hypertension.

WHAT IS THE BEST THERAPY? To answer this question, not only do clinicians need to reach the correct diagnosis and assess the severity of the condition, but they must also weigh the situation to determine the appropriate intervention. For the student, knowing exact dosages is not as important as understanding the best medication, route of delivery, mechanism of action, and possible complications. It is important for the student to be able to verbalize the diagnosis and the rationale for the therapy.

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Therapy should be logically based on the severity of the disease and the specific diagnosis. An exception to this rule is in an emergent situation such as respiratory failure or shock when the patient needs treatment even as the etiology is being investigated.

SUMMARY 1. There is no replacement for a meticulous history and physical examination. 2. There are four steps in the clinical approach to the neurology patient: making the diagnosis, assessing the severity, treating based on the severity, and following the response. 3. There are seven questions that help to bridge the gap between the textbook and the clinical arena.

REFERENCES Aminoff M, Greenberg D, Simon R. The neurological examination. In: Aminoff M, Greenberg D, Simon R, eds. Clinical Neurology. 9th ed. New York, NY: McGraw-Hill; 2015. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.

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SECTION II

Clinical Cases

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CASE 1 A 65-year-old, right-handed man is being evaluated for a tremor that has been present for approximately 20 years. The tremor began insidiously and has progressed gradually. It involves both hands, although he feels the tremor is asymmetric, with his right-hand tremor being worse. His handwriting, drinking coffee and other liquids from a cup, and any activity that requires fine motor dexterity are affected. His tremor is not present at rest, and he has noticed that drinking a glass of beer or wine often improves his symptoms. His mother and daughter have a similar tremor, though to a lesser degree. On examination, he has a regular tremor of approximately 6 to 8 cycles per second (Hz) that is most prominent when extending his hands outward and during finger-to-nose testing. Occasional tremor is also noted of his head, and his voice has a tremulous quality. The remainder of his examination is unremarkable. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 1: Essential Tremor Summary: A 65-year-old, right-handed man has a 20-year history of tremor predominantly limited to actions such as writing, drawing, or holding objects. There is also head tremor, although to a lesser degree. The history is significant for similar signs and symptoms in his family members, and alcohol use improves symptoms. šš šš

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Most likely diagnosis: Essential tremor (ET). Next diagnostic step: Depending on clinical suspicion based on a detailed neurologic examination, magnetic resonance imaging (MRI) of brain and cervical spine may be warranted. A medication trial may be warranted if clinical suspicion of ET is high. Next step in therapy: Consider primidone or propranolol.

ANALYSIS Objectives 1. Understand the differential diagnosis of tremor. 2. Describe the clinical manifestations of ET. 3. Be aware of the available treatment modalities for patients with ET.

Considerations This case is typical for ET, although at this age, Parkinson disease (PD) should also be considered. ET is the most common movement disorder and may be 10 to 20 times more prevalent than idiopathic PD. Although ET is not generally thought of as a neurodegenerative disease, it can be bothersome and debilitating, negatively impacting quality of life. The diagnosis of ET is clinical, and several aspects help to distinguish between these two disorders. The tremor associated with PD may occur upon assuming a posture; if it occurs after a latent period of several seconds, it is called a reemergent tremor. PD patients can have jaw and tongue tremor (usually at rest), and head tremor is rare. Tremors from PD are most prominent when the hands are at the sides or resting in the lap. This type of tremor typically decreases with movement of the hands. In addition, PD is associated with rigidity, bradykinesia or slow movement, and postural instability. PD patients may also have a stooped posture, shuffling gait, sleep disturbance, hypophonic speech, autonomic dysfunction, hyposmia, mood disturbances, and subcortical cognitive decline (Table 1–1).

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Table 1–1  •  ESSENTIAL TREMOR VERSUS PARKINSON DISEASE Essential Tremor (ET)

Parkinson Disease (PD)

Onset of disease

Bilateral arm involvement

Unilateral tremor, associated with stooped posture, shuffling gait, memory loss

Body affected by tremor

Arms most commonly then head, legs, larynx, trunk

Stooped posture, shuffling gait

Tremor characteristics

Associated with purposeful movement

Tremor in arms at side

Latency period

Immediate

Longer (several seconds)

Data from DeLong MR, Luncos JL. Parkinson’s disease and other movement disorders. In: Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005:2406-2418.

APPROACH TO: Tremor DEFINITIONS COGWHEEL RIGIDITY: “Ratchety” periodic resistance to passive movement. LEAD-PIPE RIGIDITY: Velocity-independent resistance felt throughout range of motion. BRADYKINESIA: Slowed ability to start and continue movements and impaired ability to adjust the body’s position. ACTION TREMOR: Tremor that occurs during voluntary muscle contraction and may include postural, kinetic, or task- or position-specific tremor. POSTURAL TREMOR: Tremor that occurs while voluntarily maintaining antigravity position. KINETIC TREMOR: Action tremor that occurs with voluntary movements, including visually or nonvisually guided actions, including speaking or finger-tonose testing. PHYSIOLOGIC TREMOR: A very low-amplitude fine tremor (between 8 and 12 Hz) that is rarely visible to the naked eye. It is present in individuals while maintaining a posture or movement and is nonpathologic. It is often enhanced by stress, caffeine, or thyroid dysfunction. DYSTONIC TREMOR: Dystonia is defined as sustained involuntary movements caused by contraction of agonist and antagonist muscles producing “twisting or turning” movements. A dystonic tremor is usually not rhythmic or oscillatory, but instead it is irregular with rhythm and amplitude and may be accompanied by additional dystonic features.

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CLINICAL APPROACH ET is considered a monosymptomatic disease; that is, it generally causes tremor alone, although some patients also experience difficulty with tandem gait. The tremor usually begins gradually and will likely increase in severity over time. More often, tremors begin in mid-to-late life, with a mean age of onset of 45. The most common sign is an oscillatory movement of the hands or, more precisely, at the wrist joint where flexion and extension can be seen. The tremor may also occur in the legs, head, or voice. Symptoms of ET are typically bilateral, although some patients describe an asymmetric tremor. Tremors usually occur only when the patient engages in a voluntary movement, such as drinking a glass of water, writing, or threading a needle. Actions requiring fine motor skills, such as using utensils or small tools, can be especially difficult. Fatigue, anxiety, and temperature extremes may exacerbate symptoms, but tremors usually disappear when asleep or at rest. Low doses of alcohol, such as a glass of beer or wine, can dramatically decrease the tremor in approximately one-half of cases. Besides tremor, there can be mild impairments of balance. There is no confirmatory imaging or laboratory test to definitively diagnose the disorder; the diagnosis is made clinically using functional assessments such as writing, drawing spirals, or pouring water from one cup to another while performing a complete neurologic examination to rule out other potential diagnoses.

Pathogenesis Approximately half of all cases of ET are associated with an autosomal dominant inheritance pattern. The cause of ET in patients without identifiable genetic abnormality remains unclear. Histopathologic changes, including loss of Purkinje cells and presence of Lewy bodies (alpha-synuclein aggregates), have been described but are of uncertain significance.

Diagnosis In addition to ET and PD, other etiologies for tremors should be considered. Tremor as part of dystonic conditions is typically more asymmetric than ET and may have a jerky quality. Purely kinetic (occurring with action or voluntary movement) and intention tremors (when attempting a precise movement) are sometimes seen with disruption of cerebellar output tracts or damage to the red nucleus, which is involved in cerebellar motor pathways. Hyperthyroidism and other metabolic conditions associated with increased adrenergic activity can cause enhanced physiologic tremors that may resemble ET. ET is a clinical diagnosis and requires thorough evaluation to rule out other conditions. Laboratory studies, including thyroid function tests (thyroid-stimulating hormone [TSH]) and serum copper or ceruloplasmin levels (Wilson disease), should be considered based on the clinical picture. Neuroimaging may be indicated if diagnosis of ET is unclear or another neurologic condition is suspected. ET may be difficult to distinguish from tremor-dominant parkinsonian syndromes, including idiopathic PD. Traditional computed tomography (CT) or MRI of the brain may not show differences between the two conditions. 123 I-FP-CIT SPECT (DaTscan) imaging can differentiate ET from idiopathic

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PD and other primary parkinsonian disorders. DaTscan allows measurement and visualization of dopamine transporters (DaT) in the brain. In the setting of idiopathic PD, DaTscan will show asymmetric basal ganglia uptake, indicative of diminished dopamine transporter density in the striatum, whereas it is often normal in ET.

Management If there is an underlying medical cause such as hyperthyroidism, addressing it can alleviate the symptoms of the tremor. In addition, counseling the patient about lifestyle changes such as limiting caffeine intake, ensuring adequate rest, and employing stress-coping strategies can help tremor exacerbation secondary to external stimuli. Medications provide relief from tremors roughly half of the time. The mainstay of pharmacologic treatment for ET is with beta-blockers or primidone. Beta-blockers, such as propranolol, may provide relief from symptoms in many ET patients. Their common side effects include dizziness, confusion, and memory loss, particularly in older patients. They should be avoided in patients who are hypotensive or have a resting heart rate of less than 60 beats/min. There is also a relative contraindication in their use in patients with asthma, due to beta-blockade. Other medications include antiseizure medications, such as primidone (Mysoline) or topiramate (Topamax), which may be effective in patients who do not respond to beta-blockers; they are given at lower doses than those given to treat epilepsy. These medications should be initiated at low doses and increased slowly; this is particularly important for primidone, in which 25% of patients can experience acute ataxia and nausea upon starting the medications at higher doses. Topiramate can cause transient peripheral paresthesias, word-finding difficulty, weight loss, and can increase the risk for nephrolithiasis. Sedative-hypnotic agents such as the benzodiazepines diazepam (Valium) and alprazolam (Xanax) are sometimes used to treat patients whose tremors are exacerbated by tension or anxiety. Side effects can include confusion, imbalance, and sedation. It is important to note that the majority of medications used to treat patients with ET are used in an off-label manner. Botulinum toxin type A (Botox) injections can also be useful in treating some types of tremors, especially of the head and voice and dystonic tremors. Patients with refractory, functionally disrupting, or disabling tremor despite medical management may be candidates for deep brain stimulation (DBS) surgery. DBS involves surgical placement of an electrostimulator in the thalamus or subthalamic nucleus (STN) and has been shown to effectively decrease tremor in patients with ET as well as tremor-dominant PD. DBS should be avoided in patients with concurrent or preexisting psychiatric disorders, as it may worsen these conditions.

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COMPREHENSION QUESTIONS 1.1 A 59-year-old man is diagnosed with probable ET. A DaTscan is performed. In the case of true ET, which of the following is most likely to show abnormal uptake? A. Cerebellum B. Cerebral cortex C. Striatum D. None of the above 1.2 A 45-year-old woman is noted to have a distinct tremor with voluntary activity. Multiple family members also are noted to have tremors. If ET is diagnosed, what pattern of inheritance is most likely? A. Autosomal dominant B. Autosomal recessive C. X-linked dominant D. X-linked recessive E. Y-linked recessive 1.3 A 58-year-old man is noted to have a noticeable tremor that has progressed over 5 years. The tremor occurs in both hands while eating and drinking; there are mild problems with tandem gait, and there is also presence of tremor of the head. Of the following, which is more supportive of ET rather than idiopathic PD? A. Gait disturbance B. Male gender C. Slow progression of the tremor over 5 years D. Tremor in the head

ANSWERS 1.1 D. Although DaTscan may reveal diminished signal of basal ganglia structures in PD, it is generally unremarkable in ET. It has been Food and Drug Administration (FDA) approved to radiographically differentiate ET from PD. 1.2 A. An apparently autosomal dominant history of tremor is often seen in ET. A familial tendency may also be seen in PD. With autosomal dominant inheritance, half of offspring are affected, and males and females are equally affected. 1.3 D. The tremor involving the head is more typical of ET. There can be gait problems and also slow onset of tremor in both ET and PD. In general, ET is an isolated finding of tremor, whereas PD is associated with stooped posture, shuffling gait, and memory loss.

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SECTION II: CASE 1

CLINICAL PEARLS »»

Essential tremor (ET) is the most common movement disorder and affects up to 10 million adults.

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ET may be hereditary in half of patients and exhibits an autosomal dominant inheritance pattern in those cases.

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DaTscan may help distinguish ET from primary parkinsonian syndromes.

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ET is often relieved with low doses of alcohol and can be treated with beta-blockers, primidone or topiramate.

»»

Refractory, disabling ET may warrant consideration of surgical intervention such as DBS.

REFERENCES Benamer TS, Patterson J, Grosset DG, et al. Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the [123I]-FP-CIT study group. Mov Disord. 2000;15:503-510. Louis ED. Essential tremor. Lancet Neurol. 2005;4:100-110. Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet Neurol. 2010;9:613-622. Louis ED. Diagnosis and management of tremor. Continuum (Minneap Minn). 2016;22(4):1143-1158. Lyons K, Pahwa R, Comella C, et al. Benefits and risks of pharmacological treatments for essential tremor. Drug Saf. 2003;26:461-481. Pahwa R, Lyons KE, Wilkinson SB, et al. Comparison of thalamotomy to deep brain stimulation of the thalamus in essential tremor. Mov Disord. 2001;16:140-143. Tolosa E, Borght TV, Moreno E. Accuracy of DaTSCAN (123I-Ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2-year follow-up of an open-label study. Mov Disord. 2007;22(16):2346-2351. Zesiewicz TA, Elble RJ, Louis ED, et al. Evidence-based guideline update: treatment of essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2011;77:1752-1755.

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CASE 2 A 40-year-old man presents to the psychiatry emergency room for an increase in inappropriate, impulsive behavior. He works as a janitor and has had reasonably good work attendance. His coworkers say that he has appeared “fidgety” for several years. They specifically mention jerky movements that seem to affect his entire body more recently. His mother is alive and well, but his father died at age 58 in an auto accident and reportedly experienced similar symptoms. On examination, he is alert but easily distracted. His speech is fluent without paraphasias but is noted to be tangential. He has trouble with spelling the word “world” backward and serial sevens but recalls three objects at 3 minutes. When he walks, there is excessive distal hand movement and his balance is precarious, although he can stand with both feet together without falling. His reflexes are increased bilaterally, throughout. A urine drug screen is negative. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the molecular or genetic basis of this disorder?

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CASE FILES: NEUROLOGY

ANSWERS TO CASE 2: Huntington Disease Summary: A 40-year-old man is seen in the emergency room for inappropriate and impulsive behavior. He has appeared “fidgety” for several years and, more recently, has had generalized choreiform movements. He is alert but easily distracted and tangential. With ambulation, distal chorea is present, and his balance is altered. He also has evidence of pyramidal tract involvement with symmetrically increased reflexes. His deceased father reportedly experienced similar symptoms. šš

Most likely diagnosis: Huntington disease (HD).

šš

Next diagnostic step: Genetic counseling and genetic testing for HD.

šš

Molecular or genetic basis: Expanded CAG repeats on a gene called huntingtin located on chromosome 4p16.3. Repeat lengths greater than 40 are associated with clinical HD. CAG repeats greater than 36 but less than 40 correspond to incomplete penetrance.

ANALYSIS Objectives 1. Recognize the differential diagnosis of chorea. 2. Describe the basis for genetic confirmation of HD testing. 3. Be aware of the available symptomatic pharmacotherapy for patients with HD.

Considerations HD is a progressive neurodegenerative disorder inherited in an autosomal dominant fashion affecting both men and women equally. The most common motor symptom is chorea, defined as a dance-like hyperkinetic movement. Early in the disease course, affected individuals may experience personality changes or mild cognitive decline. As the disease progresses, chorea becomes more prominent along with postural instability and continued cognitive decline. Significant psychiatric features are often present, such as apathy, depression, and anxiety. This is a 40-year-old man with a history of fidgeting for several years, who now presents with increased impulsivity and, difficulty with calculations but intact short-term memory. He has more recently developed “jerky movements affecting his entire body.” He has difficulty with balance and has brisk reflexes. The distal hand movements and long history of fidgeting are typical for the chorea associated with HD. He also likely has a positive family history. The insidious onset is typical. Medications or illicit drug effects should be ruled out. Laboratory testing should be performed to evaluate for other diagnostic possibilities. These studies should include antinuclear antibody (ANA), electrolytes, glucose level, renal and liver function tests, rapid plasma reagin (RPR), thyroid-stimulating hormone level, human immunodeficiency virus

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(HIV) antibody, anticardiolipin antibodies, and vitamin B12 level. Imaging is also often recommended to evaluate for secondary or structural causes of chorea. Lumbar puncture may also be considered for infectious, inflammatory, or paraneoplastic etiologies. Genetic testing is the best diagnostic test for HD.

APPROACH TO: Huntington Disease DEFINITIONS CHOREA: Sudden, jerky, irregular movements with muscle contractions that are not repetitive or rhythmic but appear to flow from one muscle to the next. ATHETOSIS: Twisting and writhing movements often associated with chorea. DYSTONIA: Sustained muscle contractions causing twisting and repetitive movements or abnormal postures. TARDIVE DYSKINESIA: A hyperkinetic disorder caused by the long-term and/ or high-dose use of dopamine antagonists, most often the typical neuroleptics. The most common movements are repetitive involuntary movements of the tongue, lips, and face.

CLINICAL APPROACH HD is inherited in an autosomal dominant fashion. The disease is associated with increases in the length of a CAG triplet repeat present in a gene called huntingtin located on chromosome 4p16.3. Repeat lengths greater than 40 are associated with full penetrance and definite phenoconversion to HD. CAG repeats 36 to 39 are associated with incomplete penetrance and uncertain phenoconversion. There is an inverse correlation between the number of CAG repeats and age of onset of clinical symptoms. The average age of onset is 40. The repeat length can increase from generation to generation, particularly with paternal transmission, often resulting in a phenomenon known as anticipation. If one parent has 39 repeats and the child has 42, the parent may show symptoms late in life or never, while the child can have onset at age 40, which can contribute to confusing inheritance patterns in the family history. HD is manifested by motor, cognitive, and behavioral symptoms. The most common motor feature is chorea (from the Greek word for dance) and consists of involuntary, random movements involving the limbs, trunk, and face. Difficulty with coordination, dexterity, and balance can also occur. As the disease progresses, difficulty with swallowing (dysphagia) occurs, with aspiration pneumonia being the most common cause of death. Slowing of saccades (fast eye movements) is an early sign, and increased reflexes with disinhibition of primitive reflexes may be seen. Executive dysfunction is common, and patients often develop a subcortical pattern of dementia. Behavioral disinhibition, depression, impulsivity, and anxiety are often seen. Suicide is another common cause of death in patients with HD. While the

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most common symptoms and signs are listed previously, there is significant phenotypic variability between patients. Juvenile-onset HD is rare (~ 5% of patients) and is termed the Westphal variant. Unlike adults with HD who have hyperkinetic motor manifestations, patients with juvenile HD have hypokinetic motor features and are often described as parkinsonian. The primary symptoms include bradykinesia and rigidity. Dystonia, myoclonus, and seizures can also occur. Diagnosis has been greatly aided by the ability to test for the number of repeats in the huntingtin gene. Anatomically, the predominant involvement is of the striatum; bilateral atrophy of the head of caudate nucleus and putamen (Figure 2–1) can be seen via neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]). There is a fairly extensive differential diagnosis for chorea, including other conditions that are inherited, autoimmune, metabolic, and drug- or toxin-induced (Table 2–1). In the context of an adult with an insidious onset and slow progression over several years, the likelihood of a neurodegenerative disease increases. The most common cause of a hereditary neurodegenerative cause of chorea is HD. An example of an autoimmune form of chorea is Sydenham chorea; it is an acute, usually self-limited disorder of younger individuals, usually between ages 5 and 15, more common in females than males. Sydenham chorea is closely linked with group A beta-hemolytic streptococcal infection, with approximately 30% of patients with preceding rheumatic fever. Antistreptolysin-O (ASO) and anti-DNase B titers may be elevated and can assist in supporting the diagnosis. Symptomatic treatment to attenuate the chorea is often necessary.

A

B

Figure 2–1.  CT of the brain in Huntington dementia. Image A is a patient with HD, and image B shows a normal brain as comparison. (Reproduced, with permission, from Ropper AH, Brown RH. Adams and Victor’s Principles of Neurology. 8th ed. New York, NY: McGraw-Hill; 2005:912.)

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Table 2–1  •  DIFFERENTIAL DIAGNOSIS OF CHOREA IN ADULTS Hereditary   Huntington disease (HD)a   HD–like syndrome type 2   Spinocerebellar ataxia 1, 2, 3, 17a  Pseudohypoparathyroidism/pseudopseudohypoparathyroidism   Dentatorubropallidoluysian atrophy   Fahr disease  Neuroferritinopathy Autoimmune   Systemic lupus erythematosusa   Polyarteritis nodosaa   Behçet diseasea   Sjögren syndromea   Sydenham chorea   Antiphospholipid syndromea   Multiple sclerosisa   Celiac disease Neoplasia   Directly involving striatum   Paraneoplastic syndromea Vascular  Infarct   Arteriovenous malformation   Subdural hematoma Infectious Metabolic  Hyponatremia/hypernatremia  Hypocalcemia  Hypoglycemia/hyperglycemia  Hyperthyroidisma   Hepatocerebral degeneration   Renal failure   Thiamine deficiency   Niacin deficiency  Hypoparathyroidism  Polycythemia   Chorea gravidarum Toxins   Alcohol (intoxication and withdrawal)   Carbon monoxide  Mercury  Manganese  Postanoxia Drugs   Neuroleptics (tardive)a   Antiparkinsonian medications  Anticonvulsantsa  Amphetaminesa  Steroids  Opiates Entities that merit consideration in this case.

a

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Management Currently, there is no Food and Drug Administration (FDA)-approved agent to slow or halt disease progression in patients with HD. As this is a relentless disease affecting motor, cognitive, and psychiatric function, it is important to discuss end-of-life issues with the patient and family before impairment becomes severe and communication ability is lost. Although experiments on transgenic mice with the huntingtin gene have suggested that certain compounds may exert a diseasemodifying effect, this remains to be confirmed in humans with HD. The motor and psychiatric symptoms are usually treated symptomatically. 1. Chorea is typically improved with drugs that interfere with dopaminergic function. Tetrabenazine (TBZ) is the only FDA-approved medication to treat HD chorea. TBZ reversibly depletes monamines from nerve terminals, ultimately decreasing the release of dopamine. Atypical neuroleptics such as olanzapine or risperidone may also be used to attenuate chorea if TBZ is not appropriate for the patient or poorly tolerated. High-potency neuroleptics such as haloperidol may be used for chorea attenuation. With the exception of TBZ, these medications carry the risk of causing tardive dyskinesia, though this has rarely been reported in this condition. As HD progresses, bradykinesia and rigidity may become more apparent but can also be caused by neuroleptics, so close follow-up is important and medication adjustment may be necessary. It is not uncommon for these agents to be discontinued as the disease progresses. 2. Depression is very common, as is irritability and anxiety, and is usually treated with selective serotonin reuptake inhibitors (SSRIs). There is a high risk of suicide in patients with HD due to the high incidence of depression and impulsivity. 3. Problems with swallowing and aspiration are apparent later in the course. Discussion in consideration of percutaneous endoscopic gastrostomy (PEG) tube is advised, especially early in the course of the disease to provide adequate nutrition and decrease aspiration. 4. Genetic counseling of the patient’s relatives is extremely important. 5. Support services such as physical, occupational, and speech therapy should be initiated early to decrease the risk of falling, injury, and aspiration.

COMPREHENSION QUESTIONS 2.1 A 33-year-old man is noted to have dancing-like movements of his arms and trunk. He is apathetic and depressed. His dad and grandfather had similar symptoms. Which of the following is the best test to confirm the suspected diagnosis of Huntington disease? A. Cerebral positron emission tomography (PET) scanning B. Genetic testing C. MRI of the brain D. Rectal biopsy

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SECTION II: CASE 2

2.2 The same patient noted in Question 2.1 is noted to have disabling chorea. Which of the following is most likely to be helpful for the choreiform movements? A. Haloperidol 1 mg one to three times per day B. Carbidopa/levodopa three times per day C. Deep brain stimulation of the subthalamus D. Fluoxetine 10 mg daily 2.3 Which of the following clinical features is associated with juvenile or childhood HD? A. Seizures B. Myoclonus C. Rigidity D. Dystonia E. All of the above

ANSWERS 2.1 B. A result showing greater than 40 CAG repeats in the huntingtin gene confirms the diagnosis of HD. 2.2 A. Judicious use of dopamine-blocking agents is effective in many patients with chorea. Patients need to be monitored for side effects, particularly parkinsonism and tardive dyskinesia. Levodopa can worsen chorea, although in HD patients with significant bradykinesia, it can be helpful. 2.3 E. Onset of HD in childhood (~ 5% of patients) is more severe and is called the Westphal variant. It causes parkinsonism with prominent bradykinesia and rigidity. Dystonia, myoclonus, and seizures are additional clinical features that may occur.

CLINICAL PEARLS »»

Huntington disease (HD) is a progressive neurodegenerative disease that encompasses motor, cognitive, and psychiatric symptoms.

»»

HD is inherited in an autosomal dominant fashion and is the most common inherited cause of chorea.

»»

HD is a triplet repeat disease. Individuals with greater than 40 CAG repeats will manifest symptoms associated with HD.

»»

While there is no approved disease-modifying agent for HD, effective symptomatic treatments are available and should be used when appropriate.

»»

Paternal inheritance is associated with earlier symptom onset (anticipation) and increased disease severity.

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REFERENCES Anderson KE, Marshall FJ. Behavioral symptoms associated with Huntington’s disease. Adv Neurol. 2005;96:197-208. Bates GP. History of genetic disease: the molecular genetics of Huntington disease—a history. Nat Rev Genet. 2005;6:766-773. Handley OJ, Naji JJ, Dunnett SB, et al. Pharmaceutical, cellular and genetic therapies for Huntington’s disease. Clin Sci (Lond). 2006;110:73-88. Mestre T. Chorea. Continuum (Minneap Minn). 2016;22(4):1186-1207. Nance M, Paulsen JS, Rosenblatt A, Wheelock V. A Physician’s Guide to the Management of Huntington’s Disease. 3rd ed. New York, NY: Huntington’s Disease Society of America; 2011. Paulsen JS, Nehl C, Hoth KF, et al. Depression and stages of Huntington’s disease. J Neuropsychiatry Clin Neurosci. 2005;17(4):496-502. Semaka A, Creighton S, Warby S, et al. Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clin Genet. 2006;70:283-294.

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CASE 3 You are called for a consult on a 28-year-old woman in the psychiatric ward of the hospital who has a seizure. The patient was admitted 2 weeks ago for a new onset of psychosis. Her mom notes the patient had “the flu” for a few days at the beginning of the month. She was recovering but then started to make odd statements, like mentioning someone was following her on the street. One day, the patient’s mother got a call that her daughter had not shown up to work that morning, which is not typical. When the mom arrived at the patient’s apartment, she found her cowering in a corner, yelling at an imaginary attacker. The patient had no history of psychiatric illness, so her mother called emergency medical services (EMS). Once admitted to the psychiatric ward, the patient was treated with neuroleptics and her hallucinations improved, but her mother feels she continues to decline in other ways. The patient no longer recognizes friends and family, does not understand where she is, and spends all day sleeping. After the new-onset seizure, the psychiatrist agreed neurology needed to be involved. On your examination, painful stimulus is required to wake the patient. She is not oriented to place or time. Most questions are not answered, and instead the response is tangential or stereotyped. Both her blood pressure and pulse are high, although review of her vital signs over 24 hours shows that her blood pressure and pulse have been fluctuating wildly throughout her stay. The patient does not participate in a formal neurologic examination. You do note she has abnormal movements of the mouth and tongue. Her mother says these were present even before she was started on antipsychotics. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 3: NMDA Encephalitis Summary: The patient is a 28-year-old woman with a subacute onset of psychosis following a flu-like prodrome. Several weeks into the illness, she becomes hard to arouse, disoriented, and tangential. Her vital signs have fluctuated irregularly throughout her stay, and she has abnormal facial movements. Neurology is consulted for a new-onset seizure. šš

šš

šš

Most likely diagnosis: Autoimmune (or paraneoplastic) encephalitis, most likely N-methyl-d-aspartate (NMDA) receptor encephalitis. Next diagnostic step: Magnetic resonance imaging (MRI) of the brain; electroencephalography (EEG), lumbar puncture (LP), and computed tomography (CT) of the chest/abdomen/pelvis. Next step in therapy: Plasma exchange, corticosteroids, and tumor resection.

ANALYSIS Objectives 1. Describe the typical presentation of anti-NMDA receptor (NMDAR) encephalitis. 2. Understand the diagnostic and treatment approach for NMDAR encephalitis. 3. Know how to differentiate NMDAR encephalitis from diseases with similar presentation.

Considerations This is a young woman with no psychiatric history who presented with frank psychosis. Given that the most likely explanation for this scenario is an initial presentation of schizophrenia, it is unsurprising this patient was admitted to a psychiatric ward. It is thus essential that primary care providers, emergency physicians, and psychiatrists are familiar with the features of organic diseases that may present with prominent psychosis in this population. On further examination, this patient’s illness began with flu-like symptoms prior to the onset of psychosis. Later, after the psychotic symptoms were treated, she developed a depressed level of consciousness (stupor), disorientation, dysautonomia, orofacial dyskinesia, and finally a seizure. The subacute course, global cognitive symptoms, and lack of glaring focal neurologic findings suggest an inflammatory etiology for this patient’s condition, either infectious or autoimmune. Given the vastly divergent treatments these two classes of disease would require, the first priority is to rule out an infection. Bacterial meningitis or encephalitis is typically fatal within days if not treated, so this is less likely. Fungal or mycobacterial infections are possible, though unusual in a young patient with an intact immune system. The classic infection in this

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presentation would be viral encephalitis, most commonly herpes simplex virus (HSV) or related herpes viruses, enterovirus, or one of the named encephalitis viruses (eg, West Nile or St. Louis). Cerebrospinal fluid (CSF) studies should be obtained. In addition to cell count, glucose, and protein levels, one should send specific viral serologies when possible. Since it is the only virus with a specific treatment, HSV is of particular significance, and some neurologists will treat empirically with acyclovir until the HSV polymerase chain reaction (PCR) comes back negative. When an infectious etiology is eliminated, an autoimmune process becomes the most likely diagnosis in this case, namely a syndrome called limbic encephalitis (LE). Much like HSV encephalitis, LE is characterized by inflammation affecting primarily the temporal lobes and the orbitofrontal cortex (the cortical structures that overlie the skull base). LE can be paraneoplastic, with autoimmunity triggered by a cancer, or it can be an inherent autoimmune process with no tumor. Numerous antibodies have been described as causative of LE, although the absence of these antibodies does not rule out LE in patients. Antibodies directed at the NMDAtype glutamate receptor produce a classic syndrome, often in young women, typified by this patient’s scenario (new-onset psychosis that progresses to severe cognitive impairment, seizures, and dysautonomia). Since giving a specific diagnosis may be impossible, a priority is placed on empiric treatment with therapies to suppress the immune system. Plasma exchange, intravenous immune globulin (IVIg) or high-dose IV corticosteroids are often used in concert. If these measures offer no improvement, chemotherapeutic agents such as rituximab may be used.

APPROACH TO: NMDA Encephalitis DEFINITIONS LIMBIC ENCEPHALITIS: An inflammatory process involving primarily the limbic cortex (ie, the mesial temporal lobes, hippocampus, amygdala, and related structures). It is classically caused by an autoimmune or paraneoplastic process. PARANEOPLASTIC: Any syndrome that results as a remote effect of a tumor, often an autoimmune process in which antibodies produced in response to the tumor attack otherwise normal cells in the body. Lambert-Eaton myasthenic syndrome and dermatomyositis are other examples of neurologic paraneoplastic syndromes. HERPES SIMPLEX VIRUS: A ubiquitous virus that primarily infects the trigeminal ganglion. It can rarely travel to the brain and cause a deadly encephalitis, which targets the same limbic structures and leads to similar symptoms as autoimmune limbic encephalitis. The infection is hemorrhagic, so red blood cells (RBCs) will be found in CSF. This should be treated with acyclovir.

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ANTI-NMDA RECEPTOR ENCEPHALITIS: It is a common cause of paraneoplastic or autoimmune encephalitis caused by antibodies targeting the NMDA-type glutamate receptors. It often begins with psychosis and subsequently progresses into depressed consciousness, seizures, and ultimately coma. It was first described in young women with ovarian teratomas.

CLINICAL HISTORY AND FEATURES Anti-NMDA receptor encephalitis was first described in 2007. Patients present with rapidly progressive memory deficits, seizures, and psychiatric symptoms. About 86% of patients in one case series had a nonspecific prodrome of headache, low-grade fever, and other flu-like symptoms. This progresses to psychiatric symptoms, including agitation, bizarre behavior, disinhibition, delusions, and hallucinations. These soon blend into cognitive dysfunction of short-term memory, concentration, and orientation. Seizures are characteristic of the later stages of the disease. Patients also can have dyskinesias, particularly of the mouth and face, which can be mistaken for seizures. Neither status epilepticus nor dysautonomia is uncommon, both of which will necessitate an intensive care setting.

Pathology NMDA receptors are a subtype of glutamate receptors in the brain. Antagonism at the NMDA receptors in the thalamus leads to disinhibition of the frontal cortex, which manifests with a syndrome summarized above. (Phencyclidine [PCP] and ketamine are both NMDA receptor antagonists that produce a similar presentation.) In the case of autoimmune encephalitis patients, the antagonism of the receptors is by antibodies directed at the NR1a subunit. NMDAR encephalitis was originally described as a paraneoplastic syndrome in a series of young women found to have ovarian teratomas. It is thought that the abnormal tissue in the teratoma resembles the receptor subunits, and antibodies developed to attack the tumor ultimately cross-react with the healthy receptors in the brain. Since the initial description of NMDAR encephalitis, many patients have been diagnosed with the anti-NMDA antibodies who were not found to have cancer. This is termed the autoimmune subtype of the disease, compared to the paraneoplastic form.

Diagnostic Studies The definitive diagnosis of NMDAR encephalitis is performed by direct detection of the antibodies in either CSF or serum. Unfortunately, this test is a send-out laboratory test that can take a week or more to return, so an extensive initial workup is required to exclude other diagnoses, obtain circumstantial evidence to support a diagnosis of NMDAR encephalitis, and direct empiric treatment. MRI of the brain may show hyperintensities in the limbic cortex and other deep structures but is normal in 70% of cases. CSF generally shows mild increase in protein and lymphocytes. LP is most valuable to exclude viral etiologies, particularly HSV. Patients with HSV classically

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will have elevated protein, lymphocytosis, and red blood cells not accounted for by procedure-related trauma. HSV PCR can be confirmatory. EEG typically reveals generalized slowing unless a frank seizure is captured. This is very helpful for differentiating primary psychotic illnesses such as schizophrenia from encephalitis, as the latter usually has an abnormal EEG. CT of the chest, abdomen, and pelvis is recommended in any patient suspected of having a paraneoplastic condition. In addition to helping to confirm the diagnosis, resection of the tumor is often curative.

Treatment First-line treatment of the underlying autoimmune process is typically with corticosteroids, often in combination with IVIg or plasma exchange. In severe cases, it may be necessary to resort to chemotherapy, such as rituximab or cyclophosphamide. If a tumor, such as a teratoma, is found, it should be removed as soon as possible. Symptomatic treatment of psychosis and other behavioral disturbances is appropriate, though caution must be used with antipsychotics, as they contribute to movement and dysautonomia symptoms.

COMPREHENSION QUESTIONS 3.1 A 23-year-old woman presents with several days of psychosis. MRI shows hyperintensities in the temporal and orbitofrontal cortex. Interictal EEG demonstrates frequent epileptic discharges originating in the bilateral temporal lobes. CSF shows normal glucose, elevated protein, elevated white cell count with a lymphocytic predominance, and elevated red blood cell count. The spinal tap was performed by radiology and was not traumatic. Which of the following is the most likely diagnosis? A. Bacterial encephalitis B. Autoimmune encephalitis C. Viral encephalitis D. Schizophrenia 3.2 You suspect that a 27-year-old woman diagnosed with new-onset schizophrenia may actually have anti-NMDA receptor encephalitis. Which of the following tests is least likely to inform the diagnosis? A. MRI of the brain B. CSF C. EEG D. Serology for anti-NMDA antibodies

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3.3 A 30-year-old woman is confirmed to have anti-NMDA encephalitis. She appears to be significantly ill. CT imaging reveals an ovarian teratoma. Which is the best initial step in the management of this patient? A. Interferon-alpha therapy B. IV corticosteroids C. Transfusion with fresh frozen plasma D. Tumor resection

ANSWERS 3.1 C. Normal glucose, elevated protein, and lymphocytosis point to a viral infection. The presence of RBCs and temporal lobe involvement with partial seizures are all classic for HSV encephalitis. The patient should be started on acyclovir. 3.2 A. MRI is normal in 70% of patients with NMDAR encephalitis. CSF is abnormal in most patients with NMDAR encephalitis, though the abnormalities are nonspecific, and it would be normal in schizophrenia. EEG is abnormal in 90% of NMDAR encephalitis patients, whereas it would be normal in psychiatric disease. A positive serology for NMDAR encephalitis would confirm the disease. 3.3 B. Immune suppression is essential with corticosteroids being the first line of therapy. If a tumor is found in a patient with a paraneoplastic syndrome, timely resection can be curative, but medical therapy for stabilization in this patient is prudent. Fresh frozen plasma and interferon alpha have no role.

CLINICAL PEARLS »»

Anti-NMDAR encephalitis is a cause of new-onset psychosis, classically in young women, that progresses to severe cognitive impairment, seizures, and dysautonomia.

»»

NMDAR encephalitis can be paraneoplastic or autoimmune (without an underlying tumor).

»»

NMDAR encephalitis should be promptly treated with immune suppression. Tumor should be sought with full-body CT and resected if found.

»»

HSV encephalitis also affects the temporal lobes. Classic CSF profile includes protein, red blood cells, and lymphocytes. Treatment is with acyclovir.

REFERENCES Barry H, Bryne S, Cotter D, Murphy KC, Cotter DR. Anti-N-methyl-D-aspartate receptor encephalitis: review of clinical presentation, diagnosis, and treatment. BJPsych Bull. 2015;39:19-23. Wandinger K, Saschenbrecker S, Stoecker W, Dalmau J. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol. 2011;231:86-91.

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CASE 4 A 55-year-old Caucasian man with a history of hypertension presents with complaints of tremor and impaired dexterity in his right hand and arm. Two years ago, he noticed a tremor in his right hand, which was more pronounced at rest and while walking. Though it was initially not bothersome, it has gradually progressed and he now finds it embarrassing while speaking to his colleagues at work. He describes a change in his handwriting, noting that it has gotten progressively smaller. More recently, he has developed difficulty walking and has occasional hesitation in his gait. He has also noticed tremulousness of his right foot, though to a lesser degree than in his hand. His wife reports that he sometimes acts out his dreams or “kicks” while sleeping, and she has noted this for several years prior to the onset of his tremors. Physical examination reveals a low-frequency (4-6 Hz), moderate amplitude tremor in his right hand and arm at rest, which is attenuated with movement and worsens with ambulation, or 5 seconds after holding out his arms. There is generalized slowness in purposeful movements of his hands and feet, more prominent on the right side. Tone is mildly increased in his right upper extremity (described as cogwheel rigidity) but is normal elsewhere. Facial expression is decreased, and his affect appears somewhat flat. He ambulates slowly and deliberately, with shortened stride length, stooped posture, and a decrease in arm swing on the right. He has difficulty with turns and is unable to pivot smoothly. The remainder of his physical examination is unremarkable. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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CASE FILES: NEUROLOGY

ANSWERS TO CASE 4: Parkinson Disease Summary: A 55-year-old man with hypertension presents with a 2-year history of unilateral resting tremor associated with slowness of movement and change in gait. šš šš

šš

Most likely diagnosis: Idiopathic Parkinson disease (PD). Next diagnostic step: If clinical history and examination are consistent with PD and no atypical features (see below) are present, no specific neuroimaging is required. Next step in therapy: Dopaminergic therapies may be considered, with drug selection based on patient’s age, symptom severity, side-effect profile, and preference. Mainstay dopaminergic medications include carbidopa/levodopa, dopamine agonists, monoamine oxidase type B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors.

ANALYSIS Objectives 1. Describe the cardinal features of parkinsonism. 2. Describe the difference between parkinsonism and PD. 3. Provide a differential diagnosis for parkinsonism based on clinical features and risk factors. 4. Describe the distinguishing clinical and histopathologic features of PD. 5. Recognize the unique features of the neurodegenerative “Parkinson plus” syndrome, including multiple system atrophy (MSA), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and diffuse Lewy body (DLB) disease. 6. Describe current treatment options for PD.

Considerations This 55-year-old man has a history of tremor and impaired right-hand motor precision, which is a common presentation of PD. The patient has had progressive tremor over the past 2 years. The micrographia (small handwriting) is also a common finding. He has noticed gait problems, with tremor and hesitation. The physical examination shows a low-frequency (4-6 Hz), moderate amplitude tremor in his right hand and arm at rest, which is attenuated with movement and worsens with ambulation, or 5 seconds after holding out his arms, which are also common features of PD. In its later stages, PD affects cognition leading to dementia. This patient has generalized slowness in purposeful movements of his hands and feet, more prominent on the right side. There is also mildly increased tone in his right upper extremity (described as cogwheel rigidity) but is normal elsewhere.

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PD patients also have decreased facial expression, and his affect appears somewhat flat. He ambulates slowly and deliberately, with shortened stride length, stooped posture, and a decrease in arm swing on the right, which is described as a “shuffling gait.” He has difficulty with turns and is unable to pivot smoothly. This patient presents with many of the classic findings of PD. An evaluation should be performed to assess for secondary causes of PD such as medications or cerebral conditions such as cerebrovascular accident (CVA). There is no single test to diagnose PD, but rather clinical evaluation is used to rule out other causes.

APPROACH TO: Parkinsonism Parkinsonism has classically been defined with the clinical triad of bradykinesia, rigidity, and resting tremor, regardless of the etiology of these manifestations. Postural instability is sometimes included as a fourth cardinal feature. The most common cause of parkinsonism is idiopathic PD.

DIFFERENTIAL DIAGNOSIS Causes of secondary parkinsonism, most commonly associated with drug exposure or stroke, should be considered in patients depending on their clinical history and examination. Moreover, atypical parkinsonian disorders other than PD should be considered.

Primary Parkinsonism Idiopathic Parkinson disease (PD) is among the most common neurologic disorders, affecting 1% of individuals older than 60 years. As a distinct diagnostic entity, PD is associated with loss of pigmented dopaminergic neurons in the substantia nigra as well as intracytoplasmic inclusions of alpha-synuclein aggregates called Lewy bodies. Clinically, PD consists of both motor and nonmotor symptoms. Motor symptoms of PD include bradykinesia, rigidity, resting tremor, postural instability, and gait disturbance. Nonmotor symptoms include rapid eye movement (REM) sleep behavioral disorder, hyposmia (inability to smell odors), autonomic dysfunction such as constipation, urinary frequency, and orthostatic hypotension and psychiatric disorders including depression and anxiety.

Secondary Parkinsonism Vascular parkinsonism resulting from subcortical infarcts affecting the extrapyramidal motor system should be considered in patients with cardiovascular risk factors, including history of stroke or coronary artery disease. In general, vascular parkinsonism is more commonly associated with “negative”—inhibited movement— parkinsonian features (bradykinesia, rigidity) than with tremor. Drug-induced parkinsonism is usually caused by dopamine blocking agents, including antipsychotics and antiemetics such as metoclopramide. Contamination of synthetic opioids with chemicals such as 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) was implicated in the development of parkinsonian features in intravenous drug users in the 1970s.

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Parkinson Plus Syndromes Multiple system atrophy (MSA) is a multifocal neurodegenerative condition that is often associated with parkinsonism or cerebellar features and prominent autonomic insufficiency. Two variants exist: MSA-P, the parkinsonian form, previously called striatonigral degeneration, with symmetric features that distinguish it from PD, and MSA-C, previously termed olivopontocerebellar atrophy, which presents as a predominantly cerebellar syndrome. Both may have prominent and early autonomic insufficiency, including orthostatic hypotension, constipation, urinary frequency, and impotence. Diffuse Lewy body (DLB) disease, also called Lewy body dementia, is a neurodegenerative dementia syndrome which frequently is associated with parkinsonism. In addition to cognitive dysfunction, key features include parkinsonism, clinical fluctuation, visual hallucinations, and marked sensitivity to neuroleptics. As psychiatric symptoms are common and may be the predominant manifestation of disease, psychopharmacotherapy may be required. The atypical antipsychotics quetiapine and clozapine are preferred, as they are less likely to worsen symptoms. In addition to DLBs (intracytoplasmic alpha-synuclein inclusions), there is significant loss of cholinergic neurons, similar to Alzheimer disease. Accordingly, recommended first-line pharmacotherapy is with cholinesterase inhibitors. Unfortunately, the parkinsonian symptoms in DLB are generally less responsive to l-dopa therapy, and dopaminergic medications may worsen cognitive or psychiatric symptoms. Corticobasal degeneration (CBD) is a neurodegenerative disorder associated with parkinsonism and prominent apraxia. The hallmark finding described is the alien limb phenomenon, in which a patient may feel that the limb has “a mind of its own,” controlling its own movement. Similar to PD, CBD is predominantly unilateral. Progressive supranuclear palsy (PSP) is a neurodegenerative condition, which commonly presents with parkinsonism and impaired voluntary vertical gaze (supranuclear ophthalmoplegia). Impaired downward gaze is the most specific historical finding. Interestingly, vertical oculocephalic or doll’s eye testing remains intact, as brainstem (infranuclear) pathways are unaffected. Gaze limitations lead to frequent falls, which is often the sentinel symptom.

Essential Tremor See Case 1.

CLINICAL APPROACH In 1817, James Parkinson enumerated the hallmark features of the disease “paralysis agitans” in An Essay on the Shaking Palsy. Jean-Martin Charcot later proposed that the disease be renamed to honor Parkinson’s contributions. Features of PD can be expressed in other ways, including difficulty rising from a chair, difficulty turning in bed, micrographia, masked face, stooped, shuffling gait with decreased arm swing, and sialorrhea (excess drooling). Although PD is thought of as a motor disorder, sensory systems are also affected. Loss of sense of smell occurs in 80% to 100% of patients. Patients also frequently develop constipation, which can present before or after the diagnosis of PD is made.

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Figure 4–1.  Lewy bodies on microscopy. (Reproduced, with permission, from Watts RL, Koller WC. Movement Disorders: Neurologic Principles and Practice. 2nd ed. New York, NY: McGraw-Hill; 2004:146.)

The classic pathologic feature of PD is loss of pigmented cells in the substantia nigra. The remaining neurons may show intracytoplasmic eosinophilic inclusions called Lewy bodies (Figure 4–1). PD is associated with marked striatal dopamine (DA) depletion and is considered by many to be a striatal dopamine deficiency syndrome. At death, DA loss is greater than 90%, while a loss of approximately 70% striatal DA is required to develop symptoms. Severity of DA loss best correlates with bradykinesia in PD; correlation with tremor is poor. Clinically, patients can present with both motor and nonmotor symptoms. The Movement Disorders Society has proposed clinical criteria that incorporate the cardinal motor symptoms of bradykinesia, resting tremor, and rigidity as essential criteria along with supportive criteria, such as clear and dramatic beneficial response to dopaminergic therapy; presence of levodopa-induced dyskinesias; rest tremor of a limb; and/or presence of either olfactory loss or cardiac sympathetic denervation. “Red flag” or atypical features for PD include the following: šš

Early onset of, or rapidly progressing, dementia

šš

Rapidly progressive course

šš

Supranuclear gaze palsy

šš

Upper motor neuron signs

šš

Cerebellar signs—such as dysmetria or ataxia

šš

Urinary incontinence

šš

Early symptomatic postural hypotension (within 5 years of the disease)

šš

Early falls

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CASE FILES: NEUROLOGY

Inherited forms of PD have been described but they constitute only a small percentage of PD patients. Approximately 90% of patients with PD do not have a family history and are considered to be sporadic. Familial PD, while rare, does occur and is most commonly associated with early- or young-onset PD, for which multiple genes have been implicated. Routine neuroimaging is usually unremarkable in PD. Functional imaging designed to visualize the dopamine stores in the striatum using I-123 single-photon emission tomography (DaTscan) may provide better diagnostic predictive value in the future. While a DaTscan may help differentiate patients with primary parkinsonian syndromes (idiopathic PD, Parkinson plus syndromes) from differentials such as essential tremors or normal controls, it cannot differentiate reliably within the primary parkinsonian syndrome subtypes.

TREATMENT OPTIONS Treatment is initiated when the patient’s quality of life is negatively affected and usually consists of carbidopa/levodopa, a dopamine agonist and/or an MAO-B inhibitor. There is currently no FDA-approved treatment for disease modification; therefore, symptomatic treatment is the mainstay of therapy. This includes pharmacologic and surgical interventions. Physical measures such as physical therapy, speech therapy, and exercise are important, and they have a major impact on the lives of patients with PD.

Pharmacologic Therapy šš

šš

šš

šš

Dopaminergic agents are the mainstay of treatment for the cardinal features of PD. Levodopa crosses the blood–brain barrier, while dopamine does not; levodopa is converted to dopamine in the brain. Peripheral breakdown in the gut is inhibited by the addition of aromatic amino acid decarboxylase inhibitors (carbidopa). Thus, a carbidopa/levodopa formulation is generally preferred. Levodopa can also be broken down peripherally by the enzyme COMT so that COMT inhibitors such as entacapone and tolcapone are used. Treatment paradigms generally favor l-dopa–sparing therapies for initial treatment, unless symptoms are severe at the time of diagnosis. Dopamine agonists cross the blood–brain barrier and act directly at predominantly D2-type receptors without requiring conversion. These agents include pramipexole, ropinirole, and rotigotine. Compared to other therapies, dopamine agonists are more likely to cause problems with impulsivity, including gambling, shopping, or hypersexual tendencies. MAO-B inhibitors such as selegiline and rasagiline can improve symptoms in both patients with mild disease (as monotherapy) and patients already on levodopa therapy. Many clinicians prefer monotherapy with MAO-B inhibitors for early, mild PD. MAO inhibitors have previously been implicated with development of serotonin syndrome and should be used cautiously when combined with selective serotonin reuptake inhibitors (SSRIs).

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šš

45

Amantadine is felt to act primarily by blocking glutamate N-methyld-aspartate (NMDA) receptors and has a mild attenuation of the cardinal symptoms of resting tremor and dystonia. Amantadine has also been shown to help alleviate levodopa-induced dyskinesias.

Although no treatment definitively slows the progression of PD, mortality has been reduced and quality of life has been improved by levodopa therapy. Over time, the response to levodopa becomes unstable, resulting in “on-off ” fluctuations. Also, patients can develop troublesome abnormal involuntary choreiform and dystonic movements called dyskinesias. Younger patients are more at risk for dyskinesia and are likely to be treated for long periods of time. Surgical treatment with the placement of deep brain stimulators (DBSs) may be considered in patients with significant motor fluctuations and dyskinesias despite medication adjustment. DBS involves placement of stimulating electrodes into the subthalamic nucleus (STN) or globus pallidus interna (GPi) bilaterally. Comorbid or prior history of dementia is an exclusion criterion for DBS placement, as worsening of cognitive function after DBS implantation has been reported.

COMPREHENSION QUESTIONS 4.1 A 55-year-old woman presents with a 5-year history of gradual loss of function. The patient’s daughter has been researching on the Internet and suspects PD. Which of the following signs is most suggestive of PD rather than the other neurodegenerative diseases? A. Unilateral resting tremor B. Supranuclear downward gaze palsy C. Orthostatic hypotension early in the course of the disease D. Early falls E. Abnormal cerebral magnetic resonance imaging (MRI) 4.2 A 61-year-old man is diagnosed with mild PD. In discussion about therapy, you review the medication rationale and also the side effects associated with the medications. Which of the following medications is most likely to be able to help relieve his mild symptoms of PD without increasing risk of dyskinesias? A. Levodopa B. Dopamine agonists C. Amantadine D. Anticholinergics E. Haloperidol

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CASE FILES: NEUROLOGY

4.3 A 35-year-old man is being evaluated for resting tremor, rigidity, and difficulty with balance. In reviewing the medications, you suspect drug-induced parkinsonism. Which of the following medications would be most likely to be responsible? A. Trihexyphenidyl B. Metoclopramide C. Diazepam D. Carbidopa E. Levodopa

ANSWERS 4.1 A. Resting tremor is an early manifestation of PD. The other answer choices are more atypical of PD and may indicate other neurologic disorders. 4.2 C. Amantadine can decrease the incidence of levodopa-induced dyskinesia. It acts by blocking glutamate NMDA receptors and has a mild attenuation of the cardinal symptoms of resting tremor and dystonia. 4.3 B. Antiemetic agents such as prochlorperazine (Compazine) and metoclopramide can cause a drug-induced parkinsonism. The three classes of drugs most likely to cause drug-induced PD are dopamine receptor blocking agents (prochlorperazine and metoclopramide), dopamine depleting agents (reserpine, tetrabenazine), and atypical antipsychotic agents. Although there are some subtle differences between drug-induced PD and PD, it is often difficult to differentiate between the two.

CLINICAL PEARLS »»

The cardinal features of parkinsonism are resting tremor, rigidity, bradykinesia, and postural instability.

»»

Patients with idiopathic PD should have a unilateral onset of motor symptoms such as tremor, rigidity, and bradykinesia.

»»

Postural instability leading to falls occurs relatively late in the clinical course of PD.

»»

Failure to respond clinically to large doses of levodopa may suggest a diagnosis other than idiopathic PD.

»»

The mainstay of therapy for PD is carbidopa/levodopa that, after long-term use, can lead to motor fluctuations and dyskinesias.

»»

MAO-B inhibitors or dopamine agonists can be considered as first-line monotherapy in patients younger than 75 years with early or mild PD.

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SECTION II: CASE 4

REFERENCES Hess C, Okun M. Diagnosing Parkinson disease. Continuum (Minneap Minn). 2016;22(4):1047-1063. Horstink M, Tolosa E, Bonuccelli U, et al. European Federation of Neurological Societies; Movement Disorder Society—European Section. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society—European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol. 2006;13:1170-1185. Kägi G, Bhatia KP, Tolosa E. The role of DAT-SPECT in movement disorders. J Neurol Neurosurg Psychiatry. 2010;81:5-12. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525-535. Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet. 2011;12:301-325. Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268-1278. Pahwa R, Factor SA, Lyons KE, et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: treatment of PD with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66:983-995. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591-1601. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol. 2006;5:75-86.

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CASE 5 A 57-year-old man of Portuguese descent noticed that he had difficulty marching in line as a soldier. From age 20 until the age of 40 he had a slow progression of symptoms. Since then, he has experienced a rapidly progressive gait disturbance, diplopia, dyssynergia, and paraesthesias in the limbs. At age 45, he was confined to a wheelchair. On examination, he is intellectually normal but has severe dysarthria and constant drooling. He has bulging eyes, slow saccades, and impaired voluntary up- and downgaze but no nystagmus. He has fasciculations and dyscoordination of the tongue but no facial fasciculations. A general moderate muscle weakness and atrophy are revealed, but muscle tone is normal. Deep tendon reflexes are absent and Babinski signs are present bilaterally. Vibration and proprioception are impaired. Severe ataxia, dysmetria, and dysdiadochokinesia are present. A constant static tremor is seen in the hands. His mother and maternal grandfather as well as his sister and her son also had problems with gait, which were progressive and began during adulthood. Magnetic resonance imaging (MRI) of the brain reveals cerebellar atrophy. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 5: Ataxia, Spinocerebellar Summary: This is a case of a previously healthy man who had the insidious onset and gradual progression of a syndrome heralded by gait difficulties, which was later characterized as ataxia. šš

Most likely diagnosis: Autosomal dominant cerebellar degeneration with additional neurologic features with normal cognition—most likely spinocerebellar ataxia type 3 (SCA-3).

šš

Next diagnostic step: DNA testing for dominant ataxias.

šš

Next step in therapy: Supportive care, genetic counseling, and rehabilitation.

ANALYSIS Objectives 1. Describe the movement disorder of ataxia. 2. List the differential diagnosis of ataxia, including genetic and nongenetic etiologies.

Considerations This patient was an otherwise healthy man who had an insidious onset and gradual progression of a syndrome that started with gait difficulties later characterized as ataxia. It progressed to cause dysarthria, abnormal saccades, lower motor neuron findings, a sensory large-fiber neuropathy, and upper motor neuron findings. This clinical picture suggests that multiple systems are involved with the most prominent features being ataxia and poor coordination of voluntary movements. These can be caused by problems with motor control because of pathology of the cerebellum and cerebellar connections, and impaired proprioception occurs because of involvement in these sensory pathways. Chronic ataxias can present in isolation or in conjunction with other neurologic abnormalities or involvement of other body systems. This patient has other neurologic abnormalities but no evidence of other systemic involvement. In addition, there is a strong suggestion for this being an inherited condition; specifically, there are four successive generations affected in his family, with both sexes affected. This inheritance pattern suggests an autosomal dominant disorder. This is reinforced in that autosomal recessive ataxias tend to have other body systems involved, whereas adult-onset autosomal dominant disease do not. The differential diagnosis of chronic ataxias includes disorders that affect the cerebellum intrinsically and extrinsically. Intrinsic disorders include infarcts, hemorrhage, toxins such as ethanol and phenytoin, trauma, primary cerebellar neoplasms, metastatic, autoimmune/demyelinating disorders, and remote effects of radiation. Extrinsic factors include paraneoplastic cerebellar degenerations

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(PCDs) associated with specific tumor-type antineuronal antibodies. This is a relatively frequent cause of late-onset ataxia and is characterized by a subacute progressive course and requires prompt diagnosis and treatment of the underlying neoplasm. A link between gluten sensitivity and some sporadic ataxias has been suggested due to the high prevalence of presence of antigliadin antibodies, but this remains controversial. Other causes of chronic ataxias are vestibular disorders and sensory neuropathies due to involvement of the peripheral nerves or spinocerebellar tracts as seen with acquired or inherited axonal or demyelinating disorders (ataxia telangiectasia, Friedreich ataxia) and vitamin deficiency (B12). In addition to hormonal and nutritional causes, abnormalities such as hypothyroidism and vitamin E deficiencies can cause ataxia.

APPROACH TO: Autosomal Dominant Cerebellar Ataxia DEFINITIONS ATAXIA: An unsteady and clumsy motion of the limbs or torso caused by a failure of the gross coordination of muscle movements. TRINUCLEOTIDE REPEAT EXPANSION DISEASE: Caused by stretches of DNA in a gene that contains the same trinucleotide sequence repeated many times. These repeats are a subset of unstable microsatellite repeats that occur throughout all genomic sequences. If the repeat is present in a gene, an expansion of the repeat results in a defective gene product and often leads to disease.

CLINICAL APPROACH Autosomal dominant cerebellar ataxias (ADCAs) are characterized in terms of their genetic locus and are referred to as spinocerebellar ataxias (SCAs). At this point, there are 43 such disorders, and the number continues to increase. The most common types are listed in Table 5–1. Many of these can be definitively diagnosed by DNA genetic testing. Clinical phenotype and ethnic origin/geographic location can be helpful in prioritizing the order of genetic testing. There are several gene mutations on different chromosomes that cause SCA, and the gene frequency within different populations varies considerably. In general, the incidence is thought to be approximately 1 to 5 per 100,000 people, with equal gender distribution. Most of the ADCAs are caused by a genetic defect that involves an expansion in the DNA sequence, and most of these are trinucleotide repeat expansions (SCA types 1-3, 6-10, 12, and 17). Other types of repeat expansions that cause SCA have been discovered. For example, SCA-10 involves an ATTCT repeat expansion of the SCA10 gene, and SCA-8 involves an expansion in the SCA8 gene with the nucleotides CTG repeated. Finally, SCA-4 involves a mutation in a gene that does not involve a trinucleotide repeat expansion. The average age of onset for all of these types is from 20 to 30 years except for SCA-6, which usually occurs between the ages of 40 and 50. People with SCA-8

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Table 5–1  •  SELECT LIST OF AUTOSOMAL DOMINANT SPINOCEREBELLAR ATAXIAS Incidence Locus Disease (%) Protein

Mutation

Clinical Features

Oculomotor Abnormalities

SCA-1

6

6p23 Ataxin-1

CAG repeats (38-83)

Ataxia, dysarthria, pyramidal signs, peripheral neuropathy, hyperreflexia, cognitive impairment

Nystagmus, hypermetric saccades, slow saccades, ophthalmoparesis

SCA-2

14

12q24 Ataxin-2

CAG repeats (35-64)

Ataxia, dysarthria, peripheral neuropathy, hyporeflexia, dementia, myoclonus

Slow saccades, ophthalmoplegia

SCA-3

21

14q32 Ataxin-3

CAG repeats (61-84)

Ataxia, dysarthria, spasticity, parkinsonism, amyotrophy

Lid retraction, nystagmus, saccade dysmetria, ophthalmoparesis, square-wave jerks

SCA-6

15

19p13 CACNA1A

CAG repeats (20-33)

Ataxia, dysarthria, sometimes episodic ataxia, very slow progression, lack of family history

Nystagmus (60% downbeating), saccadic pursuit

SCA-7

5

3p14 Ataxin-7

CAG repeats (37- >300)

Ataxia, dysarthria, retinopathy, peripheral neuropathy, pyramidal signs, infantile phenotypes

Saccadic smooth pursuit, slow saccades

SCA-8

2-5

13q21

CTG (3’UTR) (100-250)

Ataxia, dysarthria, mild sensory neuropathy

Nystagmus, saccadic pursuit

Data from C Mariotti, R Fancellu, S Di Donato. An overview of the patient with ataxia. J Neurol. 2005;252:511-518.

usually develop symptoms in their late 30s. SCA-2 patients usually develop dementia and slow eye movements. Generally, both SCA-8 patients, who have normal life spans, and SCA-1 patients have very active reflexes. SCA-7 patients develop visual loss. In SCA types 1 to 3 and 7, there can be an earlier age of onset with increased severity (called anticipation) from one generation to the next. The size of the repeat expansion zone in the affected genes roughly correlates with the severity and age of onset. Penetrance is quite high; however, there are rare cases in which people do not develop symptoms. The reason for the lack of complete penetrance is currently unknown. The diagnosis of SCA is initially suspected by the adult onset of symptoms. An MRI or computed tomography (CT) of the brain can detect atrophy (wasting) of the cerebellum and a variety of other subcortical structures (Figure 5–1). Genetic testing should be guided by clinical signs such as retinal degeneration, prominent involvement of noncerebellar symptoms, age of onset, eye-movement disorders, reduced stochastic (random pattern) velocity, and pyramidal signs as well as

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Figure 5–1.  Sagittal MRI of the brain in spinocerebellar ataxia. (Reproduced, with permission, from Kasper DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2004: 2421.)

the patient’s ethnic origin/geographic location. The clinical features of the most common inherited ADCA disorders are listed in the accompanying table (see Table 5–1). Once the genetic defect is characterized, family members can also be tested. These results must be interpreted cautiously, as there are intermediate ranges of repeats that show reduced penetrance, and age of onset and severity cannot be precisely predicted even in larger repeats. There are also cases of SCA diagnosed clinically that cannot be explained by any of the known genetic defects. It is estimated that in approximately 50% to 60% of Caucasian patients with a dominant familial form of cerebellar ataxia, DNA testing can provide a definitive diagnosis. SCA-3 or Machado-Joseph disease (MJD) is the most common SCA subtype in most populations. The phenotype is one of the most variable among SCAs. The presenting syndromes for SCA-3 include pure cerebellar ataxia, familial parkinsonism, hereditary spastic paraplegia, hereditary neuropathy, and restless legs syndrome (RLS). A rarely recognized but common and rather specific sign of SCA-3 is impaired temperature discrimination in all limbs and even the trunk and face. Pseudoexophthalmos (bulging eyes caused by lid retraction), faciolingual myokymia, and dystonia have been thought to be characteristic, but not specific, signs of SCA-3. SCA-3 MJD is an autosomal dominant inherited disorder with variable expression first described by Nakano and coworkers (1972) in an American family of Portuguese-Azorean descent. Since then more families with MJD have been reported worldwide. Three different clinical subtypes are described. Type I is

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characterized by an early age of onset (20-30 years), pyramidal and extrapyramidal signs, progressive external ophthalmoplegia (PEO), and minor cerebellar deficits. Type II involves an intermediate age of onset. Type III occurs after age 40 and includes ophthalmoparesis and anterior horn disease. At neuropathologic examination, degeneration of the cerebellum and the thoracic cord is always present in SCA-3, but degeneration of the striatum, substantia nigra, basis pons, oculomotor nuclei, and peripheral nerves is variable.

TREATMENT There is currently no cure for ADCA and no treatment to slow the progression of the disease. Supportive treatment is important. Drugs that help control tremors are not effective for treating cerebellar tremors but they can be effective for parkinsonism, dystonia, RLS, and a variety of other neurologic symptoms. Physical therapy likely does not slow the progression of loss of coordination or muscle wasting, but affected patients should be encouraged to be active. Occupational therapy can be helpful in developing ways to accommodate the patient in performing daily activities. Walkers and other devices can assist the patient to have mobility. Other modifications such as ramps for a wheelchair, heavy eating utensils, and raised toilet seats can make patients more independent. Speech therapy and computerbased communication aids often help as the person loses his or her ability to speak. Persons with SCA usually die one to two decades after symptoms develop. The prognosis for SCA-11 and SCA-6 is typically less severe, with a very slow worsening of symptoms, and persons with SCA-8 and SCA-11 have a normal life span.

COMPREHENSION QUESTIONS 5.1 A patient with SCA-3, in addition to having ataxia, has bradykinesia with rigidity and tremor at rest. Which of the following drugs is most likely to be helpful for the latter symptoms? A. Carbidopa/levodopa B. Haloperidol C. Diazepam D. Phenytoin 5.2 What radiologic feature is most characteristic of SCAs? A. Cerebellar atrophy B. High T2 signal in the cerebellar cortex C. High signal lateral to the striatum D. A high signal “hot cross bun” sign in the brainstem

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5.3 Which of the following cases would be most suspicious for an ADCA? A. Involvement of four of four siblings (two boys, two girls ages 4-12) and father in the same household affected with onset within 1 week of each other, but no other first- or second-degree relatives in a large kindred. B. Male proband; affected proband’s father and one of two sisters and a paternal grandfather and uncle; unaffected, none of two brothers. C. Male proband; neither parent affected; one of two brothers and one of two sisters in addition to a paternal great grandfather affected. D. Male proband; parents, two brothers and two sisters unaffected; paternal grandfather and uncle affected.

ANSWERS 5.1 A. The tremor of SCA is often responsive to levodopa. 5.2 A. The cerebellum is most often affected. Optic nerve atrophy and spinal lesions may also be present in some SCAs. Answer B (high T2 signal in the cerebellar cortex) is characteristic of neoplastic cerebellar degeneration. Answer choices C (high signal lateral to the striatum) and D (high-signal “hot cross bun” sign in the brainstem) are seen with multisystem atrophy. 5.3 B. This option is typical for the autosomal dominant inheritance pattern; answer choices C and D might be seen in a disease with poor penetrance. Answer choice A is suggestive of a toxic or infectious exposure.

CLINICAL PEARLS »»

Hereditary SCAs commonly present in adulthood clinically with cerebellar ataxia. Other neurologic signs may be present but rarely with nonneurologic system involvement.

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The presence of an autosomal dominant inheritance pattern is common, and the phenomenon of anticipation is common in trinucleotide repeat diseases (each subsequent generation from the proband presents earlier and with more severe disease manifestations).

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DNA testing can be diagnostic, but clinical correlation is helpful in focused ordering of tests.

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Pharmacologic therapy does not alter the natural course of cerebellar ataxia but can help to relieve neurologic symptoms.

REFERENCES Bataller L, Dalmau J. Paraneoplastic neurologic syndromes: approaches to diagnosis and treatment. Semin Neurol. 2003;23(2):215-224. Bird TD. Hereditary ataxia overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington; 1993-2016. http://www.ncbi.nlm.nih.gov/ books/NBK1138/. Last accessed Nov 1, 2016.

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Duen AM, Goold R, Giunti P. Molecular pathogenesis of spinocerebellar ataxias. Brain. 2006;129: 1357-1370. Hadjivassiliou M, Grunewald R, Sharrack B, et al. Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain. 2003;126:685-691. Harding AE. Hereditary spastic paraplegias. Semin Neurol. 1993;13:333-336. Hekman KE, Gomez CM. The autosomal dominant spinocerebellar ataxias: emerging mechanistic themes suggest pervasive Purkinje cell vulnerability. J Neurol Neurosurg Psychiatry. 2015;86:554-561. Løkkegaard T, Nielsen JE, Hasholt L, et al. Machado-Joseph disease in three Scandinavian families. J Neurol Sci. 1998;156:152-157. Mariotti C, Fancellu R, Di Donato S. An overview of the patient with ataxia. J Neurol. 2005;252: 511-518. Schelhaasa HJ, Ippel PF, Beemerb FA, et al. Similarities and differences in the phenotype, genotype and pathogenesis of different spinocerebellar ataxias. Eur J Neurol. 2000;7:309-314. Schöls L, Bauer P, Schmidt T, et al. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3:291-304. Ruuskanen A, Kaukinen K, Collin P, et al. Gliadin antibodies in older population and neurological and psychiatric disorders. Acta Neurol Scand. 2013;127:19-25. Tan EK, Ashizawa T. Genetic testing in spinocerebellar ataxias: defining a clinical role. Arch Neurol. 2001;58(2):191-195.

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CASE 6 A 65-year-old woman was referred to the neurologist for a recent onset of abnormal, involuntary movements of the mouth and face. She has been in good health until 3 years ago, when she developed problems with nausea and constipation. She was placed on metoclopramide and omeprazole with some relief of symptoms. A complete gastrointestinal (GI) workup was negative, although it was hypothesized that she had decreased gastric motility. The patient was also started on methimazole for hyperthyroidism. The abnormal movements began approximately 6 months ago, and they have been getting progressively worse. The movements do not interfere with speech but do interfere with eating. She also occasionally has arching spasms of the back and neck. Her examination is remarkable for stereotypical repetitive movements of the tongue and jaw and sustained neck extension. »» »»

What is the most likely diagnosis? What is the next step in therapy?

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ANSWERS TO CASE 6: Tardive Dyskinesia Summary: A 65-year-old woman was referred to a neurologist for recent-onset abnormal involuntary movements of the mouth and face. She was placed on metoclopramide and developed these movements nearly 1 year later. The movements are getting progressively worse. They do not interfere with speech but do interfere with eating. She also occasionally has arching spasms of the back and neck. Her examination is remarkable for stereotypical repetitive movements of the tongue and jaw and intermittent neck and back extension. šš šš

Most likely diagnosis: Tardive dyskinesia (TD). Next step in therapy: Discontinuation of metoclopramide. Consider treatment with benzodiazepines, baclofen, or tetrabenazine if the movements persist.

ANALYSIS Objectives 1. Recognize the differential diagnosis of involuntary oral movements. 2. Describe the potential motor complications of dopamine receptor antagonist use. 3. Distinguish the treatment options available for the treatment of TD.

Considerations This is an older woman who has developed abnormal involuntary movements involving primarily the oral–buccal–lingual muscles. Her symptoms started rather insidiously and progressed gradually. Her examination is remarkable for stereotypical hyperkinetic movements, which include tongue protrusion and lip smacking. She has been treated with a medication to help her with GI symptoms, but it is also a very potent blocker of dopamine receptors. Differential diagnosis could include TD, Huntington disease (HD), Wilson disease, neuroacanthocytosis, Sydenham chorea, antiphospholipid antibody syndrome, and anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis. TD is mostly likely in light of her medication history. TD is a disorder that develops relatively late after the initiation of medications that block dopamine receptors, such as the metoclopramide. The proton pump inhibitor omeprazole is associated with GI side effects or headaches; methimazole can cause bone marrow suppression or rarely arthralgias. Various movement disorders can be caused by these medications (Table 6–1).

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Table 6–1  •  CLASSIFICATION OF DYSKINETIC DISORDERS I. Acute Acute dystonia Acute akathisia Drug-induced parkinsonism II. Chronic Common:   Tardive dyskinesia   Tardive dystonia   Tardive akathisia   Perioral tremor (rabbit syndrome) Uncommon:   Tardive myoclonus   Tardive tics   Tardive tremor

APPROACH TO: Tardive Dyskinesia TD is caused by long-term treatment with dopamine-blocking agents, such as antipsychotics (neuroleptics) or certain antiemetics (eg, metoclopramide). The actual mechanism for TD is unknown. It is thought that prolonged dopamine receptor blockade by dopamine antagonists leads to upregulation of striatal dopamine receptors. In addition, it is possible that structural changes in the neurons or receptors may have taken place. These could lead to increased sensitivity of the dopaminergic neurons to dopamine, resulting in a hyperkinetic state, dyskinesia (compare this to Parkinson disease [PD] where the loss of dopaminergic neurons results in a hypokinetic state manifesting as hypokinetic movements). The diagnosis of TD is based on the presence of involuntary dyskinetic movements, a history of at least 1 month of dopamine receptor antagonist treatment, and the exclusion of other causes of dyskinesias. TD or tardive syndrome (TS) is characterized by repetitive, involuntary, purposeless movements. Features of the disorder may include grimacing, tongue protrusion, lip smacking, puckering and pursing, and rapid eye blinking. Rapid movements of the arms, legs, and trunk may also occur. Involuntary movements of the fingers may also be present. Though these abnormal movements are often more distressing to the family than patients, they can be quite debilitating and result in significant damage to dentition and interference with oral intake of nutrition. Differentiating TD from idiopathic dystonia syndromes is sometimes difficult. Dystonia can occur as a focal manifestation around the mouth, as well as in a socalled segmental form involving the muscles of the face and neck. However, arching spasms of the back and neck are characteristic of the tardive condition. TD is sometimes associated with more appendicular involuntary movements. As such, it can be confused with HD. However, the chorea of HD drifts in a random fashion around the musculature, whereas TD tends to be more stereotypic.

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Because patients with HD can have chorea and behavioral problems that are treated with neuroleptics, the two conditions can coexist. Withdrawal of the offending medication can ultimately result in cessation of the involuntary movements, with an average reversibility of about 50%; however, the data supporting this estimate is not very strong. It has been estimated that up to 50% of patients who are treated with dopamine receptor antagonists develop TD eventually. The strongest risk factors for TD include advanced age, female gender, and coexistent brain damage. Treatment with typical antipsychotic agents can be associated with permanent TD in these individuals. The incidence of TD appears to have decreased with the use of atypical antipsychotics that do not cause such complete dopamine receptor blockade. Metoclopramide is used in the treatment of nausea and gastroparesis. There are other agents for nausea that have much less risk for the development of TD, though the currently approved agents for gastroparesis are limited in the United States. Domperidone is an excellent alternative for metoclopramide but must be obtained from outside the United States. It is a potent dopamine receptor blocking agent but does not cross the blood–brain barrier.

Treatment The best treatment is prevention, and care should be instituted to avoid using dopamine receptor-blocking agents unless absolutely necessary. Treatment options include benzodiazepines, baclofen, and vitamin E, which are usually only effective in mild cases. Treatment with increased doses of dopamine receptor blocking agents may improve TD temporarily, but most clinicians believe that this results in worsening of the condition. Medications that deplete dopamine do not seem to cause this disorder but can be very beneficial in its treatment. Alpha methyl-p-tyrosine inhibits catecholamine formation by blocking the enzyme tyrosine hydroxylase, and reserpine irreversibly blocks the vesicular monoamine transporter (VMAT). Although useful, these agents have high incidences of side effects including orthostatic hypotension, depression, and parkinsonism. Tetrabenazine is another medication that selectively depletes monoamines at the nerve terminals and appears to be more effective with fewer side effects. Botulinum toxin injections into the relevant muscles may also be useful.

COMPREHENSION QUESTIONS 6.1 A 65-year-old woman is on multiple medications. Her son who is studying pharmacology is concerned about a movement disorder as a side effect of the medications. Which of the following drugs has the highest risk of causing TD? A. Haloperidol B. Trihexyphenidyl C. Levodopa D. Diazepam

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6.2 The patient in Question 6.1 is examined and found to have mainly involuntary movements of the mouth. Which one of the following agents results in decreased severity of oral dyskinesias caused by TD? A. Fluphenazine B. Trihexyphenidyl C. Levodopa D. Dexedrine 6.3 A 25-year-old man who began treatment for schizophrenia 1 week ago presents to the emergency room (ER) for forceful sustained twisting movements of the neck. Which of the following medications is the best treatment? A. Diphenhydramine B. Corticosteroids C. Haloperidol D. Metoclopramide

ANSWERS 6.1 A. Haloperidol is a dopamine receptor blocker. Although levodopa can be associated with dyskinesia in patients with PD, this does not occur in association with other disorders. 6.2 A. Further and more complete dopamine receptor blockade will often decrease the manifestations of TD but is felt by many to represent increased risk for long-term continuation. 6.3 A. An anticholinergic medication such as diphenhydramine given intravenously (IV) usually will arrest the dystonic reaction. The acute onset of sustained involuntary twisting (cervical dystonia) soon after the initiation of antipsychotic medications is typical of an acute dystonic reaction.

CLINICAL PEARLS »»

The cause of tardive dyskinesia (TD) is chronic use of dopamine-blocking agents, such as typical antipsychotic agents.

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TD may develop months after beginning dopamine receptor-blocking agents and most frequently causes stereotypical movements of the mouth and surrounding regions.

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Successful treatment or elimination of tardive dyskinesia is challenging; therefore, the best course is to avoid initiating offending agents.

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Backward arching movements of the neck (sustained neck extension), termed retrocollis, is strongly suggestive of an acute dystonic reaction.

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REFERENCES Bhidayasiri R, Boonyawairoj S. Spectrum of tardive syndromes: clinical recognition and management. Postgrad Med J. 2011;87:132-141. Chou KL, Friedman JH. Tardive syndromes in the elderly. Clin Geriatr Med. 2006;22:915-933. Fernandez HH, Friedman JH. Classification and treatment of tardive syndromes. Neurologist. 2003;9:16-27. Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Rev Neurother. 2006;6:7-17. NINDS Tardive Dyskinesia Information Page. http://www.ninds.nih.gov/disorders/tardive/tardive .htm. Last accessed Nov 30, 2016. Soares-Weiser K, Rathbone J. Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive dyskinesia. Cochrane Database Syst Rev. 200625;(1):CD000459. Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia: is risk declining with modern anti-psychotics? Mov Disord. 2006;21(5):589-598.

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CASE 7 A 13-year-old right-handed adolescent boy is brought to the emergency room (ER) following a moderate speed motor vehicle accident (MVA). The patient was an unrestrained front-seat passenger but was not ejected during the head-on collision (~ 35-40 mph). According to the paramedics accompanying the patient, there was significant front-end damage to the car, and the patient’s head appeared to have impacted the windshield. On arrival at the scene, approximately 4 minutes after the accident, the patient was found to be unresponsive with flaccid muscle tone, bradycardia, and inadequate respiratory effort. His cervical spine was immobilized, he was intubated to maintain adequate ventilation, and he was transported to the ER secured to a rigid backboard. On examination, he is afebrile with irregular respiratory effort, requiring mechanical ventilator support. Noxious stimulation of his face produces some grimacing, but there is no response to such stimulation of the extremities. There is a large contusion over his forehead but no other external signs of trauma. On neurologic examination, his pupils are equally reactive to light, and he has a brisk corneal reflex bilaterally, but there is no gag reflex. His muscle tone is significantly decreased in all four extremities, and he is areflexic throughout, including his superficial abdominal reflexes. His rectal sphincter is patulous, and there is no anal wink. According to the patient’s father, the child was healthy and neurodevelopmentally normal prior to this accident. He is on no medications and has no known allergies. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 7: Spinal Cord Injury, Traumatic Summary: This 13-year-old adolescent boy presents to the ER significantly obtunded with flaccid quadriparesis and agonal respirations following a head-on MVA in which he was an unrestrained passenger. He is now intubated, and his cervical spine is immobilized. He was previously healthy and is on no medications. šš

šš

šš

Most likely diagnosis: High cervical spine injury and traumatic brain injury (TBI). Next diagnostic step: Magnetic resonance imaging (MRI) of the brain and spine. Next step in therapy: Maintain oxygenation and perfusion pressure in a critical care setting.

ANALYSIS Objectives 1. Understand the initial management of acute spinal cord injury. 2. Know the different types of spinal cord syndromes. 3. Describe the usefulness of different imaging modalities for evaluating spinal cord injury and the importance of the patient’s age. 4. Be aware of the role of steroids, surgical intervention, and rehabilitation in spinal cord injury.

Considerations This 13-year-old adolescent boy brought to the ER following a significant MVA has findings worrisome for traumatic injury to both his brain and spinal cord. This case focuses on considerations for evaluating and managing the latter. Significant findings on the patient’s examination include flaccid quadriparesis (suggesting interruption of the corticospinal tracts in the upper cervical region), failure to grimace or otherwise respond to painful stimulation of any of his four extremities (suggesting interruption of ascending sensory tracts in the upper cervical region), preservation of pupillary light reflex and corneal reflex (indicating that the brainstem is intact above the pontomedullary junction), and poor respiratory function and absence of gag (indicative of injury to the upper cervical cord as well as the lower brainstem). These findings point to a complete or nearly complete acute spinal cord injury at a high cervical level, with ascending spinal shock also affecting the lower brainstem.

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APPROACH TO: Traumatic Spinal Cord Injury EPIDEMIOLOGY There are approximately 40 new cases per million per year of traumatic spinal cord injury in the United States. The peak age-related incidence occurs between 15 and 25 years and is more common in males than females, with a ratio of 3 to 4:1. Approximately 5% of all spinal cord injuries occur between birth and 16 years, and these pediatric patients require special consideration discussed as follows. Neonatal (birthrelated) spinal cord injury complicates approximately 1 of every 60,000 births and carries a 50% mortality rate. In childhood, the most common causes of spinal cord injury prior to 10 years of age are MVAs and falls, whereas in individuals older than 10 years, MVAs and sports-related injuries are the most common. With regard to MVAs, children younger than 13 years should be restrained passengers in the backseat only to avoid potential injury from air bag deployment. Younger children can sustain significant and often fatal cervical spinal cord injuries from passenger side air bags. The rate of nontraumatic spinal cord injury is at least threefold higher than traumatic cases, although the epidemiologic data are not as complete in this regard.

TYPES OF SPINAL CORD INJURIES Spinal cord injuries can be complete or incomplete. Complete spinal cord injuries present with complete loss of sensation and motor strength below the level of injury. Patients can also present with incomplete lesions of the spinal cord. For example, hemisection produces the classic Brown-Séquard syndrome with ipsilateral loss of motor function, fine touch, and vibration sensations starting at the level of the injury, but contralateral loss of pain and temperature one or two levels below the level of the lesion. This is a result of fibers in the dorsal column remaining ipsilateral to the brainstem while fibers in the spinothalamic tract synapse and cross within one or two spinal levels then travel contralaterally. Trauma is the most common cause of the Brown-Séquard syndrome, which rarely presents as a pure unilateral injury. Anterior cord syndrome is usually caused by either a traumatic or a vascular insult to the anterior two-thirds of the spinal cord. This results in a bilateral loss of spinothalamic tract function (loss of pain and temperature sensations) as well as bilateral loss of corticospinal tracts function (weakness) with preservation of dorsal column function, such as fine touch, proprioception, and vibration. Central cord syndrome is caused by injury to the structures around the spinal central canal. Although this can occur acutely with trauma (particularly flexionextension injury in athletes and patients with cervical spondylosis), it more commonly occurs with chronic processes such as intra-axial neoplasms or dilation of the central canal (referred to as syringomyelia). Clinically, this typically presents with a bilateral loss of pain and temperature sensation in the upper extremities (spinothalamic tract function) as well as weakness in the same distribution (corticospinal tract function) but with preservation of fine touch (dorsal column). Anatomically, this is because the spinothalamic tract decussates immediately

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anterior to the central canal. Also, motor fibers traveling to the legs (fasciculus gracilis) tend to run more laterally in the spinal cord than fibers supplying the arms (fasciculus cuneatus) and are therefore relatively spared.

INITIAL MANAGEMENT OF SPINAL CORD INJURIES Management of acute spinal cord injury follows the basic principle of ABCD: airway, breathing, circulation, and disability. Once the airway is secured and the patient is hemodynamically stable, the management is focused on preventing additional damage and disability. This begins in the field, with the first responders immobilizing the spine in a neutral position using rigid collars and backboards. Further injury can occur because of impingement of bony matter onto the cord, excessive movement of the cord as a result of spinal instability, compression of the cord by hemorrhage, or cord ischemia caused by hypotension. Given the disproportionately large head size in children relative to the trunk, it is often necessary to elevate the torso to achieve a neutral position for the neck. In the ER, once stabilization of airway, breathing, and circulation has been confirmed, a neurologic examination is performed to assess the clinical level of injury. In this patient, there are several findings pointing to an extensive and likely complete high cervical spinal cord injury. The complete loss of motor and sensory function of the upper and lower extremities, respiratory difficulties, and preservation of cranial nerve reflexes are consistent with this localization (because the upper extremity is innervated by spinal nerves from C5 to T1 and the phrenic nerve arises from C3 to C5). Superficial abdominal reflexes are elicited by scratching the skin in all four quadrants around the umbilicus and watching for contraction of the underlying abdominal musculature. Stimulating above the umbilicus tests spinal levels T8 to T10, whereas stimulating below the umbilicus tests approximately T10 to T12. In addition to loss of motor and sensory function below the level of the lesion, spinal cord transection also results in loss of autonomic function, which can produce spinal shock. The acute loss of descending sympathetic tone produces decreased systemic vascular resistance, which can result in hypotension. If vagal output is intact, its unopposed influence can further lower vascular resistance and result in a paradoxical bradycardia. In the context of spinal shock, aggressive fluid resuscitation is necessary to maintain perfusion pressure and prevent cord ischemia. The complete absence of deep tendon reflexes, superficial cutaneous reflexes, and rectal tone also suggests the presence of spinal shock. It is important to remember that, as the inflammatory response to the injury develops and edema occurs, the apparent clinical level of the injury can rise to higher spinal levels or into the brainstem. Once the patient has been stabilized and an expedited neurologic examination has been performed, the appropriate imaging modality must be selected. In blunt trauma of patients older than 9 years, no spine imaging is necessary if they are alert, conversant, nonintoxicated, and have a normal neurologic examination without cervical tenderness. If patients are younger than 9 years, imaging is recommended and should be interpreted by a radiologist accustomed to reviewing spine studies of young children. Bony structures can also be well imaged using a helical computed tomography (CT) scanner. Visualizing the spinal cord itself is best accomplished using an MRI. Children younger than 9 years can develop spinal cord

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injury without radiographic abnormality (SCIWORA). Given the greater mobility and flexibility of the pediatric spine relative to that found in adults, bony elements can be displaced into the spinal cord and then revert to their normal position. When this occurs, the patient will clinically appear to have a traumatic myelopathy (spinal cord injury) on neurologic examination, but no bony or ligamentous damage is seen with plain films or CT scans. An MRI, however, can demonstrate damage to the spinal ligaments, injury to the spinal cord, or both.

THE ROLE OF SURGERY AND STEROIDS The principal goal in managing acute spinal cord injury is to prevent secondary injury. Although the initial traumatic event can produce major damage, subsequent inflammation, edema, and ischemia can lead to significant worsening of this primary insult. Surgical intervention to stabilize the spine, remove bony matter, evacuate hemorrhage, and decompress the spinal canal has been evaluated, particularly in adult patients, and it remains controversial with little data available in children. Animal work has supported the use of early decompression within the first 8 hours in order to improve outcome. There are no evidence-based guidelines at this point. Significant compromise of the spinal canal and fixation of a very unstable spine that is not amenable to closed reduction are considered the principal indications for early surgery in traumatic spinal cord injury at this point. Because inflammation plays a major role in mediating secondary injury, administration of corticosteroids has been studied in acute spinal cord injury. Certainly, the benefits of steroids in subacute spinal cord injury, such as cord compression by tumor, are well established. However, this subject remains a matter of controversy, and limited evidence indicates that intravenous methylprednisolone can lead to improvements in motor scores for adult patients with acute spinal cord injury if administered within 8 hours of injury and continued for 24 to 48 hours. Continuing steroid therapy beyond this period has not been shown to improve outcomes and may increase side effects such as infections and wound dehiscence. The American Association of Neurological Surgeons and Congress of Neurological Surgeons currently do not recommend using steroid therapy with the current level of evidence and list it as a treatment option in adults with closed spinal cord injury rather than a treatment recommendation. Steroid therapy has been shown to worsen outcomes in TBI and in patients with polytrauma and penetrating injuries, and therefore it is contraindicated in these cases.

MEDICAL COMPLICATIONS OF SPINAL CORD INJURY Spinal cord injury can be complicated by a host of medical issues during hospitalization. This is due to a combination of sympathetic dysregulation, pain, and immobility. Because there are no widely available therapies for spinal cord injury, supportive therapy during the acute phase and mitigating medical complications is of utmost importance. Pressure sores can develop over the course of hours and have serious mortality and morbidity implications. To avoid pressure sores, backboards should be used only for transport and discontinued as soon as the spine is stabilized. Frequent turning and rolling every 2 to 3 hours should follow.

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Patients can develop urinary distention and loss of urinary control, leading to urinary stasis and overflow incontinence. This should be avoided by inserting an indwelling Foley catheter in the acute period followed by intermittent catheterization thereafter. Gastrointestinal complications include stress ulcers and paralytic ileus. Prophylactic proton pump inhibitors or H2-receptor blockers can lower the risk of stress ulcers. Prophylactic stool softeners and monitoring stool output are important as well. Patients may have sympathetic dysregulation manifesting as bradycardia, hypotension, and hypo- or hyperthermia. These should be monitored closely and treated as needed with intravenous (IV) fluids, vasopressors, cooling or warming blankets, and antipyretic agents as needed.

Long-Term Care and Rehabilitation Maximizing long-term neurologic outcome for survivors of acute spinal cord injury requires an intensive team-based approach to rehabilitation. Important issues to be addressed include development of an appropriate bowel and bladder care program, maintenance of skin integrity, and management of persistent autonomic dysreflexia. As spinal shock subsides and spasticity begins to develop over the course of 1 to 6 weeks, prevention of contractures with preservation of functional position of the joints becomes crucial. Psychological and cognitive rehabilitation is also vital, both in terms of adjusting to life after the injury and dealing with concurrent head trauma. In general, patients will spend a significant period of time in an inpatient rehabilitation setting, followed by a transitional outpatient program. Even after this period, however, the patient should continue to be evaluated by a physical medicine and rehabilitation specialist at least yearly to maximize adaptation and function.

COMPREHENSION QUESTIONS 7.1 Currently, which of the following is the best strategy for preventing further damage in patients with acute spinal cord injury? A. High-dose corticosteroids B. Immediate exploratory surgery C. Maintenance of oxygenation and spinal cord perfusion D. Intravenous diuretic therapy 7.2 A patient is brought to the ER following an MVA. On examination, he or she has weakness of the left arm and leg and loss of fine touch on the left with loss of pain and temperature sensation on the right. This clinical picture is most consistent with which of the following? A. A complete cord syndrome B. A central cord syndrome C. An anterior spinal cord syndrome D. A left spinal cord hemisection syndrome E. A right spinal cord hemisection syndrome

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7.3 A 5-year-old boy is brought to the ER following a fall from approximately 4 ft. He is now alert, moving all his extremities, and responding to touch on all four extremities, but he is somewhat irritable and has a large laceration on his chin. Which of the following is true regarding evaluating the child’s spine? A. As he is moving all extremities and appears to have intact sensation, no further spinal evaluation needs to be performed. B. Given the child’s age, spinal imaging should be performed. C. Imaging should only be performed if cervical spine tenderness can be demonstrated. D. Spinal imaging should be arranged as an outpatient.

ANSWERS 7.1 C. The most important aspect of initial management is to avoid spinal cord ischemia. 7.2 D. This patient has the classic findings of a left cord hemisection (BrownSéquard) syndrome with ipsilateral weakness, ipsilateral loss of fine touch, and contralateral loss of pain, and temperature sensation. 7.3 B. Children younger than 9 years who experience blunt trauma or falls should have their spine imaged because clinical criteria can still miss injuries. Even if this child were older, the presence of a distracting injury (the large chin laceration) can mask cervical tenderness.

CLINICAL PEARLS »»

After ensuring hemodynamic stability by securing airway, breathing, and circulation, the most important step in the emergency care of patients with spinal cord injury is stabilization of the spine. The next step is to maintain spinal cord perfusion pressure.

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The most common cause of spinal cord injury in the pediatric and adult population is MVA.

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Traumatic brain injury commonly accompanies traumatic spinal cord injury, including hemorrhage, ischemia, or diffuse axonal injury.

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Superficial abdominal reflexes are elicited by scratching the skin in all four quadrants around the umbilicus and watching for contraction of the underlying abdominal musculature. Stimulating above the umbilicus tests spinal levels T8 to T10, whereas stimulating below the umbilicus tests approximately T10 to T12.

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Medical complications of spinal cord injury include sympathetic instability, urinary retention, stress ulcers, and paralytic ileus. These complications can lead to significant morbidity and mortality if not monitored closely.

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REFERENCES Bracken MB. Steroids for acute spinal cord injury. Cochrane database Syst Rev. 2012;1:CD001046. Congress of Neurological Surgeons. Management of pediatric cervical spine and spinal cord injuries. Neurosurgery. 2002;50(suppl 3):S85-S99. Devivo MJ. Epidemiology of traumatic spinal cord injury: trends and future implications. Spinal Cord. 2012;50(5):365-372. Eleraky M, Theodore N, Adams M, Rekate HL, Sonntag VK. Pediatric cervical spine injuries: report of 102 cases and review of the literature. J Neurosurg. 2000;92(suppl 1):12-17. Heary RF, Vaccaro AR, Mesa JJ, et al. Steroids and gunshot wounds to the spine. Neurosurgery. 1997; 41(3):576-583; discussion 583-584. http://www.ncbi.nlm.nih.gov/pubmed/9310974. Accessed September 26, 2016. Hugenholtz H, Cass DE, Dvorak MF, et al. High-dose methylprednisolone for acute closed spinal cord injury—only a treatment option. Can J Neurol Sci. 2002;29(3):227-235. http://www.ncbi.nlm.nih. gov/pubmed/12195611. Accessed September 26, 2016. Hurlbert RJ, Hadley MN, Walters BC, et al. Pharmacological therapy for acute spinal cord injury. Neurosurgery. 2013;72(suppl 2):93-105. Jia X, Kowalski RG, Sciubba DM, Geocadin RG. Critical care of traumatic spinal cord injury. J Intensive Care Med. 2013;28(1):12-23. McDonald J, Sadowsky C. Spinal cord injury. Lancet. 2002;359:417-425. Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebocontrolled trial. Lancet. 2004;364(9442):1321-1328. Saveika J, Thorogood C. Airbag-mediated pediatric atlanto-occipital dislocation. Am J Phys Med Rehabil. 2006;85:1007-1010. Thuret S, Moon L, Gage F. Therapeutic interventions after spinal cord injury. Nat Rev Neurosci. 2006;7:628-643. Tsutsumi S, Ueta T, Shiba K, Yamamoto S, Takagishi K. Effects of the Second National Acute Spinal Cord Injury Study of high-dose methylprednisolone therapy on acute cervical spinal cord injuryresults in spinal injuries center. Spine. 2006;31(26):2992-2996.

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CASE 8 A 17-year-old football player returning a kickoff collided into an opposing player, causing him to lose his helmet, and was subsequently struck on the right side of his head by the defender’s knee. He fell to the ground and was unconscious for 20 to 30 seconds. He was then immediately transported to the closest hospital. Twenty minutes after the accident, he was alert and conscious without neurologic deficit; however, he suffered from amnesia for the event. Physical examination revealed a superficial bruise to the scalp in the right parietal region. Approximately 1 hour after the injury, the patient suffered a generalized tonic-clonic (GTC) seizure. Lorazepam 4 mg intravenous (IV) was administered, and the seizure was aborted. A computed tomography (CT) of the brain was performed approximately an hour and a half after the trauma was unremarkable. He was transferred to a larger hospital shortly thereafter for observation. On admission, neurologic examination showed slight psychomotor slowing and slurred speech, which was thought to be secondary to the previous lorazepam administration due to absence of any focal neurologic deficits. The Glasgow Coma Scale (GCS) score was 15 of 15. Routine laboratory investigations and electrocardiography were normal. After 8 hours of the initial trauma, he complained of a severe headache and had associated nausea and vomiting. »» »» »»

What is the most concerning diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 8: Epidural/Subdural Hematoma Summary: This was a case of a 17-year-old athlete with an acute sports-related traumatic brain injury. The injury was associated with a transient loss of consciousness and subsequent GTC seizure. Although his initial examination was nonfocal and screening of CT of the brain was normal, his condition worsened with onset of a severe generalized headache with nausea and vomiting. šš

Most concerning diagnosis: An epidural hematoma (EDH).

šš

Next diagnostic step: Repeat noncontrast CT scan of the brain.

šš

Next step in therapy: Careful observation and neurologic examination, neurosurgical consultation, and careful evaluation for other signs of trauma.

ANALYSIS Objectives 1. Understand the mechanism of why an EDH forms and expands. 2. Identify the signs and symptoms associated with an expanding EDH that require urgent neurosurgical intervention.

Considerations The key feature of this case is that the patient was a healthy individual who had a traumatic closed head injury. He experienced loss of consciousness, followed by a normal lucid period. He then suffered a GTC seizure followed by cognitive slowing after administration of lorazepam. It is not possible to exclude the neurologic symptoms as a result of the original closed head injury. One has to decide whether this suggests an underlying etiology such as migraine headaches, one that is a result of the trauma, or both. A lucid period prior to neurologic deterioration is a classic presentation for an EDH; however, less than one-third of patients with EDHs actually present as such. Other signs and symptoms include headache, nausea, vomiting, and seizure. Other possibilities include a subarachnoid hemorrhage, subdural hematoma, cerebral contusion and diffuse axonal injury, although the transient lucid period would not be typical. A patient with an EDH can rapidly deteriorate due to the expanding intracranial hemorrhage causing mass effect on the brain and brainstem. Moreover, patients with a posterior fossa EDH can have a dramatic deterioration. A patient can be conscious and talking for 1 minute and apneic and comatose the next minute and close to dying from brainstem compression if emergent neurosurgical intervention is not performed.

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APPROACH TO: Epidural Hematoma EDH is an accumulation of blood between the inner table of the skull and the outer dural membrane. The inciting event is often trauma, frequently with a “blunt instrument.” In 85% to 95% of patients, this type of trauma results in an overlying fracture of the skull. Blood vessels in close proximity to the fracture are the sources of the hemorrhage that lead to an EDH. Because the underlying brain has usually been minimally injured, the prognosis is excellent if treated early and aggressively. Outcome from surgical decompression and repair is related directly to the patient’s preoperative neurologic condition. The incidence of EDHs is about half of that of subdural hematomas. Males outnumber females by 4:1. EDHs usually occur in young adults and are rare in persons younger than 2 years or older than 60 years. This is most likely due to the dura being strongly adhered to the inner table of the skull in elderly patients. Also, the association of hematoma and skull fracture is less common in young children because of the pliability of the calvarium. EDHs may also occur in the spine, namely spinal EDHs. These are also considered a neurosurgical emergency, often times requiring surgical intervention. EDHs can be divided into acute (58%) from arterial bleeding, subacute (31%), and chronic (11%) from venous bleeding. Two-thirds of the cases of cranial EDH are in the temporal–parietal area and result from a tear of the middle meningeal artery or its dural branches. Frontal and occipital EDHs each constitute approximately 10%, with the latter occasionally extending above and below the tentorium. The rapid bleeding associated with arterial tears is one of the reasons why these lesions require rapid evaluation and intervention. Occasionally, torn venous sinuses can cause an EDH, particularly in the parietal–occipital region or in the posterior fossa. These injuries tend to be smaller and associated with a more benign course. Typically, venous EDHs only form with a depressed skull fracture due to disruption of the dura from the bone and thus create a space for blood to accumulate. The reported rate of mortality ranges from 5% to 43%. Higher rates are generally seen at both ends of the age spectrum (ie, 55 years). Mortality is also higher in patients with signs of more extensive anatomic (intradural lesions, increased hematoma volume) or clinical (rapid clinical progression, pupillary abnormalities, increased intracranial pressure [ICP], lower GCS) involvement, in addition to those with EDH in a temporal location. Mortality rates are essentially nil for patients not in coma preoperatively, approximately 10% for obtunded patients, and 20% for patients in deep coma.

EVALUATION History and Physical Examination Symptoms of EDH include the following: šš

Headache.

šš

Nausea and/or vomiting.

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šš

Seizures.

šš

Focal neurologic deficits (eg, visual field cuts, aphasia, weakness, numbness).

šš

Spinal EDHs typically cause severe localized back pain with delayed radiating pain which can mimic radicular pain seen in disc herniation. Associated symptoms can include weakness, numbness, urinary incontinence, and fecal incontinence.

The physical examination is focused to determine the localization of the deficit and identify signs of increasing ICP and/or herniation. Physical signs of expanding intracranial mass include the following: šš

Cushing response (caused by increased ICP) (triad of hypertension, bradycardia, and irregular respirations)

šš

Decreased or fluctuating levels of consciousness/GCS

šš

Dilated, sluggish, or fixed pupil(s), bilateral or ipsilateral to injury

šš

Coma

šš

Decerebrate posturing

šš

Hemiplegia contralateral to injury

šš

Other focal neurologic deficits (eg, aphasia, visual field deficits, numbness, ataxia)

In addition, the physical examination should include a thorough evaluation for evidence of traumatic sequelae: šš

Skull fractures, hematomas, or lacerations

šš

Contusion, laceration, or bony step-off in the area of injury

šš

Cerebrospinal fluid (CSF) otorrhea or rhinorrhea resulting from skull fracture with disruption of the dura

šš

Hemotympanum

šš

Instability of the vertebral column

DIAGNOSTIC STUDIES Laboratory Studies šš

šš

šš

Complete blood count (CBC) with platelets to monitor for infection and assess hematocrit and platelets for further hemorrhagic risk, including underlying predisposing disorders. Prothrombin time (PT)/activated partial thromboplastin time (aPTT) to identify bleeding diathesis. Fibrin split products and d-dimers are markers of coagulation abnormalities such as disseminated intravascular coagulation (DIC). With severe head injury, breakdown of the blood–brain barrier with exposed brain tissue is a potent cause of DIC.

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šš

šš

šš

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Serum chemistries, including electrolytes, blood urea nitrogen (BUN), creatinine, and glucose to characterize metabolic derangements that can complicate the clinical course. Toxicology screen and serum alcohol level to identify associated causes of head trauma and establish whether there is a need for surveillance with regard to withdrawal symptoms. Type and cross an appropriate amount of blood to prepare for necessary transfusions due to blood loss or anemia.

Imaging Studies Immediate noncontrast CT scan of the brain is the imaging of choice acutely for diagnosis. The CT scan shows the location, volume, effect, and other potential intracranial injuries. Cervical spine evaluation is usually necessary because of the risk of neck injury associated with an EDH. Clinical deterioration should prompt repeat imaging with a noncontrast CT of the brain. Figure 8–1 illustrates the typical findings on brain CT of an EDH: šš

Mass that displaces the brain away from the skull.

šš

Extra-axial.

Figure 8–1.  Acute epidural hematoma. The tightly attached dura is stripped from the inner table of the skull, producing a characteristic lenticular-shaped hemorrhage on noncontrast CT scan. Epidural hematomas are usually caused by tearing of the middle meningeal artery following fracture of the temporal bone. (Reproduced, with permission, from Fauci AS, et al. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill; 2008:2599.)

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šš

Smooth margins.

šš

Lenticular or biconvex homogenous density.

šš

Most of these masses are high density on the CT scan.

šš

Focal isodense or hypodense zones within EDH indicate active bleeding.

šš

šš

Rarely crosses the suture line because the dura is attached more firmly to the skull at sutures. Air in the setting of an acute EDH suggests fracture of sinuses or mastoid air cells.

TREATMENT Prior to definitive treatment with surgery, the most important considerations are to stabilize acute life-threatening conditions, initiate supportive therapy, and try to reduce ICP. Airway control and blood pressure support are vital, as is careful observation. A discussion of the exact procedures is beyond the scope of this chapter. However, elevation of the head of the bed to 30 degrees after the spine is cleared, or reverse Trendelenburg position will reduce ICP and increase venous drainage. A neurosurgeon should be consulted immediately for evaluation of EDH evacuation and repair. Consult a trauma surgeon for other life-threatening injuries. Although surgical treatment has been viewed as definitive, under certain conditions, some EDHs can be treated conservatively with careful observation.

Outcome The most important factors influencing the outcome after evacuation of an EDH are the initial GCS, pupillary response, motor examination, and associated intracranial injuries seen on the CT scan. In noncomatose individuals, a favorable outcome occurs in 90% to 100% of patients and mortality ranges from 0% to 5%. For patients who are comatose, a favorable outcome occurs between 35% and 75% of the time with a mortality rate of 10% to 40%. Of interest, normally reacting pupils prior to surgery result in a favorable outcome in 84% to 100% of patients, while the great majority of individuals with bilateral abnormal pupillary reactions tend to have a poor outcome, including death. Associated intracranial injuries such as cerebral contusions also adversely impact outcome. Rapid diagnosis and timely evacuation of the hematoma are crucial in optimizing the outcome.

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COMPREHENSION QUESTIONS 8.1 A 14-year-old adolescent girl was sideswiped by a car while she was riding her bicycle. She was not wearing a helmet and struck the pavement with her head, losing consciousness for about 45 seconds. The patient then was awake and alert, resting at home. The parents noted later that she became drowsy, slurred her words, and after a few minutes had some weakness of the arms. On examination, the patient was lethargic and did not have any evidence of nuchal rigidity. Which of the following is the most likely diagnosis? A. Acute EDH B. Chronic subarachnoid hemorrhage C. Bacterial meningitis D. Cerebral contusion 8.2 A 34-year-old woman is brought into the emergency department (ED) after a skiing accident. The patient lost control, hit a tree, and suffered trauma to her head. She was not wearing a helmet. A noncontrast CT of the brain was performed. Homogeneous high density signal throughout the ventricular system is noted. Which of the following is the most likely diagnosis? A. Acute EDH B. Subarachnoid hemorrhage with intraventricular extension due to a ruptured proximal middle cerebral artery aneurysm C. Basal ganglia hematoma D. Ruptured cavernous angioma 8.3 A 22-year-old college student is brought into the ED after suffering a head injury after falling off the railing of the second story balcony of his dorm. His neurologic examination is normal. He is alert and oriented. The CT scan of the brain performed 1 hour after the event is normal. Two hours later, the patient appears drowsy and does not respond to commands. You review the medication records, and no sedating medications have been given. Which of the following is the best next step? A. Assume illicit opiate use and give naloxone. B. Prepare the patient for neurosurgical burr holes. C. Repeat CT scan of the brain. D. Administer activated charcoal for probable overdose.

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ANSWERS 8.1 A. The lucent interval is typical of EDH. The patient had blunt trauma to the head, followed by a lucid interval, and then cranial to caudal deterioration, which are also classic for EDH. 8.2 B. Blood in the subarachnoid space appears hyperdense and usually can be seen as a homogenous high density signal in the ventricular system. 8.3 C. An evolving EDH can occur any time after the immediate injury. Repeat CT imaging of the brain is indicated if there is any change in the neurologic status of the patient. Thus, although the first CT scan was normal, a second one is indicated due to the change in the patient’s neurologic status. Taking the patient to surgery without clear confirmation is not indicated.

CLINICAL PEARLS »»

The historical hallmark of EDH is injury followed by a lucid, relatively asymptomatic period, followed by deterioration.

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With suspected EDH, deterioration can be quite rapid, and close observation is necessary.

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EDHs require emergent surgical intervention a large percentage of the time, so early neurosurgical consultation is important.

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Noncontrast CT scan of the brain is the recommended radiologic study for initial evaluation.

REFERENCES Bullock MR, Chesnut R, Ghajar J, et al. Surgical Management of Traumatic Brain Injury Author Group. Surgical management of acute epidural hematomas. Neurosurgery. 2006;58(suppl 3):S7-S15; discussion Si-Siv. Lee EJ, Hung YC, Wang LC, et al. Factors influencing the functional outcome of patients with acute epidural hematomas: analysis of 200 patients undergoing surgery. J Trauma. 1998;45:946-952. Liebeskind DS. Epidural hematoma. http://www.emedicine.com/NEURO/topic574.htm. Accessed April 17, 2006. Neely JC 2nd, Jones BV, Crone KR. Spontaneous extracranial decompression of epidural hematoma. Pediatr Radiol. 2008;38:316-318. Offner PJ, Pham B, Hawkes A. Nonoperative management of acute epidural hematomas: a “no-brainer.” Am J Surg. 2006;192:801-805. Provenzale J. CT and MR imaging of acute cranial trauma. Emerg Radiol. 2007;14(1):1-12.

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CASE 9 A 63-year-old woman is brought into the emergency department (ED) with altered mental status. Her family tells you that the patient was in her normal state of health until 3 days ago and since has become sleepier and more confused. She is a very private person and has never told her children about any health problems. The family does confide that the patient was an alcoholic for many years, but her doctor recently convinced her to stop drinking because it was “damaging her organs.” On interview, the patient answers most questions inappropriately and with anger; however, at times she answers lucidly. She denies experiencing any headache, neck pain, visual symptoms, or loss of balance. On examination, she is afebrile, her blood pressure is 124/78 mm Hg, and her pulse is 100 beats/min. She is awake but inattentive, and her focus waxes and wanes throughout the examination. Her general examination is notable for the absence of nuchal rigidity, no obvious head trauma, and a distended abdomen. Her Mini-Mental State Examination (MMSE) is 24/30 and she is having difficulty with orientation, concentration, and recall. She fluctuates with being appropriate throughout the examination. She does not have any aphasia or dysarthria but is circumstantial and tangential. Her neurologic examination is significant for grossly intact cranial nerves and intact pinprick sensation to the face. The remainder of the sensory, motor, and cerebellar examination cannot be fully assessed because she is uncooperative with much of the examination. The tests she does tolerate are largely normal; however, when asked to bend her wrists upward, she finds it difficult due to involuntary flapping with loss of tone in the wrist extensors. »» »»

What is the most likely diagnosis? What is the next diagnostic step?

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ANSWERS TO CASE 9: Delirium from Hepatic Encephalopathy Summary: A 63-year-old woman with a history of alcohol abuse presents with an alteration in mental status, which developed over 3 days. Her mental status shows attention deficits, disorganized thinking, altered psychomotor activity, difficulty focusing, memory deficits, and disorientation. Additionally, it seems that there has been some fluctuation of her symptoms. The examination is notable for absent nuchal rigidity, a distended abdomen, and flapping movements at the wrists. šš šš

Most likely diagnosis: Delirium from hepatic encephalopathy. Next diagnostic step: Computed tomography (CT) scan of the head, complete blood count (CBC), comprehensive metabolic panel, blood alcohol level, and urine toxicology screen

ANALYSIS Objectives 1. Be familiar with the clinical presentation of delirium. 2. Learn the differential diagnosis of delirium. 3. Describe how to evaluate a patient with delirium.

Considerations This 63-year-old woman presents with acute fluctuating levels of attention, confusion, and altered psychomotor activity developing over 3 days. The findings of attentional deficits, disorganized thinking, altered psychomotor activity, difficulty focusing, memory deficits, and disorientation are characteristic for delirium when there is a waxing and waning of symptoms and a relatively acute onset. Importantly, not all patients with altered mental status have delirium. The hallmarks of delirium are cognitive impairment, impaired attention, and fluctuating course. The differential of altered mental status can be quite broad and must first be accurately defined. Given the history of chronic alcoholism, a distended abdomen (likely ascites) and flapping hand motions (likely asterixis), her presentation is suggestive of hepatic encephalopathy. This occurs when there is an accumulation of harmful neurotoxic substances such as ammonia and manganese that would otherwise be removed by a healthy liver.

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APPROACH TO: Delirium DEFINITIONS DELIRIUM: A neurobehavioral disorder with a fluctuating course including inattention and acute alteration in mental status. ATTENTION: The ability to focus on specific stimuli while excluding others. ASTERIXIS: A type of negative myoclonus or loss of muscle tone in the wrist extensors, resulting in a characteristic flapping motion. It is classically caused by hyperammonemia in liver disease and can be linked to various metabolic conditions.

CLINICAL APPROACH The presentation of acute mental status change, abnormal attention, and a fluctuating course should alert the clinician to delirium. Delirium is a disorder caused by many different etiologies and is the most common neurobehavioral disorder in hospitals. It has been reported that up to 40% of hospitalized patients in intensive care units (ICUs) have delirium. There are various recognized risk factors for delirium, the most common being age (particularly >80 years), preexisting cognitive impairment, dehydration, electrolyte disturbances, and gender (men more so than women). Patients admitted to hospitals with delirium account for 10% to 24% of all admissions, with up to 26% of these resulting in death. Almost 80% of patients will experience delirium near the time of death. The pathophysiology of delirium is not well established, but there is evidence to suggest that there are multiple neurotransmitter abnormalities affecting acetylcholine, dopamine, and serotonin levels that lead to reversible impairment of cerebral oxidative metabolism. There is also an inflammatory component to the mechanism of delirium, with some studies showing that cytokines such as interleukin-1 and interleukin-6 are upregulated. The central nervous system (CNS) pathways involved in delirium are not well established; however, the ascending reticular formation in the upper brainstem, prefrontal cortex, posterior parietal cortex, and the thalamus all seem to be involved. Clinical characteristics of delirium include an acute change in mental status with a fluctuating course, disorganized thinking, and attentional deficits. Other risk factors are listed in Table 9–1. Delirium should be differentiated from dementia, which is usually marked by a slow-onset, chronic cognitive disorder.

Diagnosis The diagnosis of delirium is clinical, with an emphasis on evaluating level of attention. Attention can be evaluated by serial reversal test (such as asking the patient to spell a word backward). The history should include a review of medications the patient is taking and information obtained from friends or family. The neurologic examination may be nonfocal, although patients may have dysarthria, tremor, various motor abnormalities, or asterixis (loss of tone with passive extension of wrist).

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Table 9–1  •  DELIRIUM RISK FACTORS Elderly, ie, >80 years old

Gender: men > women

Preexisting cognitive impairment

Number and severity of medical illnesses

Dehydration/electrolyte disturbances

Infections: urinary/pulmonary

Hypoxemia/cardiorespiratory failure

Malnutrition

Drug abuse: EtOH or hypnotic dependency

Sleep disturbance

Fever/hypothermia

Polypharmacy/analgesic use

Depression

Fractures

Physical trauma

Burns

Sleep disturbance

Visual/auditory impairment

EtOH, alcohol consumption, and/or dependency

Laboratory evaluation should include a comprehensive metabolic panel with close attention to electrolyte levels, glucose, blood urea nitrogen (BUN), liver function studies, a CBC to evaluate for infection, thyroid function studies, and ammonia levels. Arterial blood gas (ABG) or pulse oximetry should be obtained, especially if the patient has a history of lung disease or smoking. Urine toxicology studies in those individuals with a history of drug abuse or at risk for drug abuse should be obtained as well. A CT scan of the head or magnetic resonance imaging (MRI) of the brain should be performed. The choice of study depends on how easy the study is to obtain and whether structural or vascular causes can be ruled out clinically. Other studies to consider, depending on the clinical presentation, include chest radiograph (evaluates for pneumonia), electrocardiograph (ECG) (excludes myocardial infarction or arrhythmia), electroencephalograph (EEG), and lumbar puncture, especially if there is concern for CNS infection. The differential diagnosis for delirium is extensive (Table 9–2) and includes metabolic causes, infections, drug-related causes, primary neurologic abnormalities, Table 9–2  •  SELECTED LISTING OF ETIOLOGIES OF DELIRIUM Etiologies Metabolic disorders: hypoglycemia, hyponatremia, uremia, hypoxia, hypo/hypercalcemia, endocrinopathies (thyroid, pituitary), vitamin deficiencies, hepatic encephalopathy, toxic exposures (lead, carbon monoxide, mercury, organic solvents) Neurological: head trauma, cerebrovascular accidents, brain tumors, epilepsy, hypertensive encephalopathy Infections: encephalitis, meningitis, neurosyphilis, human immunodeficiency virus (HIV), brain abscesses Drug related: narcotics, sedatives, hypnotics, anticholinergics, antihistamine agents, beta-blockers, antiparkinson medications, illicit drugs (cocaine, amphetamines, hallucinogens) Perioperative: anesthetics, hypoxia, hypotension, fluid and electrolyte abnormalities, sepsis, embolism, cardiac, or orthopedic surgery Other: cardiovascular, CNS vasculitis, dehydration, sensory deprivation

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trauma, and perioperative causes. Importantly, delirium must be differentiated from dementia. Typically, demented patients have a history of chronic (>6 months) progression with normal attention (except in advanced cases) and level of consciousness. Perceptual disturbances and a fluctuating course are less common with dementia.

Treatment The treatment is dependent on the etiology of delirium, with the use of drug-related treatments being directed toward symptoms such as agitation, hallucinations, and paranoia. The most common medications used include the neuroleptics such as haloperidol (Haldol), quetiapine (Seroquel), risperidone (Risperdal), and rarely benzodiazepines. These medications should be used judiciously and only when absolutely necessary, especially in the geriatric population. Nonpharmacologic measures, such as optimizing the sleep–wake cycle with lights on during the day and off at night, minimizing unnecessary stimulation, introducing familiar faces and objects, and keeping a routine, should be employed prior to initiating medications if possible. Elderly patients who are hospitalized, particularly in the ICU setting, often become disoriented and are prone to delirium.

CASE CORRELATION šš

See also Case 10 (Concussion), Case 20 (Alzheimer Dementia) and Case 21 (Lewy Body Dementia)

COMPREHENSION QUESTIONS 9.1 An 82-year-old man presents to the emergency room with acute disorientation, hallucinations, and agitation. He had been healthy until last year when he developed diabetes mellitus and suffered a myocardial infarction. His examination is normal except for the symptoms mentioned above. Which of the following is the best next step? A. Obtain a stat CT scan of the head followed by a lumbar puncture. B. Review his medication list and talk to family about his recent cognitive state. C. Obtain a CBC, comprehensive metabolic panel, and urinalysis. D. Begin treatment with risperidone.

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9.2 A 21-year-old man is brought in by emergency medical services (EMS) to the emergency room with agitation, disorientation, hyperalertness, and recent personality changes. He is not known to have any medical problems and had been doing well until yesterday after attending a fraternity party. No one else is known to be ill, and he has not had fever or complained of headache or other symptoms. His examination is unremarkable except for a mildly elevated blood pressure of 146/90 mm Hg. What is the most likely diagnosis? A. Bacterial meningitis B. Brain tumor C. Cerebrovascular accident D. Hallucinogen use 9.3 A 65-year-old man is admitted to the ICU with an acute change in mental status. Which of the following features is more likely to be delirium versus dementia? A. Chronic loss of recent memory B. Loss of cognitive ability C. Fluctuating level of attention D. History of head trauma

ANSWERS 9.1 B. History is key in trying to determine the etiology of delirium, so obtaining further information from caregivers or family including reviewing his medication list is critical. It is possible that his symptoms are caused by medications he is taking or that he has suffered another myocardial infarction and complained of chest pain before having an alteration in mental status. Obtaining a CBC, comprehensive metabolic panel, and urinalysis are important and will need to be performed, but they are not the next step in this patient’s evaluation. 9.2 D. The most likely culprit of his delirium is hallucinogen use, as he is in an age group at risk for this. He does not have fever or meningismus to suggest bacterial meningitis, and the lack of focal findings on examination argues against a brain tumor or stroke. 9.3 C. Typically, demented patients have a history of chronic (>6 months) progression with normal attention (except advanced cases) and level of consciousness. Perceptual disturbances and fluctuating course are less common with dementia. Up to 40% of ICU patients develop delirium. About 25% of patients admitted for delirium will die. Fluctuation of level of attention is the distinguishing feature of delirium.

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CLINICAL PEARLS »»

Delirium is differentiated from dementia in that delirium involves acute changes in mentation with fluctuating altered levels of consciousness and attention.

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Delirium has a myriad of etiologies including toxins, medications (illicit and nonillicit), electrolyte or acid/base disturbances, and infections such as urinary tract infections or pneumonia.

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Delirium often lasts only approximately 1 week, although it can take several weeks for cognitive function to return to normal levels. Full recovery is common.

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The history and physical examination are the most important tools in evaluating delirium.

REFERENCES Chan D, Brennan NJ. Delirium: making the diagnosis, improving the prognosis. Geriatrics. 1999; 54(3):28-30, 36, 39-42. Mendez AM. Delirium. In: Bradley WG, Daroff, RB, Fenichel G, Jankovic J, eds. Neurology in Clinical Practice. 4th ed. Philadelphia, PA: Butterworth-Heinemann; 2003. Patidar KR, Bajaj JS. Covert and overt hepatic encephalopathy: diagnosis and management. Clin Gastroenterol Hepatol. 2015;13(12):2048-2061. Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiat. 1997;9(2): 105-107. Wilber ST, Ondrejka JE. Altered mental status and delerium. Emerg Med Clin North Am. 2016;34(3): 649-665.

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CASE 10 A 15-year-old right-handed adolescent boy presents to the clinic 1 day after suffering a head injury during football practice. He complains of headache, nausea, and light sensitivity. He denies any neck pain or any other new focal neurologic complaints. Immediately following his injury, the athletic trainer noted that he was oriented only to the place and the name of his coach. He had no memory of the series of plays immediately prior to being tackled. His speech was quite slow and deliberate. His pupils were equal, round, and reactive to light, and he had no facial asymmetry. Finger-to-nose testing was somewhat slow and deliberate with mild past-pointing. His gait was mildly wide-based and unsteady. When tested again 15 minutes after his injury, he was oriented to person, place, and time, but he still had no memory of the events preceding his injury, and his gait remained unsteady. He was taken to a local emergency center for further evaluation. A computed tomography (CT) scan of the brain revealed no acute abnormalities, and he was discharged with follow up instructions. Your examination reveals some mild instability when he stands with his feet together and closes his eyes, but otherwise the neurologic examination is unremarkable. He has no significant neurologic or medical history and was not taking any medications. He was not suffering from any kind of illness recently. There was no history of neurologic problems in the family. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 10: Cerebral Concussion Summary: This is a case of a previously healthy and neurodevelopmentally normal 15-year-old adolescent boy who experienced a head injury during a football game with new-onset mild but persistent nonfocal neurologic symptoms. He is now in the clinic seeking further evaluation and treatment. šš šš

šš

Most likely diagnosis: Concussion. Next diagnostic step: Serial examinations, including standardized concussion testing. Next step in therapy: Rest, symptomatic treatment, reassurance, and education on a progressive return-to-activity plan.

ANALYSIS Objectives 1. Be aware of the epidemiology of concussion. 2. Be able to recognize the signs and symptoms of concussion. 3. Understand the clinical criteria for obtaining imaging following a head injury. 4. Be aware of initial concussion management, including “return-to-play” guidelines for sports-related concussions. 5. Describe clinical features and the usual course of the postconcussion syndrome.

Considerations The neurologic status of this 15-year-old adolescent boy is now steadily improving following his sports-related concussion. Always err on the side of caution when evaluating head traumas, particularly in the pediatric and adolescent setting. Transfer to the emergency department was a reasonable response. While a CT scan cannot diagnose concussion, it will rule out more severe injury such as an intracranial hemorrhage. The most important part of his care at this time will be education on the management and expected outcome of the concussion.

APPROACH TO: Cerebral Concussion DEFINITIONS CONCUSSION: A traumatic alteration in cerebral physiologic function with or without loss of consciousness. Concussion is best thought of as a mild traumatic brain injury (TBI).

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Table 10–1  •  CONCUSSION INCIDENCE IN SPORTS  

Injury Rate per 1000 Games High School

College

Football

1.55

3.02

Soccer

0.59

1.38

Basketball

0.11

0.45

Baseball

0.08

0.23

Sports—Females

 

 

Soccer

0.97

1.80

Basketball

0.60

0.85

Softball

0.04

0.37

Sports—Males

Data derived from AAN Summary of evidenced-based guideline update: evaluation and management of concussion in sports, 2013.

EPIDEMIOLOGY Between 1.6 and 3.8 million sports-related mild TBIs occur each year in the United States. The rate continues to rise, but this is still likely an underestimate due to underdiagnosis. For males, the sport with highest risk of concussion is football (Table 10–1). In women’s sports, the rate of concussion is highest in soccer and basketball. In fact, even though males sustain more concussions, female athletes have a higher rate of concussions than males when compared within the same sport. Rugby, ice hockey, wrestling, and lacrosse also account for higher rates of concussions. Between 2009 and 2013, all 50 states in the United States passed legislature regarding concussions in sports for youth and students.

PATHOPHYSIOLOGY The clinical syndrome following exposure to a rapid acceleration/deceleration force results in diffuse metabolic derangement in the brain involving impaired neurotransmitter function, excitotoxicity, and disrupted ion homeostasis. Diffuse axonal injury due to stretching and shearing may also play a role. Since the ascending reticular-activating system (ARAS) is a key structure mediating wakefulness, transient interruption of its function can be partly responsible for temporary loss of consciousness following a head injury. The junction between the thalamus and the midbrain, which contains reticular neurons of the ARAS, seems to be particularly susceptible to the forces produced by rapid deceleration of the head as it strikes a fixed object.

CONCUSSION DIAGNOSIS The diagnosis is based on history, clinical examination, and physician experience. Even the most skilled examiner may have difficulty with making a definitive diagnosis in some cases due to the lack of an objective test. Imaging will not aid in the

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Table 10–2  •  COMMON SIGNS AND SYMPTOMS OF CONCUSSION Signs

Symptoms

Amnesia, anterograde or retrograde

Headache or “pressure” in head

Appears dazed or stunned

Nausea and/or vomiting

Confusion

Dizziness or feeling off balance

Slow response times (motor or verbal)

Double or blurry vision

Mood, behavior, or personality changes

Light or noise sensitivity

Loss of consciousness (any duration)

Concentration and memory difficulty

Altered coordination

Fatigue

Balance problems (ie, unsteady gait)

Feels sluggish, hazy, foggy, etc

Slurred speech

Change in sleep (excessive sleep or insomnia)

diagnosis of concussion, but it will allow one to rule out more severe and/or concomitant intracranial pathology. The previous American Academy of Neurology grading system of concussion severity is no longer used; current recommendations place the emphasis on unique patient cases in diagnosing and managing the injury. Headache is the most common acute symptom, occurring in 90% of patients (Table 10–2). Based on the examiner’s degree of certainty, the concussion may be designated as possible, probable, or definite.

INITIAL MANAGEMENT OF CONCUSSION If a concussion is suspected, the person should be removed from physical activity until they can undergo further evaluation by a medical professional. Assessment of airway, breathing, and circulation is followed by a neurologic examination. Several tools have been developed to help with assessment, such as the Post-Concussion Symptom Scale, Graded Symptom Checklist, Standardized Assessment of Concussion, Balance Error Scoring System, Sensory Organization Test, Sport Concussion Assessment Tool 3 (SCAT3), and Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). Most of these tools are readily available online for free and can be administered reliably even by nonphysicians. Assessment with one of the aforementioned diagnostic tools acutely following the injury (ie, in the locker room 5 minutes after the injury) may be useful in tracking the recovery over time. Of note, symptoms may continue to develop over several hours following the injury, and the patient should be monitored closely for the next 24 to 48 hours. No athlete with a suspected concussion can return to play on the same day as the injury. Urgent evaluation in the emergency room should be pursued if the patient has evidence of new or worsening neurologic signs, focal deficits, potential spinal injury, and/or a Glasgow Coma Scale score of less than 15. Red flags for a cervical injury include new-onset numbness or weakness, neck pain, and respiratory difficulty. If a cervical spine injury is suspected, the spine should be immobilized and any headgear should remain in place until removed by a trained health care provider. Intracranial hemorrhage should be considered after any head trauma,

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though the incidence is relatively low. A noncontrast CT scan is the imaging study of choice to assess for bleeding. Indications include loss of consciousness, altered or worsening mental status, severe or worsening headache, anisocoria, seizure, focal deficits, and repeated vomiting. A magnetic resonance imaging (MRI) scan is not necessary and would only be considered later if the concussive syndrome does not resolve as expected. Always consider the individual patient and situation in your clinical decision-making. Once the diagnosis is made, care focuses on symptom management. While in the acute symptomatic phase, patients should limit physical and mental activity. This includes sports play, some school work, and “screen time” on the computer, tablet, or phone. Acetaminophen may be given in the first 48 hours for pain. If there is no hemorrhage, anti-inflammatory medications such as ibuprofen may be added later if needed. Frequent follow-up with a physician is important to ensure symptoms are improving and adequately treated. A neuropsychologist may be consulted to help in the evaluation, monitoring, and eventual return-to-play decisions. As symptoms begin to improve, the patient may try a slow return-to-school/work and social activities. Modifications in length of time spent in school or on assignments may be needed until symptoms improve. When the patient has no signs or symptoms of concussion at rest, then they may begin a gradual return to physical activity.

RETURN-TO-PLAY GUIDELINES For sports-related concussions, an important consideration is when the athlete will be able to return to playing. Determining when an athlete returns to play after a concussion should follow an individualized course since each athlete will recover at a different pace. Under no circumstances should any athlete return to play the same day the concussion occurred. No athlete should return to play while still symptomatic at rest or with exertion. Although the vast majority of athletes with concussions will become asymptomatic within a week of their concussions, numerous studies have demonstrated a longer recovery of full cognitive function in younger athletes compared with college-aged or professional athletes—often 7 to 10 days or longer. Because of this longer cognitive recovery period, although they are asymptomatic, there should be a more conservative approach to deciding when pediatric and adolescent athletes can return to play. A matter of ongoing debate is the issue of when an athlete should retire (whether in high school or playing at a professional level) from a sport in which they have sustained multiple concussions. These recommendations apply to athletes experiencing their first concussion of the season. For a second concussion, even more conservative management should be employed. Studies show that recurrent concussions are associated with prolonged recovery time and more severe symptoms with loss of consciousness than those with first time concussion injury. A postconcussion-rehabilitative approach should be employed for all concussion cases. The program should be characterized by a stepwise incorporation of activity between 1- and 5-day increments based on the individual’s injury and rate of recovery (Table 10–3). If symptoms reoccur, the athlete should return to rest for 24 hours and then resume activity at the last stage that was well tolerated.

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Table 10–3  •  RETURN-TO-PLAY EXERCISE PROGRAM Rehabilitation Stage

Functional Exercise

1.  No activity

Complete physical and cognitive rest

2.  Light aerobic activity

Walking, swimming, stationary cycling at 70% maximum heart rate; no resistance exercises

3.  Sport-specific exercise

Specific sport-related drills but no head impact

4.  Noncontact training drills

More complex drills, may start light resistance training

5.  Full-contact practice

After medical clearance, participate in normal training

6.  Return to play

Normal game play

COMPLICATIONS SECOND-IMPACT SYNDROME: This is a rare but life-threatening syndrome of cerebral vascular congestion and diffuse cerebral edema that may occur when an athlete sustains a second head injury before recovering from the initial injury. Since a history of previous impact is always documented, it remains unclear if the excessive inflammatory response occurs due to the repetitive injury or the mild TBI itself. Pediatric and adolescent patients are at the highest risk for this condition, as most cases have occurred in patients of 20 years or younger. POSTCONCUSSION SYNDROME: Postconcussion syndrome is the constellation of symptoms, such as headache, dizziness, inability to concentrate, insomnia, and irritability, experienced by the patient following a concussion. While in most patients these symptoms will quickly begin to resolve, some will have persistent symptoms for weeks, months, or years. It is considered chronic if symptoms persist longer than 1 year. Patients with a history of a previous concussion are at higher risk for prolonged symptoms with repeat head injury. Inadequate concussion management in the acute and subacute stages can also prolong postconcussion syndrome. Neuropsychology consultation may also be utilized for evaluation of persistent symptoms. It is helpful to educate patients at the time of their initial injury regarding common symptoms and the benign self-limited nature of postconcussion syndrome. LONG-TERM EFFECTS: There is some evidence to suggest that chronic neurocognitive impairment can occur in athletes exposed to multiple head injuries. More recently, media and research focus has been on chronic traumatic encephalopathy, a syndrome of progressive cognitive decline and behavior change seen years later in athletes who have sustained multiple head injuries. Some patients may also experience motor symptoms such as tremor, ataxia, and increased tone. Autopsy findings show diffuse brain atrophy and tau deposition.

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COMPREHENSION QUESTIONS 10.1 Which of the following patients should have a CT of the head performed? A. A 27-year-old man who was momentarily dazed after striking his head on a tree branch but is back to baseline within 5 minutes B. An 18-year-old ice hockey player who did not lose consciousness after being hit by a flying puck but did have significant dizziness and ataxia that resolved after 30 minutes C. A 68-year-old man who slipped and hit his head on the pavement, was unconscious for less than 30 seconds, and was back to baseline within 5 minutes D. A 22-year-old patient who suffered a concussion 1 week ago and who continues to have a mild-to-moderate headache 10.2 Which of the following is true regarding return-to-play guidelines for sportsrelated concussions? A. The number of concussions experienced during a season does not matter as long as there is no loss of consciousness. B. A postconcussion-rehabilitation program should be initiated and tailored for each individual case. C. As long as an athlete is symptom-free at rest, they can return to play after the concussion. D. Any loss of consciousness necessitates removing the athlete from play for the remainder of the season. 10.3 A 15-year-old high school athlete suffered a loss of consciousness during football practice. The parents ask about postconcussion syndrome. Which of the following is the most accurate statement regarding this condition? A. It is an uncommon sequelae of traumatic brain injury. B. A characteristic symptom would be progressively increasing lethargy. C. Many high school athletes feign postconcussion symptoms to avoid schoolwork. D. It is usually self-limited and resolves over weeks to months.

ANSWERS 10.1 C. Any patient who has experienced loss of consciousness should have a head CT obtained. Also, patients older than 60 years should be imaged given the higher incidence of hemorrhage with increasing age. 10.2 B. A postconcussion-rehabilitation program should be employed for all players, especially young and adolescent players, to ensure appropriate time for recovery and monitoring.

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10.3 D. Postconcussion syndrome is a common sequelae of head injury and usually resolves over weeks to months. It is not a form of malingering. Progressively increasing lethargy would be concerning for an evolving hemorrhage or other serious process, and the patient would need further evaluation.

CLINICAL PEARLS »»

A concussion is a traumatic injury to the brain as a result of a violent blow, shaking, deceleration, or spinning resulting in altered cerebral function.

»»

No athlete may return to play the same day they sustain a concussion due to the risk of prolonging their recovery and the rare occurrence of second-hit syndrome.

»»

All 50 states have laws regarding concussions in young athletes and return to play. The return-to-play procedure is a multistep progression from no activity to full participation.

»»

Postconcussion syndrome is the constellation of cognitive, physical, affective, and sleep symptoms experienced by a patient after a concussion that may persist for weeks to months in a small number of patients.

»»

Second-hit syndrome is a rare inflammatory reaction of malignant cerebral edema triggered by head injury in young athletes. It can have devastating outcomes, including death.

REFERENCES Giza CC. Pediatric issues in sports concussions. Continuum (Minneap Minn). 2014;20(6):1570-1587. Giza CC, Kutcher JS. An introduction to sports concussions. Continuum (Minneap Minn). 2014; 20(6):1545-1551. Giza CC, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(24):2250-2257. Halstead ME, Walter KD. American Academy of Pediatrics. Clinical report—sport-related concussion in children and adolescents. Pediatrics. 2010;126(3):597-615. Jordan BD. Chronic traumatic encephalopathy and other long-term sequelae. Continuum (Minneap Minn). 2014;20(6):1588-1604. Kutcher JS, Giza CC. Sports concussion diagnosis and management. Continuum (Minneap Minn). 2014;20(6):1552-1569.

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CASE 11 A 68-year-old right-handed woman was brought to the emergency room 30 minutes after suddenly developing speech difficulty and weakness of the right arm and leg. She was found by her family members to be mute and slumped down in her chair. Her past medical history is significant for hypertension and angina, for which she takes atenolol and amlodipine. The patient’s temperature is 36.6°C (98°F); heart rate is 115 beats/min; and blood pressure is 172/86 mm Hg. Her physical examination reveals no carotid bruit, but she has an irregularly irregular cardiac rhythm. Neurologic examination reveals a lethargic but arousable patient who is able to follow some simple commands but has severe impairment of word fluency, naming, and repetition. There is a left gaze deviation and right lower facial droop. There is total paralysis of the right upper extremity and, to a lesser degree, weakness of the right lower extremity. The left side displays full antigravity power without drift for 5 seconds. An electrocardiogram reveals atrial fibrillation. »» »» »»

What is the most likely diagnosis and what part of the brain is likely affected? What is the best next diagnostic step? What is the best next step in therapy?

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ANSWERS TO CASE 11: Acute Cerebral Infarct Summary: A 68-year-old woman presents with 30 minutes of right hemiparesis and aphasia, with vascular risk factors of hypertension and coronary artery disease and physical findings of atrial fibrillation. šš šš

šš

Most likely diagnosis: Acute cerebral ischemia in the left middle cerebral artery Next diagnostic step: Noncontrast computed tomography (CT) scan of the head Next step in therapy: Thrombolytic therapy if eligible by criteria, and consideration of endovascular treatment with embolectomy if appropriate

ANALYSIS Objectives 1. Recognize the clinical presentation of an acute stroke. 2. Be familiar with the evaluation and treatment of stroke. 3. Describe the risk factors and pathophysiology of stroke.

Considerations When a patient presents with the abrupt onset of focal neurologic deficits, the most likely diagnosis is an acute cerebrovascular event. This patient’s neurologic deficits, right hemiparesis of the upper more than lower extremity, aphasia, and gaze deviation point to a perfusion defect in the left middle cerebral artery territory. Focal neurologic deficits can include hemiparesis, hemisensory loss, speech disturbance, hemineglect, homonymous hemianopia, or hemiataxia. Other diagnostic considerations include hypoglycemia, a seizure with postictal Todd paralysis, or complicated migraine. If the acuity of onset is less certain, a brain tumor, subdural hematoma, multiple sclerosis, herpes encephalitis, or a brain abscess can mimic a subacute stroke. The distinction between a stroke and a transient ischemic attack (TIA) rests on the duration of symptoms. The symptoms of a TIA resolve within 24 hours, usually lasting from several minutes to 1 to 2 hours. While the definition of TIA varies in some references, imaging criteria are now the preferred means for determining if an event is a TIA or an infarct. Magnetic resonance imaging (MRI) using a diffusionweighted sequence can reliably determine the presence of an infarct, even if the clinical symptoms have resolved. Furthermore, distinguishing between an ischemic stroke and an intracerebral hemorrhage requires a brain imaging study, either CT or MRI. The etiologies and treatment of ischemic stroke and intracerebral hemorrhage are quite different. Because intervention can improve the outcome, the patient should be rapidly assessed for possible thrombolytic therapy (a hemorrhage on CT is a contraindication for thrombolytics). Recent studies have also pointed to a potential benefit of endovascular treatment with embolectomy or intra-arterial tissue plasminogen

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activator (tPA) for patients with a large proximal occlusion and a salvageable ischemic penumbra or area surrounding the stroke. The treatment of hemorrhagic stroke is primarily supportive and involves controlling hypertension and careful intracranial pressure (ICP) monitoring. If there is any evidence of elevated ICP, treatment strategies include hyperventilation, osmotic therapy, and, occasionally, surgical decompression with hemicraniectomy and durotomy.

APPROACH TO: Acute Cerebral Infarct DEFINITIONS ISCHEMIC STROKE: Cerebral infarction associated with acute neurologic symptoms. TRANSIENT ISCHEMIC ATTACK (TIA): A cerebral ischemic event associated with focal neurologic deficits lasting less than 24 hours with no evidence of cerebral infarction on brain imaging, preferably MRI. INTRACEREBRAL (OR INTRAPARENCHYMAL) HEMORRHAGE: A cerebrovascular event characterized by arterial rupture and parenchymal hemorrhage. HOMONYMOUS HEMIANOPIA: The loss of one-half of the field of view on the same side in both eyes. TODD PARALYSIS: A brief period of temporary paralysis following a seizure.

CLINICAL APPROACH Stroke, or cerebrovascular accident (CVA), is a neurologic deficit of sudden onset attributable to the loss of perfusion of a portion of the brain from vascular occlusion or hemorrhage. Ischemic stroke is caused by vascular insufficiency, whereas hemorrhagic stroke is associated with mass effect or cytotoxicity related to a parenchymal hematoma. Understanding the vascular supply to the brain can help in correlating the neurologic finding to the affected artery. The carotid arteries are the vascular supply for the frontal and parietal lobes and most of the temporal lobes and basal ganglia. The main branches of the carotid artery are the middle cerebral and the anterior cerebral arteries. The vertebrobasilar territory encompasses the brainstem, cerebellum, occipital lobes, and thalami. The posterior inferior cerebellar artery is the only large artery that arises directly from the vertebral artery. The posterior cerebral, superior cerebellar, and anterior inferior cerebellar arteries are branches of the basilar artery. When a patient presents with weakness, sensory loss, or speech difficulties, a brain imaging study such as a CT or MRI is necessary to distinguish between an ischemic stroke and an intracerebral hemorrhage and to help rule out a stroke mimic. In general, CT is preferred in the acute setting because it is readily available, accurate for the detection of blood, and rapid. MRI is more sensitive for detecting

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acute ischemia; however, it is rarely necessary in the first few hours of stroke evaluation and can be performed after a patient is stabilized and able to lie still. An electrocardiogram and laboratory studies including a complete blood count, glucose, prothrombin time (PT), and partial thromboplastin time (PTT) are also essential. With recent studies showing the potential benefit of endovascular embolectomy or thrombectomy, vascular imaging with CT angiogram or CT perfusion may be pertinent in determining an appropriate candidate for this added treatment. A patient with an acute intraparenchymal hemorrhage should be admitted to the intensive care unit (ICU) in most circumstances for at least 24 hours of monitoring and blood pressure lowering. A patient with an ischemic stroke may not require ICU care but should be admitted to a specialized unit that provides neurologic and cardiac monitoring. Intravenous (IV) fluids to maintain euvolemia (normal volume status) should be considered, and dysphagia should be evaluated to avoid potential aspiration pneumonia. All patients with stroke, either hemorrhagic or ischemic, should have prophylaxis for deep venous thrombosis, albeit nonpharmacologic in the first days after a hemorrhagic stroke. Hypertension is often encountered in the stroke patient; in general, the blood pressure should be monitored and if necessary, it can be cautiously lowered in the first few days of an ischemic stroke. Abrupt lowering of the blood pressure is not recommended and may worsen collateral flow to the ischemic penumbra. Conversely, accelerated hypertension will place a patient at risk of hemorrhagic conversion. A judicious approach to blood pressure control, informed by the size of the infarct, the patient’s preexisting blood pressure, and the mechanism of the infarct, is more appropriate than following precise numerical goals. In addition to a CT and MRI (if possible), the diagnostic evaluation for an ischemic stroke may include a carotid ultrasound, transcranial Doppler, echocardiogram, magnetic resonance angiogram of the head and neck, and/or a cerebral arteriogram. Cardiac telemetry monitoring for at least 24 hours while in the acute setting is recommended to rule out any arrhythmias that may change treatment for secondary stroke prevention. A fasting lipid panel and hemoglobin A1C are usually warranted. Other laboratory studies are low yield but may be considered if there is a valid clinical suspicion; these studies include serum B12, folate, homocysteine levels, erythrocyte sedimentation rate (ESR), rapid plasma reagent (RPR), human immunodeficiency virus (HIV), and toxicology screens.

Etiologies The most common etiologies of ischemic stroke include cardiac embolism, largevessel atherothrombosis, and small-vessel intracranial occlusive disease, although the comprehensive list of potential stroke etiologies is quite extensive (see also Case 13). As many as 30% of ischemic strokes remain cryptogenic (without discernible etiology) after a thorough diagnostic evaluation. Acknowledged sources of cardiac embolism to the brain include atrial fibrillation, mechanical prosthetic heart valves, acute myocardial infarction, low left ventricular ejection fraction less than 30%, focal myocardial hypokinesis, patent foramen ovale, and endocarditis. Large-vessel atherosclerosis can affect the carotid bifurcation, the major intracranial vessels, or the extracranial vertebral artery. Small-vessel strokes, also known as lacunar strokes, are often characterized by classic clinical

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syndromes (pure motor stroke or pure sensory stroke, ataxic hemiparesis, dysarthria/ clumsy hand) and are related to occlusive disease of penetrating arteries in the brain usually associated with hypertension and/or diabetes. Major risk factors for stroke are similar to those of coronary heart disease and include age, hypertension, smoking, diabetes, hyperlipidemia, heart disease, and family history.

CLINICAL PRESENTATION Hemiparesis involving mostly the right arm, aphasia, and left gaze deviation point to an anatomic localization in the left middle cerebral artery territory (Figure 11–1). Cortical symptoms such as aphasia (impairment of the ability to use or comprehend words), hemineglect, agnosia (loss of ability to recognize objects, persons, sounds, shapes, or smells), and apraxia (loss of the ability to execute or carry out learned purposeful movements) indicate a lesion in the anterior (or carotid) circulation. Symptoms such as diplopia, vertigo, crossed facial and body findings, and homonymous hemianopia, however, suggest a posterior (or vertebrobasilar) circulation lesion. The symptoms of an intracerebral hemorrhage cannot be reliably distinguished from those of an ischemic stroke on clinical grounds alone. The presence of headache, depressed level of consciousness, or extreme elevations in blood pressure, however, can raise the suspicion of a hemorrhagic stroke.

Treatment Treatment of ischemic stroke begins with assessment of eligibility for thrombolysis. Treatment must be initiated urgently. IV tPA can significantly improve the odds of

Figure 11–1.  Noncontrast axial CT image of a subacute left major coronary artery infarction. (Reproduced, with permission, from Chen MY, Pope TL, Ott DJ. Basic Radiology. New York, NY: McGraw-Hill; 2004:338.)

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neurologic recovery but must be administered within 4.5 hours of onset of stroke symptoms. tPA is associated with a risk, albeit minimal if contraindications have been ruled out, of hemorrhagic conversion of an ischemic infarct. Thus, urgent imaging of the brain such as a CT scan is imperative to assess for hemorrhagic stroke. Contraindications to tPA include active bleeding, recent stroke, or a history of intracerebral hemorrhage. Recent studies have shown benefits of intra-arterial endovascular therapy for patients with proximal anterior circulation occlusions within 6 hours of symptom onset. Other studies have shown benefits of endovascular treatment up to 8 hours after onset of symptoms. In these cases, screening patients with moderate to severe strokes with vascular imaging, such as CT angiogram, may be useful since neurointervention may be indicated if a large-vessel occlusion is present. Other acute stroke treatments are currently under investigation and could in the near future include administration of IV tPA in the field via the Mobile Stroke Unit as well as neuroprotective therapies. Patients who are not candidates for thrombolytic or endovascular therapy should be acutely treated with aspirin unless contraindicated. Secondary stroke prevention should be implemented. Antiplatelet drugs such as aspirin, clopidogrel, or the combination of aspirin and extended-release dipyridamole are the mainstays of stroke prevention treatment for most patients with ischemic stroke and TIA. Patients with high-risk cardioembolic conditions such as atrial fibrillation, however, warrant long-term anticoagulation with warfarin or another novel oral anticoagulant, which has been demonstrated to be superior to antiplatelet treatment for this indication. Newer oral anticoagulants, such as dabigatran, rivaroxaban, edoxaban, and apixaban, have had success to varying degrees in clinical trials, and for some patients they may be safer and more effective than warfarin. Risk factor management is crucial to preventing recurrent stroke. Long-term control of hypertension is most important. Treatment should be initiated as soon as a patient is stable after an ischemic stroke. Statins for hyperlipidemia lower the odds of stroke recurrence, and current guidelines recommend a target low-density lipoprotein (LDL) of under 100 mg/dL. Ipsilateral carotid stenosis of greater than 50% in a patient with ischemic stroke or TIA is an indication for carotid endarterectomy or, in a patient who is at high surgical risk, carotid stenting. Rehabilitation is especially beneficial for patients who have gait difficulty or aphasia or who require assistance with activities of daily living. It can especially help with resuming gainful employment after a stroke. The treatment of hemorrhagic stroke is primarily supportive and involves control of hypertension. ICP monitoring may be considered if the Glasgow coma scale is less than 8, and if the ICP is elevated, it can potentially be addressed with osmotic therapy. Surgical decompression remains an unproven strategy in hemorrhagic stroke but may be considered, especially in cases where hemicraniectomy may relieve cerebral edema. IV thrombolytic therapy is contraindicated.

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CASE CORRELATION šš

See also Case 13 (Stroke in a Young Patient)

COMPREHENSION QUESTIONS 11.1 An 81-year-old patient arrives in the emergency department with acute left hemiparesis and neglect. What finding is most important in determining eligibility for thrombolytic treatment? A. Time of last known well less than 4.5 hours B. History of any previous myocardial infarction C. Patient taking any antihypertensive medication D. Distant history of gastrointestinal (GI) bleeding 11.2 For this patient in Question 11.1, what study is most useful to rule out an intracerebral hemorrhage? A. Electrocardiogram B. Noncontrast head CT C. Complete blood count D. Cerebral arteriogram 11.3 After receiving stroke therapy, this patient is being discharged home on physical therapy. The usual treatment would include long-term medical management with antiplatelet or anticoagulation. If present, which of the following conditions would benefit most from anticoagulation instead of antiplatelet therapy? A. Diabetes B. Ischemic heart disease C. Carotid stenosis D. Atrial fibrillation

ANSWERS 11.1 A. A patient is potentially eligible for thrombolysis if they were last known well within 4.5 hours. 11.2 B. The noncontrast CT scan of the head is a rapid and reliable test to assess for cerebral hemorrhage. 11.3 D. When atrial fibrillation is present, anticoagulation is preferred over antiplatelet therapy.

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CLINICAL PEARLS »»

Sudden onset of focal neurologic deficits equals stroke until proven otherwise.

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Time is brain; treat ischemic stroke with thrombolytics within 4.5 hours to preserve brain tissue and assess for a potential benefit of endovascular/intra-arterial therapy if within 6 hours.

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Stroke risk factors are similar to those of ischemic heart disease, such as hypertension, hyperlipidemia, diabetes, and smoking.

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Cortical symptoms suggest a carotid territory stroke; brainstem or cerebellar findings suggest a vertebrobasilar territory stroke.

REFERENCES Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11-20. Mohr JP, Wolf PA, Grotta J, et al. Stroke: Pathophysiology, Diagnosis, and Management. 5th ed. New York, NY: Elsevier; 2011. Ropper AH, Brown RH. Adams and Victor’s Principles of Neurology. 8th ed. New York, NY: McGraw-Hill; 2005.

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CASE 12 A 50-year-old woman is brought to the emergency department (ED) after experiencing a sudden onset of severe headache associated with vomiting, neck stiffness, and left-sided weakness. She was noted to complain of the worst headache of her life shortly before she became progressively confused. Two weeks ago, she returned from jogging and noted a moderate headache with nausea and photophobia. She has a history of hypertension and tobacco use. On examination, her temperature is 37.6°C (99.8°F); heart rate is 120 beats/min; respiration rate is 32 breaths/min; and blood pressure is 180/90 mm Hg. She is stuporous and moaning incoherently. Her right pupil is dilated with papilledema and ipsilateral ptosis, and she vomits when a light is shone in her eyes. She has a left lower face droop and does not withdraw her left arm and leg to pain as briskly compared to the right. Her neck is rigid. Her chest examination reveals tachycardia and bibasilar crackles. During the examination, her head suddenly turns to the left, and she exhibits generalized tonic-clonic activity that lasts approximately 2 minutes before spontaneously abating. STAT laboratory tests show a sodium level of 125 mEq/L. The electrocardiograph (ECG) shows broad, deeply inverted T waves and a prolonged QT interval. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 12: Subarachnoid Hemorrhage Summary: A 50-year-old woman with a history of hypertension and tobacco use presents with sudden onset of the worse headache of her life associated with confusion, vomiting, neck stiffness, and left-sided weakness. She was noted to complain of a headache 2 weeks ago. She is now hypertensive. Her neurologic examination is significant for stupor, right cranial nerve III paralysis, left-sided weakness, neck stiffness, and a new-onset seizure. Her workup is significant for hyponatremia and ECG changes. šš

Most likely diagnosis: Subarachnoid hemorrhage

šš

Next diagnostic step: Noncontrast computed tomography (CT) of the head

šš

Next step in therapy: Cerebral angiography

ANALYSIS Objectives 1. Identify the epidemiology and risk factors for subarachnoid hemorrhage. 2. Understand the prognosis and complications of subarachnoid hemorrhage. 3. Know a diagnostic and therapeutic approach to subarachnoid hemorrhage.

Considerations This 50-year-old woman has multiple risk factors for subarachnoid hemorrhage caused by an underlying aneurysm: (a) her age (mean age for subarachnoid hemorrhage is 50); (b) gender (slightly higher risk for females); (c) hypertension; and (d) tobacco use. The complaint of “the worst headache of my life” to describe its sudden severe onset is classic, and it may or may not be associated with altered mentation and focal neurologic deficits. There is usually a history of a recent moderate headache as a result of a sentinel bleed, as in her case after running. Approximately 60% of subarachnoid hemorrhages occur during physical or emotional strain, head trauma, defecation, or coitus. The clinical severity of a subarachnoid hemorrhage is graded based on the degree of stupor, nuchal rigidity, focal neurologic deficits, and elevation of intracranial pressure (ICP). This patient exhibits neurogenic pulmonary edema, one of the many systemic complications of subarachnoid hemorrhage. Her neurologic signs localize to a ruptured right posterior communicating artery aneurysm, with the bleed causing compression of the nearby ipsilateral cranial nerve III with mydriasis, ptosis, and impaired extraocular movements. Her contralateral hemiparesis and complex partial seizure with secondary generalization can result from either parenchymal extension of the hemorrhage, edema, or middle cerebral artery (MCA) vasospasm, all three of which are complications of subarachnoid hemorrhage. Hyponatremia is frequently seen on chemistries, correlating with an elevation of

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atrial natriuretic factor, cerebral salt wasting, and/or the syndrome of inappropriate antidiuretic hormone (SIADH). ECG changes, especially QT prolongation, T-wave inversion, and arrhythmias, are also systemic complications common to subarachnoid hemorrhage.

APPROACH TO: Subarachnoid Hemorrhage DEFINITIONS SUBARACHNOID SPACE: The spongy potential space between the arachnoid mater and the pia mater. The headache and nuchal rigidity are caused by chemical inflammation of the pia and arachnoid from blood degradation products in this space. SENTINEL BLEED: Intermittent aneurysmal subarachnoid hemorrhage causing lesser headaches that precede the “worst headache” that occurs with rupture of the aneurysm. VASOSPASM: Most alarming complication of aneurysmal subarachnoid hemorrhage in which irritation causes constriction of major cerebral arteries, vasospasm, lethargy, and delayed cerebral infarction. Vasospasm occurs mostly with aneurysms rather than other causes of subarachnoid hemorrhage, and it peaks between 4 and 14 days. Transcranial Doppler can be used to detect a change in flow velocity in an affected MCA. ACUTE COMMUNICATING HYDROCEPHALUS: Complication that occurs because of obstruction of the subarachnoid granulations in the venous sinuses by the subarachnoid blood. CT shows enlarged lateral, third, and fourth ventricles, with clinical signs of headache, vomiting, blurry and double vision, somnolence, and syncope.

CLINICAL APPROACH Etiologies Subarachnoid hemorrhage is the underlying cause of approximately 10% of stroke presentations and results from a number of etiologies. Ruptured saccular or berry aneurysms account for up to 80% of nontraumatic subarachnoid hemorrhage and portend the worst prognosis. More than three-fourths of intracerebral aneurysms arise in the anterior circulation. The most frequent sites of aneurysms are in the anterior communicating artery (up to one-third of aneurysmal subarachnoid hemorrhages), followed by the bifurcation of the internal carotid artery with the posterior communicating artery and then by the bifurcation of the internal carotid artery with the MCA. One-fourth of patients will have more than one aneurysm, with risk for rupture increasing with the size of the aneurysm. Fibromuscular dysplasia is an associated etiology in one-fourth of aneurysm patients, whereas polycystic kidney disease is related to 3% of cases. Other risk factors for aneurysms include chronic

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severe hypertension with diastolic blood pressure greater than 110 mm Hg, liver disease, tobacco and alcohol use, vasculitides, collagen vascular disorders such as Marfan syndrome, infections (mycotic aneurysms), and oral contraception. Nonaneurysmal causes of subarachnoid hemorrhage include trauma, arteriovenous malformations, and cocaine or amphetamine abuse.

Diagnosis and Prognosis CT of the head without contrast is the most sensitive neuroimaging study for detecting subarachnoid bleeding, appearing as hyperdensity within the cerebral convexities, cisterns, and parenchyma (Figure 12–1). Intraventricular hemorrhage portends a worse prognosis and increased risk for hydrocephalus. Sensitivity of CT is greatest 24 hours after the event, with 50% of cases still detectable after 1 week. Negative CT of the head occurs in 10% to 15% of cases and should be further evaluated with lumbar puncture looking for xanthochromia (yellowish discoloration of cerebrospinal fluid [CSF]) and increased red blood cells. CSF studies are most sensitive 12 hours after onset but can be negative in 10% to 15% of patients, in which case the prognosis is better. CT, magnetic resonance imaging (MRI), or conventional angiography can be used to screen for an underlying aneurysm (Figure 12–2).

Figure 12–1.  Noncontrast CT scan subarachnoid blood in the left sylvian fissure (bright) and within the left lateral ventricle. (Reproduced, with permission, from Kasper DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2004:2389.)

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Figure 12–2.  Conventional angiogram of the right vertebral and basilar artery showing the large aneurysm. (Reproduced, with permission, from Kasper DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2004:2389.)

Up to 60% of patients die in the first 30 days after a subarachnoid hemorrhage, 10% instantly without warning. First month mortality is 40% for hospitalized patients, with worsening of mortality to 50% to 80% with rebleeding. Severity of cases and their prognoses can be graded using a variety of scales. One of the most common is the Hunt and Hess scale based on alertness and presence of focal signs: šš

šš

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Grade I subarachnoid hemorrhage patients are alert with mild headache and nuchal rigidity and have a 5% chance of deteriorating with a 3% to 5% mortality risk. Grade II patients have moderate-to-severe headache and nuchal rigidity and a 6% to 10% mortality risk. Grade III is similar to Grade II but with drowsiness, confusion, and a mild focal deficit. Grade IV patients have stupor and moderate-to-severe hemiparesis. Grade V patients are comatose with signs of severe increased ICP, and they have the worst prognosis with 80% chance of deteriorating, 25% to 30% rebleeding rate, and 50% to 70% mortality risk. Delayed vasospasm is a potentially serious complication that occurs in up to 20% of cases.

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Treatment Grades I and II subarachnoid hemorrhage may be observed after diagnostic measures. Emergent conventional angiography is warranted if ruptured aneurysm is suspected and neurosurgical intervention is required. Repeat angiography can be necessary if the underlying etiology is obscured by vasospasm. Endovascular coiling is indicated to reduce rebleeding in low-grade cases of subarachnoid hemorrhage and has been shown to be superior to clipping. Clipping should be performed in the first 48 hours after onset or be delayed for 2 weeks to avoid the window of greatest risk for vasospasm, especially with complicated high-grade cases. The most notable complication of subarachnoid hemorrhage is delayed cerebral ischemia, which may be secondary to vasospasm or microthrombi. To avoid this often fatal complication, it is essential to support cerebral perfusion by administering fluids with the goal of euvolemia and allowing some degree of hypertension. Nimodipine, a calcium channel blocker, is often utilized to reduce vasospasm. It is also important to address other complications, including metabolic derangements (hyponatremia, SIADH, cerebral salt wasting), respiratory (neurogenic pulmonary edema) and cardiac (arrhythmias) complications, seizures, and hydrocephalus, which may require ventriculostomy.

COMPREHENSION QUESTIONS Match the following etiologies (A-C) to the clinical situation of Questions 12.1 to 12.3: A. Anterior communicating artery aneurysm B. Posterior communicating artery aneurysm C. Vasospasm 12.1 A 35-year-old woman was admitted last week for a subarachnoid hemorrhage caused by a left MCA aneurysm. Today during rounds, she appears much less alert. 12.2 A 45-year-old man with a history of alcohol consumption complains of a “thunderclap headache,” nausea, and blurry vision with right anisocoria and diplopia on examination. 12.3 A 20-year-old woman is found to have hypertension, kidney cysts, and intermittent headaches. 12.4 An emergency room physician consults you for the best first study to evaluate a possible subarachnoid hemorrhage in a 54-year-old woman who came in for severe headache. A. Transcranial Doppler study B. Electroencephalograph (EEG) C. Positron emission tomography (PET) scan of the brain D. CT scan of the head without contrast E. MRI of the brain without contrast

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12.5 An internist consults you for the best study to evaluate for the possible development of vasospasm 1 week after admission for a subarachnoid hemorrhage. Which of the following would be the most appropriate first study? A. Transcranial Doppler study B. EEG C. PET scan of the brain D. CT scan of head without contrast E. MRI of the brain without contrast

ANSWERS 12.1 C. Delayed vasospasm (and acute hydrocephalus) can arise days after a ruptured aneurysm with subarachnoid hemorrhage. Emergent neuroimaging should be performed to assess the need for angiography or ventriculostomy. 12.2 B. Ipsilateral ptosis, pupil dilation, and ophthalmoplegia result from compression of the third nerve by a posterior communicating artery aneurysm and bleed. 12.3 A. The most common site for a cerebral aneurysm in polycystic kidney disease is in the anterior communicating artery, although multiple aneurysms may be observed. 12.4 D. CT of the head without contrast is a rapid and sensitive imaging modality to detect subarachnoid blood. If it is negative and a high suspicion remains, a lumbar puncture should be performed. 12.5 A. Transcranial Doppler is sensitive for detecting elevated MCA velocity, a finding caused by vasospasm, although conventional angiography is usually needed to confirm vasospasm. For acute changes in level of consciousness, CT of the head is preferred as a faster way to evaluate for hydrocephalus and need for ventriculostomy.

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CLINICAL PEARLS »»

Most cases of subarachnoid hemorrhage with no history of head trauma are caused by an underlying aneurysm.

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Subarachnoid hemorrhage severity and prognosis can be assessed by the degree of change in consciousness, headache, nausea and vomiting, nuchal rigidity, focal deficits, and seizures.

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Mass effect from edema and parenchymal spread, vasospasm from subarachnoid involvement, and hydrocephalus from intraventricular spread are all serious delayed neurologic complications of subarachnoid hemorrhage that may not be apparent on the initial evaluation.

»»

Ensuring euvolemic volume status and using nimodipine are important parts of medical management of subarachnoid hemorrhage. Endovascular coiling and clipping are surgical options with appropriate windows of intervention.

REFERENCES Al-Shahi R, White PM, Davenport RJ, Lindsay KW. Subarachnoid haemorrhage. BMJ. 2006; 333(7561):235-240. Dority JS, Oldham JS. Subarachnoid hemorrhage: an update. Anesthesiology Clin. 2016;34(2):577-600. Feigin VL, Findlay M. Advances in subarachnoid hemorrhage. Stroke. 2006;37(2):305-308.

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CASE 13 A 22-year-old previously healthy college student presents to the emergency department with a chief complaint of gait instability and a right eyelid droop. He began noticing these symptoms 2 days ago, the morning after a friend put him in a choke hold during a wrestling match. He managed to break free after a struggle and subsequently noticed a right temporal headache after the wrestling match. The patient’s temperature is 36.4°C (97.6°F); heart rate is 64 beats/min; and blood pressure is 118/78 mm Hg. General physical examination is unremarkable. The neurologic examination reveals ptosis of the right eye and anisocoria, with a pupillary diameter of 2 mm on the right and 4 mm on the left. Light reactivity is intact directly and consensually. Extraocular movements are normal. There is a mild left hemiparesis involving the left lower face and left arm and leg. His has a hemiparetic gait and tends to fall to the left without assistance. The electrocardiogram (ECG) is normal. Complete blood count, electrolytes, blood urea nitrogen (BUN), creatinine, glucose, urinalysis, prothrombin time (PT), and partial thromboplastin time (PTT) are normal. Noncontrast computed tomography (CT) of the head shows an area of a hypodensity in the right frontal-parietal region. »» »»

What is the most likely diagnosis and mechanism? What is the next diagnostic step?

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ANSWERS TO CASE 13: Stroke in a Young Patient (Acute Ischemic) Summary: A 22-year-old man presents with a right Horner syndrome and right hemispheric ischemic stroke after relatively minor trauma to his neck. šš

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Most likely diagnosis and mechanism: Acute ischemic stroke caused by right carotid artery dissection as a result of trauma Next diagnostic step: Cerebral arteriogram

ANALYSIS Objectives 1. Understand the signs and symptoms of stroke. 2. Recognize the less typical stroke etiologies that often affect younger patients. 3. Be familiar with the diagnostic workup of stroke in a young patient.

Considerations The diagnosis of a stroke relies on an appropriate clinical history, neurologic findings, and supportive brain and often vascular imaging studies. Although the majority of strokes occur in patients 65 years or older, many strokes occur in patients 55 years or younger. Just as in older patients, a stroke should be suspected in a younger patient presenting with acute/subacute focal neurologic deficits. In the case presented, a “choke hold” injured the patient’s right carotid artery, leading to ischemia to the right side of the brain and associated structures supplied by the right carotid artery.

APPROACH TO: Stroke in a Young Patient DEFINITIONS CAROTID DISSECTION: A tear in the carotid arterial wall can result in luminal obstruction, thromboembolic complications, and/or pseudoaneurysm formation. Dissections can also occur in the vertebral arteries, or less commonly, the large intracranial arteries. PATENT FORAMEN OVALE (PFO): A persistent opening in the interatrial septum associated with paradoxical embolism in patients with cryptogenic stroke. ARTERIOVENOUS MALFORMATIONS: Congenital high-pressure, high-flow cerebral vascular malformations characterized by direct arteriovenous shunting.

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CLINICAL APPROACH The diagnostic evaluation in a younger patient suffering from a stroke is typically more extensive than an older individual because of the greater likelihood of a nonatherosclerotic etiology. Some of these thrombophilia conditions are discussed next. The workup may include brain magnetic resonance imaging (MRI), cerebral computed tomography angiography (CTA) or magnetic resonance angiography (MRA) of the intracranial and cervical vessels, transesophageal echocardiogram, and laboratory studies including lipid panel, homocysteine levels, protein C, protein S, antithrombin III, anticardiolipin antibody, lupus anticoagulant, factor V Leiden mutation, prothrombin gene mutation, and a toxicology screen. Other studies that can be indicated in the appropriate clinical setting might include lumbar puncture to evaluate for infection/inflammation, blood cultures, vasculitis serologies, screening for HIV or sickle cell disease, Holter monitoring, and “formal” cerebral angiography.

ETIOLOGIES AND CLINICAL PRESENTATIONS The same causes of stroke in older patients can affect younger adults, especially in younger patients who possess the traditional atherosclerotic risk factors such as hypertension, coronary heart disease, diabetes mellitus, and hyperlipidemia. The largest categories of stroke in the general population are cardioembolic, large-vessel atherothrombotic, and lacunar infarcts. A patent foramen ovale (PFO) is detectable in approximately 15% to 30% of the general population, but its prevalence is higher in younger patients with cryptogenic ischemic stroke. The mechanism is presumed to be paradoxical embolism. Transesophageal echocardiography (TEE) is the most common tool to detect a PFO, although its sensitivity is impaired by the need to sedate a patient for the examination. Alternatively, a transcranial Doppler bubble study is highly sensitive for a right-to-left cardiac shunt but may result in false positives from a noncardiac source, such as a pulmonary arteriovenous malformation (AVM). Atrial septal aneurysms are also linked to cryptogenic stroke and best evaluated by TEE. The clinical manifestations of arterial dissections depend on the vessel involved. Carotid artery dissections typically begin with ipsilateral neck pain or headache and a Horner syndrome (ipsilateral ptosis, miosis, and depending on the location of the dissection, anhydrosis) followed by retinal or cerebral ischemia. The presence of any two of the three elements in the triad strongly suggests the diagnosis of carotid dissection. Craniocervical dissection is commonly, but not always, preceded by head or neck trauma such as a motor vehicle accident, chiropractic neck manipulation, or a bout of severe coughing, vomiting, or sneezing (Figure 13–1). Fibromuscular dysplasia, Ehlers-Danlos syndrome, and Marfan syndrome are predisposing conditions for spontaneous craniocervical dissection due to associated pathology of the arterial wall. Conversely, vertebral artery dissections typically present with occipitocervical pain, which may be followed by a variety of posterior circulation ischemic symptoms including vertigo, dysarthria, visual field deficit, ataxia, and diplopia. AVMs and the lower-flow cavernous angiomas are associated with intracerebral hemorrhage as well as seizures and other neurologic presentations.

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Figure 13–1.  Cerebral arteriogram of internal carotid artery (ICA) dissection. (Reproduced, with permission, from Brunicardi FC, et al. Schwartz’s Principles of Surgery. 8th ed. New York, NY: McGraw-Hill; 2004:Fig. 22–92.)

Moyamoya disease is an idiopathic noninflammatory cerebral vasculopathy characterized by progressive occlusion of the large arteries at the circle of Willis, most commonly the distal internal carotid artery. The characteristic moyamoya vessels refer to collateral circulation formed by the small penetrating arteries that hypertrophy in response to chronic cerebral ischemia, which have the appearance of a puff of smoke, which is roughly what moyamoya means in Japanese. Drugs of abuse, especially cocaine and amphetamines, are associated with both ischemic and hemorrhagic stroke. Oral contraceptives are a risk factor for thromboembolic stroke, especially in women older than 35 years who smoke. A history of intravenous drug abuse should raise the suspicion of endocarditis and HIV disease. Other rarer infectious etiologies of stroke include tuberculous meningitis and varicella zoster. Hypercoagulable conditions can also predispose to stroke. These include malignancy, antiphospholipid antibodies, protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden mutation, prothrombin gene mutation, and hyperhomocysteinemia. Some of these entities are most clearly linked to venous thromboembolism, which is particularly relevant to patients with cerebral venous thrombosis or a PFO.

Treatment Treatment is tailored to the specific stroke etiology. Antithrombotic drugs are a mainstay of secondary prevention and therapy for most patients with ischemic stroke. Very few randomized clinical trials have been performed to help guide the choice

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of antiplatelet or anticoagulant treatment for the specific stroke subtypes discussed above. One such trial revealed no significant difference between aspirin and warfarin in patients with ischemic stroke associated with an antiphospholipid antibody. Similar studies comparing aspirin to anticoagulation in cervical artery dissections have shown no significant difference in efficacy. Endovascular closure of PFO is currently under investigation and not recommended outside of a clinical trial. Because a substantial proportion of carotid or vertebral dissections spontaneously recanalize, stenting is usually reserved for patients who show no vessel recanalization after 3 to 6 months or who have unstable-appearing pseudoaneurysms. The treatment of AVMs can employ a combination of surgery, radiation, and endovascular therapies. Surgical revascularization procedures such as encephaloduroarteriosynangiosis or superficial temporal artery–middle cerebral artery (STA-MCA) bypass are frequently performed for moyamoya disease.

COMPREHENSION QUESTIONS 13.1 As compared to stroke in patients younger than 55, which of the following risk factors is more common in an individual older than 55? A. Atrial fibrillation B. PFO C. Carotid dissection D. Moyamoya disease 13.2 A 45-year-old woman is brought into the emergency room with symptoms of an acute stroke. She has a history of two miscarriages and unexplained leg cramping. Which of the following is most likely to be present in this patient’s condition? A. An arteriovenous malformation B. Elevated antiphospholipid antibodies C. Moyamoya disease D. Carotid dissection 13.3 An 18-year-old man is seen by his pediatrician for right-sided arm weakness. The pediatrician is suspicious of a PFO. Which of the following is the best examination to confirm this finding? A. ECG B. Auscultation of the heart C. Echocardiogram D. Arterial blood gas

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ANSWERS 13.1 A. Atrial fibrillation is more common in older adults. This predisposes patients to an intramural thrombus forming in the left atrium, which may embolize to the brain. The other etiologies (carotid dissection, moyamoya, PFO) are more common in a young patient presenting with a stroke. 13.2 B. Antiphospholipid antibody syndrome is a known cause of arterial and venous hypercoagulability and recurrent miscarriages. In this patient, who manifests other symptoms of the antiphospholipid antibody syndrome, anticoagulation is appropriate. On the other hand, in a patient with an isolated laboratory value showing antiphospholipid antibodies and stroke but no other symptoms, antiplatelet therapy has been proven to be equally efficacious as anticoagulation. 13.3 C. Most patients with a PFO are asymptomatic; however, when the patient gets older, a small deep vein thrombosis (DVT) (usually in the lower extremities) can then embolize, traveling from the right side of the heart to the left side of the heart and to the brain, leading to TIA or stroke. This patient is only 18 years old and a search for venous thromboembolism and thrombophilia workup are important. TEE is the best method to detect a PFO.

CLINICAL PEARLS »»

Horner syndrome in a patient with headache and recent head or neck injury suggests carotid or vertebral dissection.

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An etiology often discovered in a young patient with cryptogenic stroke is a PFO.

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The young patient is more likely to have an “unusual” cause of stroke, although in up to 10% of patients no etiology is found.

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Approximately 10% to 14% of ischemic strokes occur in adults ages 18 to 45 years.

REFERENCES Mohr JP, Wolf PA, Grotta J, et al. Stroke: Pathophysiology, Diagnosis, and Management. 5th ed. New York, NY: Elsevier; 2011. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;e29-e322. Ropper AH, Brown RH. Adams and Victor’s Principles of Neurology. 8th ed. New York, NY: McGraw-Hill; 2005.

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CASE 14 A 23-year-old graduate student was studying late at night for an examination. He recalls studying, but his next memory is being on the floor and aching throughout his body. He was incontinent of urine but not stool, and he felt slightly confused. No one was with him, and he did not know what to do. He called his mother, who recommended that he go to the local emergency room. The student was too busy and decided not to go to the hospital. He visited the school infirmary the next day, and the school physicians examined him. His vital signs were normal, and the neurologic examination, including motor and sensory evaluation, reflexes, and cranial nerve function, was normal. His entire neurologic and physical examinations were normal. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 14: New-Onset Seizure, Adult Summary: A 23-year-old man lost consciousness and when he awoke, he was confused, incontinent of urine, and had muscle soreness. His examinations, including neurologic examination the following day, were normal. šš šš

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Most likely diagnosis: Seizure Next diagnostic step: Electroencephalograph (EEG), magnetic resonance imaging (MRI) of the brain, and routine laboratory values Next step in therapy: Potential anticonvulsant medication, discuss driving

ANALYSIS Objectives 1. Distinguish the diagnostic approach for the first seizure in an adult, including the importance of the history, examination, and testing. 2. Understand the different types of therapy and arguments for and against treatment of the first seizure. 3. Describe the recommended evaluation and appropriate follow-up for the patient.

Considerations This young man had an episode in which he lost consciousness. If someone briefly has loss of consciousness and experiences subsequent confusion, he or she probably had a seizure unless he or she sustained a concussion. The diffuse muscle aches also suggest generalized tonic-clonic activity. Further, the urinary incontinence also suggests seizure, although if someone experienced syncope and had a full bladder, he or she might also have urinary incontinence. Stool incontinence, which this patient did not have, usually suggests seizure and is rare with syncope. It is important to determine whether this patient had previous seizures or previous episodes of loss of consciousness (he did not). It is also important to determine whether he has a family history of seizures, which he does not. Last, one needs to determine whether he had any predisposing factors to seizures, such as increased alcohol consumption, drugs that can lower seizure threshold (eg, cocaine, amphetamines, diphenhydramine, or antibiotics), or sleep deprivation. The patient described in this case stayed up late, and sleep deprivation could have lowered his seizure threshold. Adult-onset seizure is caused by tumor or stroke until proven otherwise, but most young patients are found to have epilepsy without ascertainable cause. They need to be evaluated thoroughly with the suggested modalities discussed in the following text. The EEG is an important assessment to determine a baseline and identify a possible epileptogenic focus; however, the diagnosis of seizure rests with the history, not EEG testing. EEGs examine the electrical activity of the brain but may

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only indicate real-time abnormalities. A normal EEG performed today does not preclude abnormal brain wave activity in the past. Neuroimaging, preferably an MRI of the brain, is recommended to evaluate for a possible underlying structural or vascular etiology. Routine laboratory studies should be obtained to assess for a metabolic derangement that can lower the seizure threshold, such as hypoglycemia or hyponatremia. Elevated white counts can point to infections or generalized convulsions, depending on the clinical presentation. Patients need to be instructed to contact the Department of Public Safety regarding their driving and cautioned about being in situations in which they can harm themselves (ie, being on a roof, swimming alone, scuba diving, etc) if they have a seizure. Rules concerning driving vary by states. Some states require physicians to report all seizures to their driving agencies. It is important to document the advice given to patients. Some physicians ask their patients to sign a statement that they have been informed of their obligation to report themselves to the driving agency for their state and that they are not allowed to drive. The physician should also discuss the indication, dosing, and side effects of anticonvulsant medication and prescribe a medication based on the case.

APPROACH TO: Adult-Onset Seizure DEFINITIONS LOSS OF CONSCIOUSNESS: Lack of awareness of self and surroundings. These patients usually have a window of time they cannot recall. SEIZURE: Temporary, self-limited cerebral dysfunction as a result of abnormal, self-limited hypersynchronous electrical discharge of cortical neurons. There are many kinds of seizures, each with characteristic behavioral changes and each usually with particular EEG recordings. EPILEPSY: A disorder of the brain defined either by at least two unprovoked seizures occurring more than 24 hours apart, or a single unprovoked seizure in which there remains an established risk of at least 60% for a recurrence in the next 10 years.

CLINICAL APPROACH Etiologies The current classification of seizures relates to the 1981 Classification of Epileptic Seizures promulgated by the International League Against Epilepsy (ILAE). Essentially, seizures are considered to relate to only one of the two cerebral hemispheres (these are referred to as partial or focal seizures) or both hemispheres of the brain (generalized seizures). Where the seizure pattern initiates and where it spreads determine the type of seizure, relates to prognosis, and frequently warrants different therapies.

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Table 14–1  •  PROPOSED NEW ILAE CLASSIFICATION SCHEME Generalized Seizures Tonic-clonic (in any combination) Absence  Typical  Atypical   Absence with special features   Myoclonic absence   Eyelid myoclonia Myoclonic  Myoclonic   Myoclonic atonic   Myoclonic tonic Clonic Tonic Atonic

Focal Seizures Unknown Epileptic spasms Continuous seizure types Generalized status epilepticus   Generalized tonic-clonic status epilepticus   Clonic status epilepticus   Absence status epilepticus   Tonic status epilepticus   Myoclonic status epilepticus Focal status epilepticus   Epilepsia partialis continua of Kojevnikov   Aura continua   Limbic status epilepticus (psychomotor status)   Hemiconvulsive status with hemiparesis

According to the 2010 Classification of Epileptic Seizures of the ILAE (International League Against Epilepsy), seizures are now classified as either focal or generalized seizures as seen in the table above (Table 14–1). “Focal” refers to partial seizures. The terms simple partial, complex partial, and secondarily generalized are no longer used. A generalized seizure refers to seizures with an origin in the bilateral hemispheres of the brain. Subcategorization of generalized seizures primarily reflects the type of motor disturbances present during the convulsion (eg, tonic-clonic, tonic, atonic, myoclonus). Seizures are further classified according to etiology: genetic (formerly idiopathic), structural-metabolic (formerly symptomatic), or unknown (formerly cryptogenic). There is considerable controversy about this issue. The idiopathic epilepsy syndromes, whether focal or generalized, include benign neonatal convulsions, benign childhood epilepsy, childhood/juvenile absence epilepsy, juvenile myoclonic epilepsy, and idiopathic epilepsy (ie, not otherwise specified). Structural-metabolic seizures can be focal or generalized and include infantile spasms (West syndrome), Lennox-Gastaut syndrome, early myoclonic encephalopathy, epilepsia partialis continua, Landau-Kleffner syndrome (acquired epileptic aphasia), temporal lobe epilepsy, frontal lobe epilepsy, posttraumatic epilepsy, and other forms not specified. There are other epilepsy syndromes of uncertain classification, including neonatal and febrile seizures and reflex epilepsy. Predictors of a recurrent seizure that allow a diagnosis of epilepsy after a single seizure include a previous brain injury, an EEG with epileptiform discharges, a significant abnormality on brain imaging, and a seizure occurring during sleep.

Clinical Presentation Seizure disorders can present as intermittent events. The initial event, whether reported by the patient or witnessed by an observer, is often clinically reliable as to whether a seizure begins with a focal onset or is immediately generalized.

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However, the physician must recognize that the patient may not remember initial focal symptoms because of postseizure (ie, postictal) memory loss. Shortly after the onset of a focal seizure, the patient’s consciousness can be rapidly impaired; also, the area of the brain in which the seizure begins may not have focal symptoms. In many cases, the classification of the kind of seizure the patient has is more important than the actual description of the seizure. This is because other relevant clinical information, of which the seizure may be only one variable, is also important. Within this context, the history (ie, brain trauma, recent fever or headaches rendering suspicion for meningitis, family history of epilepsy, etc) is important, as is the neurologic examination. Further, the results of EEG, neuroimaging, and blood tests are also important. Blood tests should include electrolytes, glucose, calcium, magnesium, renal and liver function, complete blood counts, and, if clinically suspected, lumbar puncture to rule out meningitis, as well as toxicology screens in the urine and blood. Approximately 75% to 90% of patients who experience a seizure without an obvious etiology do not see a physician after having only one seizure. This is usually a tonic-clonic event and most have no risk factors for epilepsy. These patients usually have a normal neurologic examination, normal EEG, and normal neuroimaging. Of these patients, one-quarter will prove to have epilepsy.

Treatment There have been multiple studies and discourse on what to do for patients who do not initially seek treatment, as three-quarters will never seize again but one-quarter will. It is generally accepted that treatment following the first seizure decreases the relapse rate, but there is no evidence that this treatment alters the prognosis of epilepsy. Many neurologists wait until the second seizure before initiating treatment, unless the first seizure has positive EEG or MRI findings. The physician should discuss with the patient the implications of treatment or nontreatment, medicolegal issues, driving laws in the patient’s state, and options for therapy. Different seizures have different therapies. Table 14–2 provides a reasonable guideline for treatment of different seizures.

Table 14–2  •  THERAPY FOR VARIOUS SEIZURE DISORDERS Partial seizures

Phenytoin, carbamazepine, oxcarbazepine, valproate, lamotrigine, topiramate, levetiracetam, gabapentin, pregabalin, zonisamide, lacosamide

Primary generalized

Valproate, topiramate, lamotrigine, zonisamide, levetiracetam

Absence

Ethosuximide, valproate, lamotrigine, zonisamide, topiramate

Myoclonic

Valproate, clonazepam, levetiracetam, topiramate, zonisamide

Tonic

Valproate, felbamate, clonazepam, topiramate, zonisamide

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CASE CORRELATION šš

See Case 15 (Absence Versus Complex Partial Seizures) and Case 16 (Cardiogenic Syncope)

COMPREHENSION QUESTIONS 14.1 A 61-year-old woman with a long history of type 2 diabetes is admitted to the hospital because of poorly controlled disease. During her hospitalization, she develops continuous tonic movements of her right arm and hand. Serum glucose is measured as greater than 600 mg/dL. Which of the following is the most appropriate step in management? A. Noncontrast CT scan of the brain B. Intravenous (IV) administration of lorazepam C. Insulin drip and frequent serum glucose monitoring D. Securing the airway 14.2 A 45-year-old man with history of embolic stroke 1 year ago presents with a generalized seizure. Which of the following is the most accurate regarding this patient? A. This patient is at risk for recurrent seizures. B. This patient requires treatment for an acute stroke. C. Anticonvulsant therapy is not indicated until he has had a second episode. D. This patient likely had a syncopal episode. 14.3 A 7-year-old girl with a history of muscle jerks in the early morning, and with sleep deprivation, presents with a generalized tonic-clonic seizure after playing video games late at night. Which of the following is the most likely diagnosis? A. Juvenile myoclonic epilepsy B. Febrile seizure C. Benign epilepsy of childhood D. Lennos Gastaut syndrome

ANSWERS 14.1 D. The ABCs are always the first step. Securing the airway is the first priority. Assessing for possible hypoglycemia, drug effects, alcohol withdrawal, and metabolic disorders is important. Imaging the brain and/or assessing for meningitis/ encephalitis should be considered. Simple focal seizures are often caused by focal lesions in the brain; however, physiologic or metabolic insults such as electrolyte imbalances, significant elevated blood glucose, or drugs/toxins can also induce simple or complex seizures and should be evaluated and managed.

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14.2 A. Epilepsy is likely to continue in this patient due to prior stroke and related epileptogenic focus. Similar to sleep deprivation, acute alcohol ingestion or intoxication can be associated with a seizure in the absence of preexisting lesions or risk factors. 14.3 A. Juvenile myoclonic epilepsy is one of the most common epilepsy syndromes. It accounts for 7% of all cases of epilepsy and is associated with myoclonic seizures (quick little jerks of the arms, shoulder, or occasionally the legs), usually in the early morning, soon after awakening. The myoclonic jerks sometimes are followed by a tonic-clonic seizure in the context of sleep deprivation or alcohol ingestion.

CLINICAL PEARLS »»

Seizures can be associated with just about any type of intermittent symptom or sign, depending on location of the epileptogenic focus. The diagnosis should be suspected in anyone with stereotyped paroxysmal events with or without loss of consciousness.

»»

In patients who experience a singular seizure without a known antecedent event, 10% to 25% will develop epilepsy (ie, have more seizures).

»»

The classification of epilepsy is based on whether the seizures are focal or generalized as well as their cause (ie, genetic, structural–metabolic, unknown).

»»

In 60% to 70% of patients with epilepsy, no cause can be found.

REFERENCES Bazil CW, Morrell MJ, Pedley TA. Epilepsy. In: Rowland LP, ed. Merritt’s Neurology. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:990-1014. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organisation of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-685. Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001;42:796-803. Engel J Jr. Report of the ILAE classification core group. Epilepsia. 2006;47:1558-1568. Jetté N, Wiebe S. Initial evaluation of the patient with suspected epilepsy. Neurol Clin. 2016;34(2): 339-350. Schacter SC. Epilepsy. In: Evans RW, ed. Saunders Manual of Neurologic Practice. Philadelphia, PA: Saunders/Elsevier; 2003:244-265.

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CASE 15 A 23-year-old man was playing cards late at night. While talking to his friends, he suddenly had lip smacking and stared into space. He appeared confused and kept mumbling the same words repeatedly. The episode lasted for approximately 20 seconds. During the episode, his friends tried to restrain him, but he became combative. Within a minute, he became asymptomatic, although he was slightly confused for 5 to 10 more seconds. His friends wanted to take him to the emergency center, but after initially refusing, he finally agreed. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 15: Absence Versus Complex Partial Seizures Summary: A 23-year-old man appeared suddenly confused and engaged in repetitive motor (including speech) behaviors. He then abruptly became asymptomatic. šš šš

šš

Most likely diagnosis: Complex partial seizure (CPS). Next diagnostic step: Magnetic resonance imaging (MRI) of the brain, which is preferable to computed tomography (CT) of the brain; and obtain an electroencephalogram (EEG) and routine blood work. Next step in therapy: Consider initiating anticonvulsant medication based on diagnostic evaluation or, if he is taking antiepileptic medication, alter the dosage or prescribe new medicines; discuss driving limitations.

ANALYSIS Objectives 1. Know the diagnostic approach and differential diagnosis of paroxysmal staring episodes. 2. List the medical therapies for complex partial and absence seizures.

Considerations In this case of a 23-year-old previously healthy man, CPS is the most likely diagnosis given his age and presentation, although absence seizures are also a possibility. CPSs are defined by an impaired level of consciousness and commonly exhibit automatisms, such as lip smacking, chewing, gesturing, repeated swallowing, repeating words or phrases, walking, running, undressing, snapping fingers, clumsy perseveration of an ongoing motor task, or some other type of complex motor activity that is not specifically directed and is not appropriate. If these patients are physically restrained during a seizure, they may become hostile or aggressive. Following the seizure, these patients are often transiently confused and disoriented; these states can last several minutes or hours. In patients with CPSs, approximately threequarters of the seizure emanates from the temporal lobe. Simple partial seizures, however, reflect epileptic discharges occurring in a limited and often focal area of the cerebral cortex. There is no alteration of consciousness. The symptoms or signs are related to the epileptogenic focus. Thus, the patient can have any type of observable manifestations during a simple partial seizure, whether this is a simple motor movement (eg, Jacksonian seizure, adversive seizure), unilateral sensory aberration, complex emotional episode, or a visual, auditory, or olfactory hallucination. Auras are simple partial seizures manifesting as altered sensation or psychic symptoms and can occur before motor manifestations of a motor seizure. The most common aura is a sensation of abdominal discomfort.

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Other auras include a feeling of unreality, detachment from the environment, déjà vu, or jamais vu. During a simple partial seizure, the patient is usually able to interact appropriately with his or her environment, except for possible limitations imposed by the seizure itself. In this case, the patient was unable to interact with his environment and therefore did not have a simple partial seizure. Absence seizures (petit mal) are another type of seizure and commonly presents with sudden staring. They can be confused with CPSs. Absence seizures present with momentary lapses in awareness; however, they are typically not accompanied by automatisms as seen with CPSs. They are characterized by motionless staring and cessation of ongoing activity. Absence seizures typically begin and end abruptly, have no aura, and are not associated with postictal confusion. Occasionally, mild myoclonic contractions of the eyelid or facial muscles, loss of muscle tone, or automatisms can accompany longer attacks. Unlike CPSs, absence seizures occur many times a day and rarely last more than 10 to 15 seconds. These types of seizures can also be precipitated by hyperventilation. The typical 3-Hz spike and wave pattern is seen. Please refer to the EEG shown in Figure 15–1. If the beginning and end of the absence spell are not distinct, or if tonic and autonomic components also occur, these spells are referred to as atypical absence seizures. Absence spells seldom begin de novo in adults, usually having their onset in childhood and beginning between ages 4 and 14, with 70% stopping by age 18. Children with classic absence epilepsy have normal development and intelligence. Atypical absence seizures usually occur in cognitively impaired children with epilepsy or in patients with epileptic encephalopathy, such as Lennox-Gastaut syndrome.

FP2 FP1 F4-A2 F3-A1 C4 C3 P4 P3 O2 O1 v

100 µV

1 sec

EM h EMG EKG CH 3.4 yr

Figure 15–1.  EEG showing a symmetrical generalized 3-Hz spike wave.

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APPROACH TO: Absence and Partial Complex Seizures DEFINITIONS ABSENCE SEIZURES: Brief episodes of staring that usually occur in childhood and last 5 to 10 seconds. If the seizure lasts beyond 10 seconds, there can also be eye blinking and lip smacking. The seizures usually occur in clusters and can occur dozens or hundreds of times a day. There is no postictal confusion, and the individual returns to baseline immediately. COMPLEX PARTIAL SEIZURES (CPSs): Partial seizures with impaired consciousness. Complex refers to impairment of consciousness (ie, impaired awareness to self and surroundings). Patients often engage in repetitive motor behavior, known as automatisms. Patients appear to be awake but do not respond normally to their environment. CPSs typically last a few minutes rather than seconds as seen with absence seizure. This is the most common type of seizure in adults with epilepsy.

CLINICAL APPROACH Clinical Features and Epidemiology CPSs cause impaired consciousness and arise from a specific area in the brain. Impaired consciousness denotes decreased responsiveness and awareness of self and surroundings. During a CPS, the patient may not communicate, respond to commands, or remember events that occurred. Consciousness might not be impaired completely. During a CPS, some patients may make simple verbal responses, follow simple commands, or continue to perform simple or, less commonly, complex motor behaviors such as operating a car. CPSs classically arise from the temporal lobe but can arise from any cortical region. Automatisms are repetitive, stereotyped, unconscious motor or verbal behaviors (automatic behaviors) that commonly accompany CPSs. The behavior is often repeated inappropriately or is inappropriate for the situation. Verbal automatisms range from simple vocalizations, such as moaning, to more complex, comprehensible, stereotyped speech. Motor automatisms are classified as simple or complex. Simple motor automatisms include oral automatisms (eg, lip smacking, chewing, swallowing) and manual automatisms (eg, picking, fumbling, patting). Unilateral manual automatisms usually indicate a seizure onset from the contralateral cerebral hemisphere. Complex motor automatisms are more elaborate, coordinated movements involving bilateral extremities. Examples of complex motor automatisms are cycling movements of the legs and stereotyped swimming movements. De novo automatisms often begin after seizure onset. In other cases, perseverative automatisms occur as repetitions of motor activity that began before the seizure. Bizarre automatisms such as alternating limb movements, right-to-left head rolling, or sexual automatisms can occur with frontal lobe seizures.

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Table 15–1  •  COMPLEX PARTIAL VERSUS ABSENCE SEIZURES Feature

Complex Partial

Absence

Onset

Can be preceded by an aura

Abrupt

Duration

Usually >30 s

Usually 65 y History of neoplasm Cerebrovascular disease Structural heart disease or CHF Abnormal ECG, particularly ventricular arrhythmias Dyspnea or pulmonary disease Anemia Systolic BP 10 days per month of triptans, ergots, combination analgesics or opioids; >15 days per month of nonsteroidal anti-inflammatory drugs (NSAIDs); or more than one medication for headache for >10 days per month. The headaches typically occur more than 15 days per month. The history is notable for worsening headaches and increased headache frequency despite medication, and headaches often result in escalating doses of medication without relief. Abrupt discontinuation of the medication results in severe headache. If the drug is an opioid, benzodiazepine, or barbiturate, there is significant risk of additional physical withdrawal symptoms that may be life threatening. Medication overuse headache requires weaning of the overused agent along with concurrent management of the withdrawal symptoms and the original headache syndrome. Some patients may require admission to the hospital for weaning therapy, but many can be slowly weaned in the outpatient setting.

Evaluation It is important to consider that all of the chronic daily headache types may be exacerbated by analgesic rebound, and a vigorous attempt should be made to get patients off regular use of OTC analgesics. Most patients with chronic daily

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headache have been seen by multiple physicians because of the chronicity of the headache. Imaging studies have typically been performed in the past and are normal; if unavailable, then an MRI/magnetic resonance angiography (MRA) should be done to evaluate for ischemia, signs of abnormal intracranial pressure, or a space-occupying lesion. Serum chemistries, complete blood count (CBC) with differential, thyroid panel, and a sedimentation rate should be drawn. A lumbar puncture (LP) after MRI clearance should be considered in those patients with headache of acute origin over a short period of time to rule out an infectious or inflammatory cause(s).

Treatment About 30% of patients with chronic daily headaches report significant improvement with therapy, but most patients gain some improvement. There are both medical and nonmedical treatments available, and both should be pursued, especially if there is a significant neck component to these headaches. The nonmedical treatment of chronic daily headache can include biofeedback and relaxation therapy, stress management, psychological interventions (cognitive behavioral therapy [CBT], individual/family counseling), and lifestyle changes (dietary modifications, sleep hygiene, daily exercise program). Keeping a headache diary can be helpful in identifying triggers as well as recognizing patterns of frequency and intensity of attacks, which can help guide treatment, especially with medication overuse. Many patients can benefit from physical therapy by a head and neck rehabilitation specialist. Massage therapy has also been shown to be helpful in certain patients. As noted previously, the first intervention in a plan of medical therapy for chronic daily headache is removal of any overused medications, which can include NSAIDs, opioids, triptans, and ergots. As the overused medication is weaned, the patient must be bridged with alternative analgesics while prophylactic therapy is initiated and titrated to therapeutic levels. The type of medication being weaned determines the rate of weaning, the medication used as a bridge, and if it is performed as an outpatient or inpatient. Rapid weaning protocols should include alternative analgesic options such as NSAIDs, steroids, triptans, or ergots. Preventative therapy for the chronic daily headache should begin at the same time and is similar to that used for migraine management. Studies using OnabotulinumtoxinA injections or topiramate show the strongest evidence for preventative therapy, but other medications may also be used, including other antiepileptics (ie, valproate) and beta-blockers (ie, propranolol, metoprolol). The only Food and Drug Administration (FDA)approved treatment for chronic migraines is OnabotulinumtoxinA injection. Acute medication is also recommended in addition to preventative therapy to substitute for the overused medication for patients with chronic migraines. However, the use of acute medication should be limited to 2 or fewer days per week. The most useful classes of medication for acute treatment are triptans, NSAIDs, or ergots, and the choice of acute medication is based on the class of the overused medication. In patients with tenderness in the occipital nerve exit zone, consider greater occipital nerve block with an injection of corticosteroid and anesthetic. Injection therapies can provide fast-acting therapy until prophylactic therapy takes effect.

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CASE CORRELATION šš

See also Case 12 (Subarachnoid Hemorrhage) and Case 18 (Migraine Headache)

COMPREHENSION QUESTIONS 19.1 A 33-year-old woman is noted to have chronic daily headaches. The workup has been negative. Which of the following is an important principle in the management of this disorder? A. Maintain analgesic dose and start antiepileptic therapy. B. Increase the analgesic dose while initiating biofeedback therapy. C. Lower the analgesic dose while beginning other therapy. D. Reassure the patient, and refer to psychiatrist. 19.2 A 24-year-old woman presents with the complaint of severe headaches. The pain is typically unilateral and throbbing, and is associated with nausea and photophobia. In the past, she had headaches one or twice a month, but these have been increasing in frequency to almost daily in the last few months. OTC medications no longer provide relief. Which headache syndrome is this patient describing? A. Occipital neuralgia B. Transformed migraine C. Chronic tension-type headache D. New daily persistent headache 19.3 A 55-year-old man comes into the physician’s office with a 2-year history of daily headaches. The sharp, stabbing pain peaks in attacks lasting about 20 minutes about five times per day. It occurs on the right side of his head, and is associated with photophobia and nausea. What is the best therapy for this patient? A. Indomethacin B. Oxygen C. Topiramate D. Sumatriptan

ANSWERS 19.1 C. Analgesic overuse often contributes to headaches or migraines becoming chronic. Therefore, the first intervention in a plan of medical therapy for chronic daily headache is removal of any OTC medications, which can include either acetaminophen or aspirin. At the same time, bridge the patient with an alternative analgesic and also begin preventative therapy for the chronic headache.

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19.2 B. This patient has a transformed migraine that is likely evolving into a chronic daily headache of the migraine type. Migraine headaches are commonly unilateral and have a throbbing quality. These can transform from episodic to chronic over a period of several months. Other types of headaches can contribute to the syndrome of chronic daily headache, including occipital neuralgia and medication overuse. However, not enough information was given about this patient to implicate other etiologies. A new daily persistent headache would not apply to this patient due to her history of headaches similar to this one. 19.3 A. This patient is most likely suffering from hemicrania continua. Response to indomethacin is both therapeutic and diagnostic. Oxygen therapy has not shown benefit in these patients, but it is helpful for patients with acute cluster headaches. Sumatriptan is only rarely effective for hemicrania, and it would not be a first-line agent like it may be for migraine or cluster headache abortive therapy. Topiramate is used to prevent migraine headaches.

CLINICAL PEARLS »»

Transformed migraine is migraine headache that transforms into daily, less severe headaches punctuated by severe and debilitating migraine attacks.

»»

Overuse of pain relievers is a major contributing factor in transformed migraines.

»»

Tension-type headaches, associated with a band-like constant bilateral pressure and pain from the forehead to the temples and often the neck, are the most common form of headache.

»»

New daily headaches that begin abruptly in a patient with no prior headache history require more extensive evaluation to rule out secondary causes of headache such as infection, inflammation, intracranial pressure abnormalities, or mass lesions.

REFERENCES Bigal ME, Sheftall FD. Chronic daily headaches and its subtypes. Continuum (Minneap Minn). 2006;12(6):133-152. Derman H. Current Neurology. St. Louis, MO: Mosby; 1994:179. Dougherty C. Occipital neuralgia. Curr Pain Headache Reps. 2014;18:411. Goadsby PJ. Trigeminal autonomic cephalalgias. Continuum (Minneap Minn). 2012;18(4):883-895. Kaniecki RG. Tension-type headache. Continuum (Minneap Minn). 2012;18(4):823-834. Lipton RB. Risk factors for and management of medication-overuse Headache. Continuum (Minneap Minn). 2015;21(4):1118-1131. Newman LC. Trigeminal autonomic cephalalgias. Continuum (Minneap Minn). 2015;21(4):1041-1057.

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Saper JR, Silberstein SD, Gordon CD, et al. Handbook of Headache Management, a Practical Guide to Diagnosis and Treatment of Head, Neck, and Facial Pain. Baltimore, MD: Williams & Wilkins; 1993. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. London, UK: Martin Dunitz; 2002. Tepper SJ. Medication-overuse headache. Continuum (Minneap Minn). 2012;18(4):807-822. Tyagi A. New daily persistent headache. Ann Indian Acad Neurol. 2012;15(suppl 1):S62-S65.

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CASE 20 A 74-year-old woman was admitted to the hospital for extreme confusion and agitation. She had been doing reasonably well until 1 to 2 weeks prior to admission; however, her family says that her memory has been getting worse over the last 3 years. Initially, she had problems remembering recent events and people’s names and had a tendency to dwell in the past. She has gotten lost several times while driving, most recently in a familiar neighborhood. She has stopped cooking because she can no longer work her electric oven. Sometimes, her words do not make sense. Her social graces have remained preserved, and she is still quite pleasant to be around, although she tends to interact less with her friends. Her family says her mood has been poor lately, with some tearful episodes. She still walks around the block every day, and her basic gait and coordination seem quite normal. Over the last week or so, her condition has acutely worsened. She is easily agitated to the point of aggression. She also appears to see and speak to her mother, who has been dead for many years. According to her family, she has developed frequent urination and incontinence, which is not normal for her. On physical examination, she was found to be inattentive and had difficulty keeping on task. She had numerous paraphasic errors but was otherwise fluent. Her neurologic examination was otherwise unremarkable. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 20: Alzheimer Dementia Summary: A 74-year-old woman was admitted to the hospital for extreme confusion and agitation. She has had short-term memory deficits over the last 3 years including becoming lost several times while driving, most recently in a familiar neighborhood. She now acutely displays confusion, memory loss, hallucinations, and urinary incontinence. She had numerous paraphasic errors but was otherwise fluent. Her neurologic examination was otherwise unremarkable. šš

šš

šš

Most likely diagnosis: Underlying dementia, probably Alzheimer disease (AD), with superimposed delirium from a urinary tract infection (UTI). Next diagnostic step: Treat UTI with antibiotics, medical evaluation, and observation. Next step in therapy: After observation and stabilization, consider treatment of the underlying dementia.

ANALYSIS Objectives 1. Recognize the differential diagnosis of dementia. 2. Understand the underlying pathophysiology of AD. 3. Appreciate the special susceptibilities of patients with dementia.

Considerations This case has two main aspects to it: a several-year history of apparent cognitive decline, and a more recent, precipitous decline with agitation and inattention. The insidious onset and gradual progression in an older person is characteristic of degenerative disease (eg, Alzheimer), although other classes of diseases can sometimes mimic this time course. In this patient, there has been decline of cognition with profound deficits of short-term memory. Long-term memory is preserved. Other symptoms include getting lost in familiar areas, suggesting visuospatial deficits, and the use of tools like the oven, which is consistent with apraxia. She had no focal neurologic dysfunction, such as deficits in her cranial nerves, motor, sensation, coordination, gait, and station. Dementia presents with decline in memory and at least one other cognitive domain that is severe enough to interfere with daily function and independence. The sudden decline and agitation is more consistent with delirium. Dementia needs to be distinguished from delirium, depression, and, more importantly, reversible organic causes of cognitive decline such as drugs or metabolic derangements. The acute onset of agitation and delirium in this patient is likely caused by a UTI, given her simultaneous development of urinary symptoms (frequency and incontinence). Patients with underlying dementia or other brain disease (eg, stroke

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and multiple sclerosis [MS]) are particularly sensitive to infections, medication changes, or metabolic abnormalities. Infections are particularly common etiologies of delirium in these patients, though medications and basic laboratory values should also be reviewed. In this patient, the first order of business is to ensure that she is medically stable. In addition, she should be checked for other causes of delirium, including metabolic and pharmacologic agents as well as vitamin and hormonal deficiencies. Urinalysis and urine culture should be obtained to confirm the diagnosis of UTI, and she should be treated appropriately. She should improve and reach a stable baseline, after which she can be examined more closely as to the nature of her dementia. Cognitive screening tests, such as the Montreal Cognitive Assessment (MoCA) or Mini-Mental State Examination (MMSE), imaging and cerebrospinal fluid (CSF) studies can be performed as indicated by the clinical picture. If the patient does not have any reversible metabolic causes of cognitive decline, consider the more common dementia syndromes: 1. Alzheimer disease (AD) 2. Lewy body dementia 3. Vascular dementia 4. Parkinson disease (PD) with dementia 5. Frontotemporal dementia (FTD) In this case, there is neither history of tremor or gait disturbance suggestive of PD nor history of visual hallucinations suggestive of Lewy body dementia. This patient’s history is also not significant for a stepwise deterioration seen with neurologic deficits of stroke, nor is it characterized primarily by personality changes such as disinhibition and impaired judgment seen in FTD. AD is therefore the most probable diagnosis, given the predominant deficits of recent memory and visual-spatial function. Treatment with an acetylcholinesterase inhibitor such as donepezil, which has been shown to delay symptom progression, would be appropriate at this point. Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can also be considered since it has benefit in moderate stages of AD. Dementia is a chronic, progressive disorder; it does not present or change acutely, and there is no need to treat it with the timing and urgency of a cardiac arrest. These patients can be very sensitive to the deleterious effect of medications. Medication should be titrated carefully, and two drugs should never be started at once unless absolutely necessary.

APPROACH TO: Alzheimer Dementia DEFINITIONS DELIRIUM: A transient, usually reversible, cause of cerebral dysfunction that manifests clinically with a wide range of neuropsychiatric abnormalities. The clinical hallmarks are decreased attention span and a waxing and waning type of confusion.

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PARAPHASIC ERRORS: The production of unintended syllables, words, or phrases during the effort to speak. NUCLEUS BASALIS OF MEYNERT: A group of nerve cells that has wide projections to the neocortex and is rich in acetylcholine and choline acetyltransferase. PSEUDODEMENTIA: A severe form of depression in which cognitive changes mimic those of dementia. DEMENTIA: Impairment of memory and at least one other cognitive function (eg, language, visual–spatial orientation, judgment) without alteration in consciousness, representing a decline from previous level of ability, and interfering with daily functioning and independent living. ALZHEIMER DISEASE (AD): The leading cause of dementia, accounting for half of the cases involving elderly individuals, correlating to diffuse cortical atrophy and hippocampal atrophy with ventricular enlargement. The pathologic changes in the brains of AD patients include neurofibrillary tangles with a deposition of abnormal amyloid in the brain. VASCULAR DEMENTIA (MULTI-INFARCT DEMENTIA): Dementia in the setting of cerebrovascular disease, occurring after multiple cerebral infarctions, whether large or small (lacunar).

APPROACH TO: Dementia Dementias can be characterized and categorized in a number of ways. One way is cortical versus subcortical. Cortical dementias involve direct damage to and atrophy of various areas of cerebral cortex. See Table 20–1 for a summary of the main cortical dementias. Cortical dementias tend to have involvement of cognitive functions while basic neurologic function is preserved. Language can be affected, but speech articulation is generally not. Cortical dementias can also be subdivided based on which lobes of the brain these primarily affect. Cortical dementia affecting the frontal and temporal lobes is typified by FTD. Damage to the frontal cortex produces problems with behavior, attention, and executive dysfunction. Patients can lose their social graces early Table 20–1  •  CORTICAL DEMENTIAS Disease

Anatomy

Classic Symptoms

Alzheimer disease (AD)

Temporal, parietal

Amnesia for short-term memories, disorientation, visuospatial deficits, acalculia (inability to do simple math calculations)

Lewy body disease

Temporal, parietal, occipital

Dementia, parkinsonism, visual hallucinations

Frontotemporal disease (aka Pick)

Frontal, temporal

Behavioral changes, disinhibition, aggression, aphasia (receptive or expressive)

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while memory and intellectual functions can be relatively preserved. Given the role Broca area and related frontal structures play in expressive speech, FTD patients can also present with a nonfluent aphasia, sometimes termed primary progressive aphasia. Semantic aphasia, a problem with word-finding and paraphasias, caused by damage to Wernicke area in the anterior temporal lobe, can result from the temporal involvement in FTD. This is termed semantic dementia. Though the temporal lobe is also the site of the hippocampus, FTD relatively preserves this structure and patients do not have prominent memory deficits. AD, in contrast to FTD, classically affects the parietal and temporal lobes, sparing the frontal lobe until late in the disease. AD almost invariably shows early involvement of recent memory, with hippocampal atrophy often visible on imaging. Given the parietal involvement, visuospatial skills, calculations, and orientation are usually affected. Patients often forget how to operate common household tools, such as remote controls or vacuum cleaners, due to apraxia. Another common cortical (and subcortical) dementia is Lewy body disease (LBD). Though not technically correct, it can be helpful to think of LBD as a combination of Alzheimer and PD. These patients frequently have the amnesia and parietal symptoms of AD along with parkinsonism that can be indistinguishable from PD. LBD is the only cortical dementia that commonly affects the occipital lobe. Atrophy of the occipital cortex can be a strong imaging finding in LBD, and this pathology is associated with visual hallucinations, the other classic symptom of the disorder. In contrast to cortical dementias, subcortical dementia tends to be characterized by attention and processing speed deficiencies, with preservation of core cognitive processes. Neuropsychological testing can show a wide range of deficits but, given enough time and repetition, the patient is often able to complete most tasks. The damage is to the axons or the basal ganglia rather than the neuron cell bodies of the cortex. These disorders can be degenerative, like PD, but can also be the result of fixed injuries, like multi-infarct dementia. Table 20–2 details the salient features of some classic subcortical dementias. Table 20–2  •  SUBCORTICAL DEMENTIAS Disease

Key Features

Multi-infarct (vascular) dementia

Stepwise progression, focal neurologic deficits

Parkinson disease (PD)

Attention and processing speed issues develop several years after parkinsonism

Progressive supranuclear palsy

Subcortical dementia, parkinsonism, vertical gaze palsy

Corticobasal degeneration

Dementia, parkinsonism, alien hand syndrome

Normal pressure hydrocephalus (NPH)

Subcortical dementia, apraxic (aka magnetic) gait, urinary incontinence

Huntington disease

Chorea, psychiatric symptoms, dementia, clear familial inheritance

Creutzfeldt-Jakob disease (CJD)

Prion disease, rapidly progressive dementia, seizures

HIV dementia

Secondary to HIV, not to AIDS-defining infections. Improves with HAART

HAART, highly active antiretroviral therapy.

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DIFFERENTIAL DIAGNOSIS If cognitive decline occurs with prominent mood disturbance, then one consideration is depression or pseudodementia. It is often difficult to distinguish which occurred first, as many elderly patients with cognitive decline and declining level of independent functioning suffer from a reactive depression. History from involved family members of the onset of symptoms, or history of prior depression or other psychiatric illness can help establish the diagnosis, and an empiric trial of antidepressants can be considered. If the patient has a history of irregular stepwise decline in functioning, especially if the patient has had apparent stroke symptoms or transient ischemic events, or has known cardiovascular disease or atrial fibrillation, then multi-infarct dementia is the most likely diagnosis. This type of vascular dementia is a common cause of dementia in the United States, comprising 10% to 20% of dementia. Other patients with cerebrovascular disease, especially as a result of long-standing hypertension, can develop diffuse subcortical white matter changes seen on imaging and an insidious rather than sudden stepwise decline in cognitive function. This condition is often referred to as Binswanger disease. Other common causes of dementia include cognitive decline caused by longstanding alcoholism or by dementia associated with parkinsonism, such as Lewy body dementia and dementia associated with PD. Both of these underlying conditions are readily discovered by the appropriate associated medical history. Less common causes of dementia include medical conditions such as Wernicke encephalopathy as a result of thiamine (vitamin B1) deficiency, vitamin B12 deficiency caused by pernicious anemia, untreated hypothyroidism, or chronic infections such as HIV dementia or neurosyphilis. A variety of primary central nervous system (CNS) diseases can lead to dementia including Huntington disease, MS, neoplastic diseases such as primary or metastatic brain tumors (although they are much more likely to produce seizures or focal deficits rather than dementia), or leptomeningeal spread of various cancers. Normal pressure hydrocephalus is a potentially reversible form of dementia where the cerebral ventricles slowly enlarge as a result of disturbances to CSF reabsorption. The classic triad is dementia, gait disturbance, and urinary or bowel incontinence. Relief of hydrocephalus through placement of a ventriculoperitoneal shunt can reverse the cognitive decline.

ALZHEIMER DISEASE AD is a degenerative disorder first identified by Alois Alzheimer, who described the clinical presentation and the characteristic histologic changes, consisting of amyloid plaques and neurofibrillary tangles (Figure 20–1). The amyloid plaques stain positively with antibodies to amyloid precursor protein. AD can be caused by a variety of factors. In 90% of AD, the cause is unknown, while about 10% of cases are associated with known mutations in the amyloid precursor protein as well as two homologous proteins, presenilin-1 and presenilin-2, that tend to present with early-onset disease. In the past, AD was considered presenile dementia with onset younger than 65 years; however, all age presentations are now considered as dementia of the

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Figure 20–1.  Photomicrograph of Alzheimer amyloid plaque and neurofibrillary tangle. (Reproduced, with permission, from Ropper AH, Brown RH. Adams and Victor’s Principles of Neurology. 8th ed. New York, NY: McGraw-Hill; 2005:901.)

Alzheimer type. Interference with metabolism of amyloid precursor protein is considered a relevant step in the pathophysiology of AD, sporadic or famililal. The diagnosis of AD is made clinically and should be suspected in an older adult with progressive decline in memory and at least one other cognitive domain, causing impaired functioning. Biomarkers and imaging studies serve mainly to exclude other diagnoses. Several biomarker studies have demonstrated that CSF amyloid beta 1–42 is decreased, whereas tau protein is increased in AD. This finding is diagnostically specific but not very sensitive. Apolipoprotein protein E (APO-E) is involved in cholesterol metabolism and plays a role in amyloid metabolism. There are three main haplotypes for this protein, and APO-E e4 is a risk factor for AD whereas e2 is protective. It is possible to order an APO-E genotype from commercial laboratories. It is important to note, however, that the presence APO-E e4 is only a risk factor and is not diagnostic of AD. Imaging studies typically show cortical atrophy, especially the parietal and temporal cortices, with hippocampal atrophy. As a correlate, functional imaging studies show hypometabolism in the temporal and parietal cortices (Figure 20–2). Pathology studies reveal particular degeneration of the cholinergic cells that project to the cortex from the basal forebrain, particularly the nucleus basalis of Meynert. The main approach to enhancing cognition in patients with AD is by trying to enhance cholinergic function by the administration of inhibitors of acetylcholinesterase that penetrate the CNS. One of the consequences of cholinergic loss is also extreme sensitivity to the deleterious effects of anticholinergic medications. For patients with AD, the average life expectancy after diagnosis is 7 to 10 years. The clinical course is characterized by the progressive decline of cognitive functions (memory, orientation, attention, and concentration) and the development of

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A

B

Figure 20–2.  A. Axial T1-weighted magnetic resonance images of AD patient showing bilateral hippocampal atrophy and generalized atrophy. B. Positron emission tomographic scan with decreased activity in the parietal lobes bilaterally. (Courtesy of TF Budinger, University of California, Berkeley. In: Kasper DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005:2399.)

psychological and behavioral symptoms (wandering, aggression, anxiety, depression, and psychosis). Patients with AD often have olfactory impairment. The goals of treatment in AD are to (1) improve cognitive function, (2) reduce behavioral and psychological symptoms, and (3) improve the quality of life. Three agents are currently available that inhibit central acetylcholinesterase: donepezil, rivastigmine, and galantamine. All three of these medications have been shown to slow the rate of AD progression. Antagonists to NMDA glutamate receptors, such as memantine, also seem to reduce the rate of decline. Symptomatic treatments of various psychiatric sequelae can also be very helpful in any dementia. Antipsychotics, such as quetiapine, can be used to treat hallucinations, delusions, or aggression. Other issues patients can develop include wakefulness, wandering, incontinence, and depression. A structured environment, with predictability, and judicious use of pharmacotherapy, such as selective serotonin reuptake inhibitors (SSRIs) for depression are helpful. The primary caregiver is often overwhelmed and needs support. The Alzheimer Association is a national organization developed to give support to family members and can be contacted through www.alz.org.

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COMPREHENSION QUESTIONS 20.1 The drugs donepezil, rivastigmine, and galantamine are used in AD to try to raise the availability of which transmitter in the brain? A. Dopamine B. Norepinephrine C. Glutamate D. Acetylcholine 20.2 Abnormal processing of which of these proteins is felt to be particularly important in the pathophysiology of AD? A. Acetylcholinesterase B. Alpha-synuclein C. Huntingtin D. Amyloid precursor protein E. Gamma aminobutyric acid (GABA) 20.3 Which one of these abnormalities on the neurologic examination would be unusual in a patient with mild AD? A. Problems drawing a clock B. Impaired sense of smell C. Hyperreflexia with positive Babinski signs D. Impaired short-term memory

ANSWERS 20.1 D. There is evidence for both acetylcholine (ACh) and glutamine as important in the development of AD. ACh is essential for the processing of memory and learning and is decreased in concentration and function in patients with AD. The agents donepezil, rivastigmine, and galantamine all inhibit acetylcholinesterase and hopefully result in elevated availability of acetylcholine in the cerebral cortex. 20.2 D. There are abnormalities of amyloid precursor protein deposition. CSF levels demonstrated in AD and mutations in the protein have been shown to cause the clinical disorder. Amyloid precursor proteins are found in the synapses of neurons and are thought to be responsible for forming and repairing synapses; abnormal forms of these proteins may lead to neuronal destruction and dementia. 20.3 C. Hyperreflexia is unusual in AD patients. Impaired olfaction is the only neurologic abnormality typically found, except those on MMSE testing.

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CLINICAL PEARLS »»

AD is a cortical dementia with insidious onset and gradual progression. In its early stages, affected patients have a normal neurologic examination except for the mental status examination and olfactory testing.

»»

AD is associated with neurofibrillary tangles with deposition of abnormal amyloid plaques in the brain.

»»

Patients with AD are unusually sensitive to deleterious effects of anticholinergic medications.

»»

Acetylcholinesterase inhibitors have been shown to improve cognition and behavior in patients with AD.

»»

AD is the most common type of dementia, followed by Lewy body dementia.

»»

Depression and reversible causes of dementia should be considered in the evaluation of a patient with memory loss and functional decline.

REFERENCES Apostolova L. Alzheimer disease. Continuum (Minneap Minn). 2016;22(2):419-434. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368:387-403. Borson S, Raskind MA. Clinical features and pharmacologic treatment of behavioral symptoms of Alzheimer’s disease. Neurology. 1997;48(5 suppl 6):S17-S24. Galasko D. The diagnostic evaluation of a patient with dementia. Continuum (Minneap Minn). 2013;19(2 Dementia):397-410. Jackson JC, Gordon SM, Hart RP, et al. The association between delirium and cognitive decline: a review of the empirical literature. Neuropsychol Rev. 2004;14:87-98. Lyketsos CG, Lee HB. Diagnosis and treatment of depression in Alzheimer’s disease. A practical update for the clinician. Dement Geriatr Cogn Disord. 2004;17:55-64. Muller-Thomsen T, Arlt S, Mann U, et al. Detecting depression in Alzheimer’s disease: evaluation of four different scales. Arch Clin Neuropsychol. 2005;20:271-276. Sperling R, Johnson K. Biomarkers of Alzheimer disease: current and future applications to diagnostic criteria. Continuum (Minneap Minn). 2013;19(2 Dementia):325-338. van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol Neurosurg Psychiatry. 2005;76(suppl 5):v2-v7.

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CASE 21 A 64-year-old woman was admitted for a possible seizure and progressive cognitive decline. The patient states that she has been having vivid nightmares and dreams for months and often wakes up screaming or falling out of bed. She was brought to the hospital because of “thrashing around” and screaming “stop” as witnessed by her niece. Her niece also stated that her aunt has shown a decline for the past year. She was previously an outgoing, active person who lived independently. In the past 6 months, she has become more reclusive, and her son has had to take over her finances as a result of an accumulation of unpaid bills. Her primary care physician had placed her on a psychotropic medicine a few months earlier, with marked worsening. It was discontinued. The patient also admits to seeing images of animals and people, primarily at night. Neurologic examination is significant for mild bradykinesia, decreased bilateral arm swing, and small, shuffling steps. There is also mild bilateral arm rigidity without tremor. A neuropsychological examination revealed changes in executive functioning (behavior, attention, judgment) and difficulties performing previously learned tasks (apraxia). »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 21: Lewy Body Dementia Summary: The patient is a 64-year-old woman with progressive alteration in personality, daily function, and cognition. The patient’s history is also significant for acting out her dreams during rapid eye movement (REM) sleep (REM sleep behavior disorder [RBD]) and visual hallucinations. Her examination reveals impairment of the extrapyramidal system and a mix of subcortical and cortical cognitive dysfunction, consistent with parkinsonism with cognitive decline. šš šš

šš

Most likely diagnosis: Lewy body dementia (LBD) Next diagnostic step: Magnetic resonance imaging (MRI) of the brain; neuropsychological evaluation Next step in therapy: Anticholinesterase medications

ANALYSIS Objectives 1. Describe the common clinical presentation of LBD. 2. Recognize the differential diagnosis of conditions with parkinsonism and dementia. 3. Understand the evaluation and management of LBD.

Considerations This is a woman who has insidiously developed cognitive, behavioral, and motor dysfunction that is most likely consistent with a diagnosis of LBD. Her history is significant for onset of cognitive and behavioral decline characterized by social isolation, inability to handle personal affairs, RBD, and hallucinations. LBD is characterized by prominent executive dysfunction and parkinsonism in addition to a number of features such as fluctuating cognition, hallucinations, sensitivity to neuroleptics, and sleep disorders. Her examination is highly suggestive of parkinsonism characterized by a shuffling gait (short, small steps), bilateral decreased arm swing, and rigidity. Formal neurocognitive testing confirmed subcortical dysfunction, including impaired concentration, judgment, and apraxia. Her history is also significant for clinical worsening with an empiric trial of a psychotropic, presumably a dopamine blocker. The differential diagnosis for dementia with parkinsonism includes both degenerative disease, like Parkinson disease dementia (PDD) and the Parkinson plus syndromes or atypical parkinsonian syndromes (Table 21–1). The primary distinguishing factor between LBD and PDD is the duration of cognitive symptoms in relation to parkinsonism. In general, patients with PDD have a relatively long history of motor symptoms or parkinsonism prior to the onset of cognitive decline, whereas patients with LBD usually have parkinsonism and cognitive decline within the first year of

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Table 21–1  •  ATYPICAL PARKINSONIAN SYNDROMES (PARKINSON PLUS SYNDROMES) Disease

Key Features

Lewy body dementia (LBD)

Cortical and subcortical dementia, fluctuating cognition, visual hallucinations, RBD

Multiple system atrophy (MSA)

Minimal cognitive involvement, dysautonomia, either ataxia or parkinsonism, RBD

Progressive supranuclear palsy (PSP)

Subcortical dementia, parkinsonism, vertical gaze palsy, axial rigidity, postural instability

Corticobasal degeneration

Dementia (cortical and subcortical features), parkinsonism, alien limb phenomenon

RBD, rapid eye movement sleep behavior disorder.

symptom onset. Atypical parkinsonian syndromes may have motor symptoms that mimic PD but also include other symptoms and are caused by different pathologies. Patients with Alzheimer disease (AD) can occasionally have parkinsonian features, but these features tend to develop only in advanced disease when cognitive impairment is severe. Alternatively, patients with AD may require treatment with antipsychotics for associated behavioral disturbances and develop drug-induced parkinsonism. Normal-pressure hydrocephalus can be confused with LBD, as patients may have mild evidence of parkinsonism, cognitive decline (subcortical dementia), gait disturbance (a magnetic or apraxic gait), and urinary symptoms (urgency or incontinence). This can be distinguished from LBD using neuroimaging and assessing the response to a high-volume lumbar puncture (removal of 30-40 cc of cerebrospinal fluid [CSF]).

APPROACH TO: Lewy Body Dementia DEFINITIONS ALPHA SYNCLEIN: A protein abundant in the human brain mainly at the presynaptic terminals and may have a role in clustering synaptic vesicles. APRAXIA: Difficulty with motor planning to perform previously learned tasks or movements in the absence of significant impairment of language, motor, or sensory deficits sufficient to explain disorder. EXECUTIVE FUNCTION: Mental capacity to control and plan mental activity, the ability to sustain or direct attention, the ability to suppress inappropriate behavioral responses, the planning of future actions, the initiation and execution of these strategies, and the ability to flexibly switch among problem-solving strategies. It is mediated by the prefrontal lobes of the cerebral cortex.

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REM SLEEP BEHAVIOR DISORDER: A parasomnia involving dissociation of the characteristic stages of sleep. The major feature is loss of muscle atonia during REM sleep leading to a dream enactment during REM sleep. RBD is a common feature of all neurodegenerative diseases with the pathologic hallmark or alphasynuclein protein aggregates in neurons. (PD, multiple system atrophy [MSA], and LBD) and often precedes their diagnosis.

CLINICAL APPROACH LBD is the second most common type of dementia behind AD. Pathologic and clinical features can overlap between LBD and AD, and in fact, 40% of AD patients have pathologic alterations felt specific for LBD. Epidemiologic studies are limited but they suggest that men are more affected than women and that the usual onset is in the late 50s and older.

Table 21–2  •  DIAGNOSTIC FEATURES OF DEMENTIA WITH LEWY BODIES 1. Central feature (essential for a diagnosis of possible or probable LBD) •  D  ementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function; prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression; deficits on tests of attention, executive function, and visuospatial ability may be especially apparent. 2. Core features (two core features are sufficient for a diagnosis of probable LBD, one for possible LBD) •  F luctuating cognition with pronounced variations in attention and alertness •  R  ecurrent visual hallucinations that are typically well formed and detailed •  S pontaneous features of parkinsonism 3. Suggestive features (one or more of these in the presence of one or more core features is sufficient for a diagnosis of probable LBD; in the absence of any core features, one or more suggestive features is sufficient for a diagnosis of possible LBD; probable LBD should not be diagnosed on the basis of suggestive features alone) •  R  EM sleep behavior disorder •  S evere neuroleptic sensitivity •  L ow dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging 4. Supportive features (commonly present but not proven to have diagnostic specificity) •  R  epeated falls and syncope •  T ransient, unexplained loss of consciousness •  S evere autonomic dysfunction •  H  allucinations in other modalities •  S ystematized delusions •  D  epression •  R  elative preservation of mesial temporal lobe structures on computed tomography/magnetic resonance imaging •  R  educed occipital activity on SPECT/PET •  L ow-uptake MIBG myocardial scintigraphy •  P  rominent slow-wave activity on EEG with temporal lobe transient sharp waves EEG, electroencephalogram; LBD, Lewy body dementia; MIBG, metaiodobenzylguanidine; PET, positron emission tomography; REM, rapid eye movement; SPECT, single-photon emission computed tomography.

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CLINICAL HISTORY AND FEATURES LBD is a progressive neurodegenerative dementia that can overlap clinically and pathologically with other parkinsonian dementias, primarily PDD and occasionally Alzheimer dementia. (See Table 21–1 for an overview of the parkinsonian dementias and Table 21–2 for diagnostic features of LBD.) If the onset of dementia is prior to or in conjunction with motor signs, particularly with visual hallucinations and episodes of reduced responsiveness, the diagnosis of LBD should be considered. The following clinical features help distinguish LBD from Alzheimer dementia: (1) fluctuations in cognitive function with varying levels of alertness and attention, (2) visual hallucinations, and (3) parkinsonian motor features that appear relatively early in LBD. Other suggestive features include RBD, severe neuroleptic sensitivity, and low dopamine transporter uptake on functional brain scans. Cognitive impairment in LBD is characterized by more executive dysfunction and visual-spatial impairment rather than the anterograde memory loss of AD. It is not unusual for someone with LBD to have a relatively severe cognitive impairment by history but with a relatively preserved delayed recall with severe constructional apraxia with neuropsychological testing. This combination is virtually never seen in AD.

PATHOLOGY Frederick Lewy first described Lewy bodies (LBs) in 1912 as cytoplasmic inclusions in the substantia nigra of patients with PD. LBs were first reported to be a rare finding associated with dementia in the early1960s. It was not until the mid1980s, when sensitive immunocytochemical methods to identify LBs were developed, that identified alpha-synuclein inclusions within LBs and dementia with LBs (LBD) was recognized as being far more common than previously thought. However, there is considerable controversy as to whether LBD and PD should be described as two different conditions or as being on the same spectrum, with the latter being more likely as they share common neuropathologic features. The synucleinopathies include PD, MSA, and LBD. In LBD, alpha-synuclein deposition is present not only in the brainstem, but also in limbic and neocortical regions.

DIAGNOSTIC STUDIES Laboratory studies should include the routine laboratory studies to evaluate for treatable causes of dementia, including a comprehensive metabolic panel, complete blood count (CBC), thyroid studies, vitamin B12 levels, syphilis serology, Lyme disease serology, and HIV testing, when appropriate. Imaging studies are important to evaluate for other conditions that can mimic this disorder (vascular dementia, tumor, normal pressure hydrocephalus, etc). Patients with LBD usually have less hippocampal atrophy than patients with AD (but more than control subjects). Whether this difference is clinically useful is under investigation, as is the diagnostic utility of functional imaging. Single-photon emission computed tomography (CT) scanning or positron emission tomography scanning can show decreased occipital lobe blood flow or metabolism in LBD but not in AD. Reduced dopamine

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transporter activity in the basal ganglia is seen with positron emission tomography scanning or single-photon emission CT scanning. Neurocognitive testing can be helpful to differentiate LBD from AD and to establish a baseline for future comparison. CSF examination is not required in routine cases; however, it has recently been found that patients with AD have higher levels of tau protein in their CSF than patients with LBD. CSF levels of betaamyloid are lower than normal in LBD and AD. Polysomnography should be considered in these patients for evaluation of RBD, especially early in the disease process when parkinsonism and/or cognitive signs are mild to absent.

TREATMENT It is important to rule out and treat reversible causes of cognitive decline or confusion such as delirium, medication toxicity, and seizures. There are no medications that have been shown to delay the progression of LBD. Symptomatically, the anticholinesterase medications (ie, rivastigmine, donepezil, and galantamine) have been demonstrated to have cognitive/behavioral symptom improvement. Disabling parkinsonism can be treated cautiously with titrated doses of levodopa or other PD medications while monitoring for increased psychosis. Conversely, if psychotic symptoms are present, atypical neuroleptic agents such as quetiapine can be used with extreme caution, and close monitoring for worsening of parkinsonism. RBD can be treated, if necessary, with melatonin or clonazepam.

CASE CORRELATION šš

See also Case 20 (Alzheimer Dementia) and Case 24 (Multiple Sclerosis)

COMPREHENSION QUESTIONS 21.1 A 68-year-old woman is diagnosed with dementia with Lewy bodies. Which of the following is the least appropriate initial treatment? A. Rivastigmine B. Donepezil C. Haloperidol D. Galantamine 21.2 A 61-year-old man is brought into the physician’s office for memory loss and confusion. Which of the following symptoms is most suggestive of AD as opposed to dementia with Lewy bodies? A. Visual hallucinations B. Dramatic fluctuations in clinical condition C. Early anterograde memory loss D. Early shuffling gait

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21.3 A 73-year-old man is noted to have a slow onset of cognitive deficits. The physical examination reveals no obvious etiology. Which of the following imaging findings is most suggestive of dementia with Lewy bodies, using either structural or functional neuroimaging? A. Medial temporal lobe atrophy B. Parietal temporal hypometabolism C. Atrophy of the midbrain D. Occipital lobe hypometabolism

ANSWERS 21.1 C. Haloperidol is a typical neuroleptic (dopamine receptor antagonist) that can have severely deleterious consequences in this disorder. The other three drugs are cholinesterase inhibitors, and evidence for their use in LBD can be found in the literature. 21.2 C. Cognitive impairment in LBD is characterized by executive dysfunction and visuospatial impairment more than the anterograde memory loss of AD. 21.3 D. Occipital lobe hypometabolism is most typical of LBD. Medial temporal lobe atrophy and parietal temporal hypometabolism are characteristic of AD. Atrophy of the midbrain is characteristic of progressive supranuclear palsy.

CLINICAL PEARLS »»

LBD is the second most common cause of dementia behind AD.

»»

The classic clinical syndrome of LBD includes cognitive decline with fluctuations in the level of awareness, parkinsonism, and visual hallucinations.

»»

RBD can be one of the first symptoms of LBD, prior to the onset of significant cognitive or motor disturbance.

»»

Levodopa can be effective for the parkinsonism but can exacerbate hallucinations.

»»

Typical antipsychotics should be avoided in patients with LBD, given their sensitivity to neuroleptics.

REFERENCES Ballard C, Grace J, McKeith I, et al. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer’s disease. Lancet. 1998;351:1032-1033. Bonner LT, Tsuang DW, Cherrier MM, et al. Familial dementia with Lewy bodies with an atypical clinical presentation. J Geriatr Psychiatry Neurol. 2003;16:59-64.

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Geser F, Wenning GK, Poewe W, et al. How to diagnose dementia with Lewy bodies: state of the art. Mov Disord. 2005;20(suppl 12):S11-S20. Gomberts S. Lewy body dementias: dementia with Lewy bodies and Parkinson disease dementia. Continuum (Minneap Minn). 2016;22(2):435-463. Korczyn AD, Reichmann H. Dementia with Lewy bodies. J Neurol Sci. 2006;248:3-8. Kurlan R, Cummings J, Raman R, Thal L; Alzheimer’s Disease Cooperative Study Group. Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology. 2007;68: 1356-1363. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65:1863-1872. Miyasaki JM, Shannon K, Voon V, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66:996-1002. Vann Jones SA, O’Brien JT. The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychol Med. 2014;44:673-683. Wang HF, Yu JT, Tang SW, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg Psychiatry. 2015;86:135-143.

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CASE 22 A 48-year-old man complains of “numbness and stiffness” in his arms for the past 4 months. His gait has gradually deteriorated because of unsteadiness. On examination, the patient appears older than his stated age. His hair is nearly completely gray. There is slight limitation of head movement to either side but no pain with neck extension. His tongue is red and depilated. His gait is broad based, and he is unable to walk in a straight line. He is able to stand with his feet together with his eyes open, but he nearly fell when his eyes were closed. He has normal arm coordination but is ataxic on the heel-knee-shin maneuver. Deep tendon reflexes (DTRs) are 3+ in the arms, trace at the knees, and absent at the ankles. Both plantar responses are extensor. He has a positive jaw jerk and a snout reflex. There is a stocking pattern decrease in sensation and a marked decrease in vibration and joint position sense in the toes and ankles. Cranial nerves are normal, and there are mild problems with memory and calculation. T2-weighted magnetic resonance imaging (MRI) of the brain demonstrates extensive areas of high-intensity signal in the periventricular white matter. MRI of the spine shows a hyperintense signal along the posterior column of the spinal cord. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 22: Subacute Combined Degeneration of the Spinal Cord Summary: This is a case of a 48-year-old patient with a progressive gait disorder characterized by sensory ataxia caused by impaired position sense and spasticity. His examination is significant for both peripheral and central nervous system (CNS) involvement, primarily affecting the white matter fibers of the posterior columns of the spinal columns and pyramidal tracts and large myelinated peripheral nerve affecting coordination and muscle tone. šš šš

šš

Most likely diagnosis: Vitamin B12 deficiency Next diagnostic step: Serum vitamin B12 level, and if the level is low, subsequent testing to determine the source of B12 malabsorption Next step in therapy: Intramuscular vitamin B12

ANALYSIS Objectives 1. Understand the range of pathologic and clinical manifestations of vitamin B12 deficiency. 2. Know the differential diagnosis of vitamin B12 deficiency. 3. Understand the types of tests to confirm the diagnosis and etiology of vitamin B12 deficiency. 4. Be aware of the proper mode of repletion of vitamin B12.

Considerations The pertinent features of this case include unsteadiness of gait, numbness, and stiffness. The physical examination helps to localize the pathology. There was a stocking pattern decrease in sensation, specifically involving vibration and joint position sense, which strongly suggests a neuropathy involving myelinated fibers ascending through sensory peripheral nerves to the dorsal columns of the spinal cord, at or above the lumbar level. The pathologically increased reflexes in the arms and knees along with the presence of primitive reflexes (jaw jerk, snout reflex, and Babinski) are “upper motor neuron signs” and suggest involvement of the corticospinal tract above the level of the cervical spinal cord. In this case, one would expect increased reflexes in the legs also, unless there is a coexistent neuropathy. The ataxic heel-knee-shin maneuver also points to aberrant input to the cerebellum, which travels through large fibers. The mild problems on mental status examination indicate possible cortical or subcortical dysfunction. All of these findings suggest involvement at multiple levels of the nervous system. The imaging study confirms involvement of myelinated regions in the spinal cord, specifically the dorsal columns, and in the brain. Assuming all these signs/symptoms are

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manifestations of a single entity, a systemic disease should be considered, such as human immunodeficiency virus 1 (HIV-1)–associated vacuolar myelopathy, Lyme disease, multiple sclerosis, neurosyphilis, or vitamin B12 deficiency. Neuropathic conditions would not be expected to give upper motor neuron signs. Additional clues on the general physical examination are the abnormal tongue and prematurely graying hair.

APPROACH TO: Subacute Combined Degeneration of the Spinal Cord Spinal cord diseases are common, and many are treatable if discovered early. The spinal cord is a tubular structure originating from the medulla of the brain and extending through the lumbar region in the vertebral column. Ascending sensory and descending motor white matter tracts are located peripherally; posterior columns govern joint position, vibration, and pressure, lateral spinothalamic tracts carry pain and temperature, and ventral corticospinal tracts carry motor fibers.

VITAMIN B12 DEFICIENCY Vitamin B12 deficiency usually presents as paresthesias in the hands and feet and loss of vibratory sense. There is a diffuse effect on the spinal cord, primarily the posterior lateral columns, explaining the early loss of vibratory sense and joint position. Late in the course, optic atrophy and cognitive changes as well a sensory ataxia can occur. Macrocytic anemia is common. Cyanocobalamin is a compound that is metabolized to a vitamin in the B complex commonly known as vitamin B12. Vitamin B12 is the most chemically complex of all the vitamins. The structure of B12 is based on a corrin ring with cobalt as the central metal ion. Once metabolized, cobalamin is a coenzyme in many biochemical reactions, including DNA synthesis, methionine synthesis from homocysteine, and conversion of propionyl into succinyl coenzyme A from methylmalonate. Dietary cobalamin (Cbl), obtained through animal meats, enters the stomach bound to animal proteins. Absorption requires many factors, including stomach acid, R-protein, intrinsic factor from parietal cells, and the distal 80 cm of the ileum for transport. Following ingestion, vitamin B12 is cleaved from other proteins by gastric acid and binds to intrinsic factor in the duodenum. The intrinsic factor cobalamin complex is absorbed in the ileum. However, 1% of vitamin B12 is absorbed passively in the terminal ileum, independent of intrinsic factor. Following absorption, vitamin B12 binds to transcobalamin II, which is responsible for the delivery of vitamin B12 to tissues. Interference in any of these points can lead to malabsorption of vitamin B12. In addition, there are a number of inborn errors of metabolism that can interfere with both the absorption and the action of vitamin B12. The most common cause of vitamin B12 deficiency is malabsorption because of pernicious anemia, a condition where antibodies are generated to the parietal cells of the stomach, and the necessary proteins, including intrinsic factor, are not available; thus vitamin B12 is unable to be absorbed. There are many other causes, however,

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that should be considered, such as bariatric surgery, intestinal parasites, various medications, and rare genetic disorders. Decreased intake may also occur in those who eat a vegan diet or are malnourished. Pathologically, in experimental subacute combined degeneration (SCD), there is edema and destruction of myelin. Thus, the clinical presentation of SCD is caused by dorsal column, lateral corticospinal tract, and sometimes lateral spinothalamic tract dysfunction. The initial symptoms are usually paresthesias in the hands and feet. This condition can progress to sensory loss, gait ataxia, and distal weakness, particularly in the legs. If the disease goes untreated, a spastic paraparesis can evolve. Common findings on examination are loss of vibratory and joint position sense (due to involvement of the dorsal column) and upper motor neuron signs (weakness, spasticity, hyperreflexia, and extensor plantar responses). The syndrome of sensory loss as well as spastic paraparesis associated with pathologic lesions in the dorsal columns and lateral corticospinal tracts is referred to as SCD. There are also effects on other body systems, most conspicuously hematologic with the macrocytic (megaloblastic) anemia.

DIFFERENTIAL DIAGNOSIS The clinical manifestations of vitamin B12 deficiency are noted in Table 22–1. The differential diagnosis for progressive spastic paraplegia includes degenerative, demyelinating, infectious, inflammatory, neoplastic, nutritional, and vascular disorders,

Table 22–1  •  CLINICAL MANIFESTATIONS OF VITAMIN B12 DEFICIENCY Neurologic •  P  aresthesia •  P  eripheral neuropathy •  C  ombined systems disease (demyelination of dorsal columns and corticospinal tract) resulting in loss of vibratory and position sense Behavioral •  Irritability, personality change •  M  ild memory impairment, dementia •  D  epression •  P  sychosis General •  L emon-yellow waxy pallor, premature whitening of hair •  F labby bulky frame •  M  ild icterus •  B  lotchy skin pigmentation in dark-skinned patients Cardiovascular •  T achycardia, congestive heart failure Gastrointestinal •  B  eefy, red, smooth, and sore tongue with loss of papillae that is more pronounced along edges Hematologic •  M  egaloblastic anemia; pancytopenia (leukopenia, thrombocytopenia)

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including HIV-1–associated vacuolar myelopathy, Lyme disease, multiple sclerosis, neurosyphilis, toxic neuropathy, and copper deficiency. The differential diagnosis of SCD is broad, but B12 deficiency should be considered in any patient with progressive sensory symptoms or weakness or even cognitive decline.

LABORATORY CONFIRMATION Testing for vitamin B12 deficiency includes a direct assay of the vitamin as well as looking at the indirect effect of abnormal reactions, resulting in altered metabolite levels. The definitions of Cbl (vitamin B12) deficiency are as follows: serum Cbl level less than 150 pmol/L on two separate occasions or serum Cbl level less than 150 pmol/L and total serum homocysteine level greater than 13 μmol/L or methylmalonic acid greater than 0.4 μmol/L (in the absence of renal failure and folate and vitamin B6 deficiencies). It is important to note that many patients with neurologic manifestations may still have normal or borderline low values of cobalamin, and the hematologic manifestations may not present until later in the disease course. Therefore, in these cases where vitamin B12 deficiency is suspected, it is important to measure levels of methylmalonic acid and homocysteine, both of which should be elevated. The hematologic manifestations of vitamin B12 deficiency can be mimicked by folate deficiency, but this does not mimic the neurologic manifestations. In addition, the multiple organ systems and subsystems affected are highly variable from patient to patient. Confirmatory effects of the anatomic and physiologic consequences of B12 deficiency involve nerve conduction studies and MRI. Findings in these cases include modest expansion of the cervical and thoracic spinal cord and increased signal intensity on T2-weighted images, primarily in the dorsal columns and lateral pyramidal tracts.

TREATMENT Treatment of vitamin B12 deficiency involves administering the vitamin in a fashion to bypass the pathologic steps in the transport process. This usually involves intramuscular administration of the vitamin, first to build up stores and then on a monthly basis—specifically, 1000 μg/d for 1 week, then 1000 μg/wk for 1 month. After this, 1000 μg/mo is given until the cause of deficiency is corrected, or for life in the case of pernicious anemia. This is effective for all forms of deficiency. There are also methods of oral administration that are sometimes effective since 1% of vitamin B12 is absorbed passively in the terminal ileum without interaction with intrinsic factor. Treatment can reverse or stop most, if not all, of the sequelae of vitamin B12 deficiency.

CASE CORRELATION šš

See also Case 24 (Multiple Sclerosis)

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COMPREHENSION QUESTIONS 22.1 Vitamin B12 repletion by which of the following routes will be effective in virtually all causes of B12 deficiency? A. Concentrated oral vitamin B12 B. Nasal vitamin B12 administration C. A diet high in red meats D. Intramuscular B12 administration 22.2 Which feature of the clinical picture might make you most suspicious of vitamin B12 deficiency as a cause for a patient with spastic paresis and sensory loss? A. Severe signs and symptoms developing over 1 day B. Loss of pain and temperature sensation in excess of vibration and joint position sense C. Severe weakness with spasticity and loss of all sensory modalities in the legs with a neurogenic bladder D. Anemia with an increased mean corpuscular volume (MCV) and hypersegmented polymorphonuclear cells 22.3 Which feature of vitamin B12 deficiency is not mimicked in at least some cases of typical multiple sclerosis? A. Loss of vibration and joint position sensation in the feet B. Positive Babinski signs C. Slowed nerve conduction velocities D. Increased signal on T2 imaging in the spinal cord

ANSWERS 22.1 D. Intramuscular administration is nearly always effective. The other forms require some aspect of the body’s B12 absorption system. 22.2 D. Megaloblastic anemia is the characteristic finding in vitamin B12 deficiency. The clinical picture usually develops over months, not days. Usually, all limbs are involved to some extent, and severe involvement of the legs and not arms makes one consider an anatomic lesion in the spinal cord. In addition, vibration and joint position sense are usually involved much more than pain and temperature. 22.3 C. Multiple sclerosis is by and large a disorder of the CNS and does not affect peripheral nerve conduction studies.

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CLINICAL PEARLS »»

Vitamin B12 deficiency typically affects peripheral nerves, as well as the dorsal columns and lateral corticospinal tracts, giving a syndrome of spasticity with ataxia as a result of loss of joint position sense. There are many more neurologic signs, however, that can variably be seen.

»»

Copper deficiency can present with signs and symptoms identical to vitamin B12 deficiency. Acquired copper deficiency is associated with intestinal disease such as celiac disease, gastric bypass surgery, excessive zinc supplementation, and liver disease such as Wilson disease. Symptoms can improve or stabilize with copper repletion and correction of cause.

»»

Nerve conduction studies can show both demyelinating and denervation features in vitamin B12 deficiency.

»»

The most common cause of vitamin B12 deficiency is pernicious anemia.

»»

Intramuscular administration of vitamin B12 is the most effective way of treating this condition and can reverse or stop the neurologic features.

»»

Vitamin B12 deficiency is associated with a macrocytic anemia.

REFERENCES Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171(3):251-259. Goodman BP. Metabolic and toxic causes of myelopathy. Continuum (Minneap Minn). 2015; 21(1 Spinal Cord Disorders):84-99. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5(11):949-960. Scalabrino G. Cobalamin (vitamin B[12]) in subacute combined degeneration and beyond: traditional interpretations and novel theories. Exp Neurol. 2005;192:463-479. Ulrich A, Müller D, Linnebank M, Tarnutzer AA. Pitfalls in the diagnostic evaluation of subacute combined degeneration. BMJ Case Rep. 2015;2015.

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CASE 23 A 23-year-old, right-handed Caucasian woman is being evaluated for 1 week of gradually worsening vision in her left eye. The patient also reports pain with left eye movement that started at the same time. The patient denied a history of trauma, redness, discharge, or headache. She denies any significant past medical or surgical history and does not take any medication. The examination revealed a visual acuity of 20/20 in the right eye and 20/40 in the left with diminished color perception. The examination revealed no ptosis. Her pupils were reactive to light, constricting from 4 to 2 mm on the right, but only 4 to 3 mm on the left. When light is swung from the right eye to the left eye, the left eye appears to dilate slightly. Extraocular movements were intact in both eyes, though the patient complained of pain in the left with movement. Slit-lamp examination was normal in both eyes. Dilated examination was normal in both eyes with no disc edema. Formal visual field testing revealed an enlarged blind spot in the left eye. The rest of the neurologic examination was normal. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 23: Optic Neuritis Summary: A 23-year-old right-handed woman is being evaluated for unilateral, subacute, painful loss of vision that is not associated with any systemic or other neurologic symptoms. She has a left relative afferent pupillary defect, and although extraocular movements are intact in both eyes, the patient reports pain with eye movement. šš šš

šš

Most likely diagnosis: Optic neuritis (ON). Next diagnostic step: ON is a clinical diagnosis that is made on the basis of the history and physical examination. Magnetic resonance imaging (MRI) of the brain should be performed, preferably within 2 weeks of the onset of symptoms to evaluate the optic nerve and other brain regions. Next step in therapy: Short course of intravenous methylprednisolone.

ANALYSIS Objectives 1. Understand the differential diagnosis of monocular visual compromise. 2. Describe the clinical manifestation of ON. 3. Understand the relationship of ON and multiple sclerosis (MS). 4. Understand when and how to treat ON.

Considerations This case is typical for ON, which is an inflammatory, demyelinating condition that causes acute, usually monocular, visual loss. It may be associated with a variety of systemic autoimmune disorders, but with typical ON the most common association is MS. ON is the presenting feature of MS in 20% of patients and occurs in 50% of MS patients at some time during the course of their illness. Most cases of acute demyelinating ON occur in women and typically develop in patients between the ages of 20 and 45. Recovery begins within several weeks of onset of symptoms, and approximately 90% of patients experience a good visual recovery. Some patients have residual deficits in contrast sensitivity, color vision, depth perception, light brightness, visual acuity, or visual field. The patient in this case requires careful neurologic and ophthalmic assessment. Brain imaging and lumbar puncture (LP) for assessment of possible demyelinating disease may be necessary. In contrast to this case, in a young child presenting with these signs and symptoms, infectious and postinfectious causes of optic nerve impairment should be considered as alternatives to ON, while in an older patient (>45 years), ischemic optic neuropathy (eg, due to diabetes mellitus or giant cell arteritis) is a more likely diagnosis than ON. The differential diagnosis of inflammatory optic neuropathy is summarized in Table 23–1.

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Table 23–1  •  CAUSES OF OPTIC NEUROPATHY Ischemic optic neuropathy

Anterior ischemic optic neuropathy

Optic neuritis

Multiple Sclerosis Neuromyelitis optica (Devic disease)

Infections

Neuroretinitis: viruses, toxoplasmosis, Bartonella, others Meningitis (any cause) Syphilis, Lyme disease

Inflammatory

Parainfectious Systemic autoimmune disease: systemic lupus erythematosus, Sjogren syndrome, others Paraneoplastic Sarcoidosis

Genetic

Leber hereditary optic neuropathy

Neoplasms (compressive, infiltrative)

Optic glioma Meningioma Metastasis Lymphoma

Compression

Abscess Carotid—ophthalmic artery aneurysm Thyroid ophthalmopathy Orbital pseudotumor Pseudotumor cerebri

Toxic/Metabolic

Drugs (ethambutol, amiodarone) Toxins Nutritional deficiency (vitamin B1, B12, folate) Tobacco—alcohol amblyopia Radiation

Trauma

Axonal injury

(Data from UpToDate: http://www.uptodate.com/contents/optic-neuritis-pathophysiology-clinical-features-anddiagnosis.)

APPROACH TO: Optic Neuritis DEFINITIONS SCOTOMA: An isolated area of diminished vision within the visual field. RELATIVE AFFERENT PUPILLARY DEFECT: When one eye has decreased afferent function relative to the other, the pupil will not constrict as well in response to direct light stimulus. This is demonstrated by shining a light alternately in one eye and then the other (“swinging flashlight test”). When the light is directed into the normal eye, both pupils constrict normally. When the light is then directed into the affected eye, the pupils will appear to dilate instead of constricting. The consensual responses should be intact in both eyes because the efferent pathways are not affected (Figure 23–1).

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A. BOTH EYES NORMAL Diffuse Illumination

5 mm 5 mm Normal reaction of both pupils Light on Normal Eye

2 mm 2 mm Normal reaction of both pupils

B. ABNORMAL RIGHT EYE

Afferent pupillary defect

4 mm

4 mm

Normal eye

Decreased reaction of both pupils

Afferent pupillary defect

2 mm

2 mm

Normal eye

Normal reaction of both pupils Figure 23–1.  Swinging flashlight test for afferent pupillary defect.

EPIDEMIOLOGY The annual incidence of unilateral ON is approximately 1 to 5 per 100,000. ON is seen most commonly in Caucasians (85% of patients) and in women (77% of patients). Rates are greater at higher latitudes, during spring, and in patients of

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northern European decent. The onset is usually between 20 and 45 years, with a mean age of 32.

PATHOPHYSIOLOGY The pathophysiology of typical ON is inflammation and demyelination of the optic nerve. It is believed that the demyelination in ON is immune-mediated, but the specific mechanism and target antigen(s) are unknown. Systemic T-cell activation is identified at symptom onset and precedes changes in the cerebrospinal fluid (CSF). Activated peripheral T cells migrate across the blood-brain barrier and release cytokines and other inflammatory mediators, causing acute demyelination and ultimately resulting in neuronal cell death and axonal degeneration. Inflammatory demyelination is the pathologic hallmark of MS, but after the acute event, axonal damage leads to axonal loss and irreversible neurologic impairment.

CLINICAL APPROACH Clinical Presentation ON is usually monocular in its clinical presentation. Bilateral optic neuropathy is more common in children but rare in adults. If symptoms occur in both eyes, either simultaneously or in rapid succession, this may indicate an alternative case of ON. The most common symptoms are pain and vision loss. Over 90% of ON patients complain of eye pain. The periorbital or retrobulbar pain may start 1 to 2 weeks before the vision loss or coincide with the change in vision. The patients often report that the pain is dull and aching in quality and is exacerbated by eye movement. Vision loss typically develops over a period of hours to days, peaking within 1 to 2 weeks. Continued deterioration after that time suggests an alternative diagnosis. Almost all types of visual field defects have been seen in patients with ON, but central scotoma seems to be the most common defect. Visual loss may also include loss of acuity, contrast sensitivity, or dyschromatopsia (color vision defects). Patients may also report positive visual phenomena such as flashes of light or floaters. On clinical examination, unilateral vision loss should be associated with a relative afferent pupillary defect. Dilated fundoscopic examination findings can be divided into two categories: šš

šš

Papillitis—Anterior ON is defined by swelling of the optic disc. It is seen in one-third of patients with ON. Figure 23–2 shows papillitis with hyperemia and swelling of the disc with blurring of disk margins. If a patient also has macular exudates giving the appearance of “macular star,” the diagnosis is neuroretinitis and much more common in infectious etiologies. Retrobulbar neuritis—The optic disc appears normal because the inflammation is located in the optic nerve after it exits the eye. Two-thirds of ON patients have a normal fundoscopic examination. The optic disc will also appear normal in perineuritis, which is inflammation of the optic nerve sheath rather than the nerve itself. This is more common in infectious processes.

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Figure 23–2.  Papillitis with hyperemia and swelling of the disc in a patient with left optic neuritis. (Reproduced, with permission, from Andrew G. Lee, MD.)

Recovery should begin within several weeks. Continued progression of symptoms after 2 weeks or lack of improvement after 8 weeks suggests an alternative diagnosis. Even after clinical recovery, signs of ON can persist. Over 90% of patients will have good visual recovery, meaning visual acuity of 20/40 or better. However, they may continue to have residual subjective and measurable defects. After the attack, optic atrophy can be seen on fundoscopic examination, especially in the temporal quadrant. Temporary exacerbations of visual problems in patients can occur with increased body temperature (Uhthoff phenomenon). Hot showers and exercise are classic precipitants. In the Optic Neuritis Treatment Trial (ONTT), recurrent ON occurred at a rate of 35% at 10 years after the first attack, with MS patients at the highest risk. It may occur in the same eye or the contralateral eye.

Diagnosis In general, ON is a clinical diagnosis based on history and examination findings. Because important findings on fundoscopic examination help differentiate typical from atypical cases of ON, an ophthalmologic examination should be considered an essential feature of the clinical evaluation. Patients with typical ON do not require further testing for diagnostic purposes, but one may consider a basic screening evaluation with blood studies such as syphilis serology, inflammatory markers, serum chemistries, or complete blood count if the patient has any additional symptoms. MRI with gadolinium contrast shows contrast enhancement of the optic nerve in about 95% of cases (Figure 23–3). MRI of the brain with and without contrast is performed to assess for additional signs of demyelinating disease, which can influence both the prognosis and the long-term treatment. At the final 15-year followup of the ONTT, patients with an abnormal baseline MRI had a much higher risk

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Figure 23–3.  T1-weighted MRI showing gadolinium enhancement of the left optic nerve. (Reproduced, with permission, from Majdi Radaideh, MD.)

of developing MS compared to those with a normal MRI (72% vs 25%). It is a common practice to start disease-modifying therapy after an initial attack of ON if the MRI is concerning for MS, as this has been shown to delay the onset of a second attack. In atypical cases (eg, prolonged or severe pain, lack of visual recovery, atypical visual field loss, evidence of orbital inflammation), MRI is used to further characterize and to exclude other disease processes. CSF analysis is not necessary in patients with typical demyelinating ON. In the ONTT, only the presence of oligoclonal bands correlated with later development of MS, and an abnormal baseline MRI was a better predictor of MS. When performed, CSF analysis for cell count, protein, immunoglobulin G (IgG) index, and oligoclonal banding might be useful for supporting a clinical diagnosis of MS in patients with typical ON. Patients with atypical ON may require an LP to exclude an alternative etiology for an optic neuropathy. Optical coherence tomography (OCT) is a noninvasive imaging study performed in the ophthalmology clinic. It may show disc edema in the acute attack and can be followed over time after the attack to assess the extent of atrophy in the retinal nerve fiber layer. Visual-evoked potentials classically show delay of the P100 waveform in demyelinating lesions of the optic nerve but are not required to make the diagnosis.

Treatment ON is treated with intravenous corticosteroids, which hasten recovery by several weeks but have no effect on long-term visual outcomes. Although corticosteroids have no effect on recurrence of ON in the affected eye, studies suggest that steroids decrease the risk of developing clinical MS in the first 2 years following treatment

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in patients who have abnormalities on their MRI at the onset of their visual loss. Treatment with oral prednisone at standard doses was actually associated with an increased recurrence rate of ON at 2 years. While the reason for this finding is unclear, oral prednisone therapy is avoided in acute ON. Many of the inflammatory optic neuropathies that mimic ON are also steroid-responsive. In patients without response to steroid therapy, there is some evidence to suggest plasmapheresis could improve visual outcomes. Intravenous immunoglobulin (IVIg) has not been proven to have a beneficial effect. Decision to treat typical ON is based on severity of symptoms and medical comorbidities. Since treatment will only serve to hasten recovery time, one must consider the risks and benefits of intravenous steroid therapy in the individual patient.

CASE CORRELATION šš

See also Case 24 (Multiple Sclerosis)

COMPREHENSION QUESTIONS 23.1 A 72-year-old man with history of arthritis, especially in his shoulders, complains of acute loss of vision to his right eye and new-onset pain in the periorbital area lateral to his eye. The examination suggests ON. Which of the following conditions is most likely to be associated? A. Giant cell arteritis B. MS C. Wegener granulomatosis D. Neuromyelitis optica 23.2 A 24-year-old man is noted to have ON and also weakness. A tentative diagnosis of MS is made. Which of the following is associated with an increased risk of developing MS? A. One lesion on MRI of the brain B. CSF with mildly elevated white blood cell count C. History of ocular trauma D. Recent history of vaccination 23.3 Which of the following would be considered atypical for ON? A. Pain with eye movement B. Decreased color vision C. Simultaneous involvement of both eyes D. Complete loss of vision in the affected eye

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23.4 Which of the following statements is true? A. An MRI of the brain is required to diagnose ON. B. Intravenous steroids are the standard of care because these help improve the visual outcomes of the patients. C. The first symptom is usually vision loss, followed by eye pain soon after. D. While most patients can be expected to make a good visual recovery even without treatment, long-term follow-up will usually reveal optic atrophy.

ANSWERS 23.1 A. Giant cell arteritis can be associated with ON in older patients. Patients may have new-onset headaches, jaw claudication, and tenderness on palpation of the temple. Polymyalgia rheumatica is strongly associated with giant cell arteritis, so it is important to ask patients about proximal joint pain. Wegener granulomatosis is more common in men but less likely at this age. Neuromyelitis optica can occur in older individuals but is very rare and usually affects individuals between ages 40 and 50. MS would be lower on the differential in this patient due to the age, sex, and associated new-onset headache. 23.2 A. ON patients with an abnormal MRI have a much higher risk of developing MS than those who had a normal MRI. Abnormal CSF studies, particularly the presence of oligoclonal bands, are also associated with an increased risk of disease. However, no CSF study is diagnostic of disease, and the MRI is considered more reliable than CSF oligoclonal bands in predicting future MS risk. 23.3 C. Bilateral ON, either simultaneously or in rapid succession, should suggest another etiology than typical ON, possibly neuromyelitis optica. Typical ON can have varied visual loss, involving color vision, contrast sensitivity, and visual acuity. Even patients with severe visual deficits can make a good recovery with typical ON. 23.4 D. Patients with a prior history of ON have optic atrophy, and many patients will continue to report vision abnormalities. An MRI is not required to make the diagnosis but is recommended to determine the risk for further demyelinating events. Intravenous steroids hasten the recovery but do not change the ultimate outcome. Over 90% of patients report eye pain, and it can start up to 1 to 2 weeks before the vision loss.

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CLINICAL PEARLS »»

ON typically presents as an acute monocular compromise of vision associated with eye pain, especially with eye movement.

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The standard treatment is IV methylprednisolone, but this has only been shown to hasten recovery and does not change the long-term visual outcomes.

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Over 90% of patients with typical ON make a good visual recovery.

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An MRI scan should be obtained in a patient with ON to assess for risk of future MS. An abnormal MRI at the time of the ON attack significantly increases the chance of developing MS in the future (72% of patients at 15 years).

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In patients with bilateral ON or poor visual recovery, consider neuromyelitis optica in the differential diagnosis. There are also many other inflammatory optic neuropathies to consider based on the history and examination findings.

REFERENCES Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006;354:1273-1280. Bermel RA, Balcer LJ. Optic neuritis and the evaluation of visual impairment in multiple sclerosis. Continuum (Minneap Minn). 2013;19(4):1074-1086. Brazis PW, Lee AG. Optic neuritis. In: Evans RW, ed. Saunders Manual of Neurologic Practice. Philadelphia, PA: Saunders/Elsevier; 2003:371-374. Brazis PW, Lee AG. Optic neuropathy. In: Evans RW, ed. Saunders Manual of Neurologic Practice. Philadelphia, PA: Saunders/Elsevier; 2003:375-383. Costello F. Inflammatory optic neuropathies. Continuum (Minneap Minn). 2014;20(4):816-837. Katz Sand IB, Lublin FD. Diagnosis and differential diagnosis of multiple sclerosis. Continuum (Minneap Minn). 2013;19(4):922-943. Pau D, Al Zubidi N, Yalamanchili S, Plant GT, Lee AG. Optic neuritis. Eye. 2011;25:833-842. Toosy AT, Mason DF, Miller DH. Optic neuritis. Lancet Neurol. 2014;13(1):83-99.

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CASE 24 A 24-year-old law student was studying late at night for an examination. As he looked at his textbook, he realized that his left arm and left leg were numb. He dismissed the complaint, recalling that 6 or 7 months ago he had similar symptoms. He rose from his desk and noticed that he had poor balance. He realized that his vision was blurred and remembered that he also had some blurred vision approximately 1 to 2 years earlier that had resolved. He had not seen a physician for any of these previous symptoms. He went to bed and decided that he would seek medical consultation the next day. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 24: Multiple Sclerosis Summary: A 24-year-old man developed multiple neurologic symptoms and, in retrospect, recognized that he had had multiple symptoms over the past 1 to 2 years. šš šš

šš

Most likely diagnosis: Multiple sclerosis (MS). Next diagnostic step: See a physician and undergo a careful neurologic assessment. Blood studies, lumbar puncture, brain imaging, and visual-evoked responses can be indicated. Next step in therapy: Probably intravenous corticosteroids followed by an immune modulatory therapy directed at improving disease course.

ANALYSIS Objectives 1. Understand the differential diagnosis of MS. 2. Describe how to evaluate for MS. 3. Understand the prognosis of MS. 4. Describe when and how to treat MS.

Considerations This is a case of a young man who notes symptoms suggestive of a hemisensory deficit, visual disturbance, and imbalance. Although the patient has not undergone a medical evaluation, his symptoms suggest involvement of at least two sites of the central nervous system (CNS), the spinal cord or brain contralateral to the side of numbness, and possibly his optic nerve affecting vision. The case presentation is also significant for similar symptoms in the past that resolved without treatment. In a young, presumably healthy person with acute onset of symptoms localized to the CNS that are separated by time (current and past symptoms) and space (different areas of the nervous system), MS is the diagnosis until proven otherwise.

APPROACH TO: Multiple Sclerosis DEFINITIONS MULTIPLE SCLEROSIS (MS): MS is a chronic immune-mediated inflammatory disease, usually beginning in young adults and characterized by relapsing, remitting, or progressive neurologic deficits due to demyelinating lesions in the brain or spinal cord.

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INTERNUCLEAR OPHTHALMOPLEGIA: A syndrome of diplopia and nystagmus caused by a lesion in the medial longitudinal fasciculus (MLF). The ipsilateral eye cannot adduct because the communication from the contralateral abducens nerve to the oculomotor nerve is disrupted, resulting in diplopia with horizontal gaze to the opposite side. The contralateral eye will also have nystagmus in horizontal gaze.

CLINICAL APPROACH Epidemiology MS is the most common cause of neurologic disability in young adults, affecting over 1 million individuals worldwide. There are between 250,000 and 500,000 patients with MS in the United States. MS is more common in northern climates in Europe and the United States, with a prevalence of approximately 1 per 1000 people in these areas. It is more common in women than men by a ratio of 2:1, with a peak incidence of 24 years. Symptoms usually begin between the ages of 20 and 40. Research studies reveal that the risk of MS is increased in individuals born or living in temperate zones, but people born or migrating to low-risk areas (ie, nontemperate zones) prior to 15 years have decreased risk. This suggests that exposure to some factor prior to age 15 is important in the genesis of MS. Migration, ethnic, and twin studies suggest that MS is related to genetic as well as environmental factors. If one member of an identical twin pair has MS, there is a 30% chance the other twin will have MS (vs a 2.6% risk for other siblings).

Pathophysiology MS is restricted to the CNS and spares the peripheral nervous system from injury. The pathologic hallmark of MS is focal demyelination within the brain and spinal cord. In MS, discrete areas of damaged myelin, termed plaques, are embedded within normal-appearing tissue. Within each plaque, damaged myelin is associated with inflammatory infiltrates of lymphocytes and macrophages, astrogliosis, and oligodendrocyte injury. It is not known whether the immune response observed in MS plaques is a primary process or secondarily caused by other etiologies, such as infectious, toxic, or metabolic injury. The resulting demyelination and subsequent degeneration of axons account for the disability of patients with MS.

DIAGNOSIS The criteria for diagnosing MS are constantly changing, in part because of increasingly sophisticated brain imaging and immunologic investigations. According to the 2010 McDonald criteria, a definitive diagnosis can be made if the patient has two or more attacks (“dissemination in time”) with objective evidence of two or more lesions (“dissemination in space”).

Clinical Features The onset of MS symptoms usually occurs over several days and is seldom sudden. Acute optic neuritis is the presenting symptom in 20% of patients and affects 50% of all patients at some point. The optic disc may appear normal if the inflammation

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is retrobulbar, but disc edema is seen in the one-third of patients with anterior optic neuritis. Patients typically complain of blurring and loss of vision with eye pain. The eye pain may precede other symptoms and usually worsens with eye movement. The brainstem is commonly involved in MS. Patients may have double vision, internuclear ophthalmoplegia, facial weakness, facial myokymia, vertigo, dysphagia, and dysarthria. Trigeminal neuralgia is characterized by very brief, severe, lancinating maxillary or mandibular pains, and occurs in 1% of MS patients. Trigeminal neuralgia can be due to causes other than MS, but when these symptoms occur in a young adult, MS should be highly suspected. Fifty percent of MS patients have cerebellar signs sometime during the course of their illness. These patients can have limb tremor, ataxia, scanning speech (ie, cerebellar dysarthria), and titubation of the head or trunk. Charcot triad, consisting of intention tremor, dysarthria, and nystagmus, is a well-recognized syndrome in MS but occurs rarely. Weakness affects up to 89% of MS patients and is typically due to a lesion involving the corticospinal tract. Spasticity can be present even without weakness and can lead to gait impairment. Patients can also have sensory symptoms, such as tingling, pins and needle sensations, numbness, or a sensation of a band around the torso. About 87% of MS patients will have sensory complaints sometime during their illness, and over 50% of patients will complain of pain/unpleasant sensations at some point. A partial transverse myelitis is seen in many patients and may result in motor, sensory, bowel, and/or bladder symptoms. Patients with MS may complain of sensations of electricity running down their spine, sometimes extending into the limbs (Lhermitte sign). This symptom is often aggravated by flexing the cervical spine (bending the head forward) and should raise suspicion of MS or other compromise of the upper cervical spinal cord. MS patients can experience sudden and transient neurologic deterioration if their body temperature is elevated (Uhthoff phenomenon). This can occur with fever, increased physical exertion, or taking a hot bath. Many MS patients have bladder dysfunction. Overactive bladder is present in two-thirds of patients, but some may have underactive bladder symptoms. Acute urinary retention may occur with transverse myelitis. Bowel dysfunction is less common but still prevalent, especially constipation; however, incontinence may occur with severe transverse myelitis. Sexual dysfunction is also prevalent among both male and female patients. Cognitive impairment in processing, executive dysfunction, and visual memory is seen in 40% to 70% of patients. This is associated with both white matter involvement and diffuse brain atrophy over time. Depression affects 30% to 45% of patients, but it is unclear if this is due to the disease process or if it is a comorbid disorder. MS patients also have a high incidence of migraine-type headache.

Diagnostic Studies Although the diagnosis of MS relies on recognition of the clinical pattern of disease, several studies are useful in confirming the diagnosis. On magnetic resonance imaging (MRI), typical MS lesions are bright lesions on T2-weighted

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sequences, especially in the periventricular, juxtacortical, and infratentorial regions (Figure 24–1). These lesions are usually linear or ovoid and at right angles to the ventricular surface, which give the classic “Dawson fingers” appearance on sagittal views. Hyperintense lesions are also commonly seen in the spinal cord. T1-weighted images may show “black holes” of old, burned-out plaques. Newer techniques

A

B Figure 24–1.  MRI of the brain T2 FLAIR sequence in a patient with multiple sclerosis demonstrating the “Dawson fingers” appearance of demyelinating plaques perpendicular to the ventricles. (A) Sagittal and (B) axial views.

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of brain imaging, such as fluid-attenuated inversion recovery (FLAIR), provide increased sensitivity and specificity for MS white matter lesions. FLAIR images detect two to three times the number of lesions observed on T2-weighed images. Analysis of cerebrospinal fluid (CSF) also helps in diagnosing MS. In cases where the MRI is normal or shows a pattern that is consistent with other disease processes, such as microvascular ischemia or infection, CSF analysis is indicated. Oligoclonal bands occur in more than 95% of patients with MS, but these are not diagnostic since they can occur in other CNS conditions such as systemic lupus erythematosus, neurosarcoidosis, subacute sclerosing panencephalitis (SSPE), subarachnoid hemorrhage, syphilis, and CNS lymphoma. Elevated immunoglobulin G (IgG) index is also seen in many MS patients but is less sensitive than oligoclonal bands. Increased CSF white cells can be seen in MS, but CSF leukocyte counts greater than 50 mm3 of CSF are rare in MS and should prompt the physician to consider other diagnoses. Electrophysiologic studies of the visual pathways and spinal cord dorsal columns are sometimes useful in documenting involvement of these pathways when imaging studies or physical findings do not support the clinical impression. Visual-evoked potentials, in which a patient views repeated reversal of light and dark checkerboard stimuli while a computer averages scalp electrode potentials, are useful in evaluating patients for MS. Prolongation of the P100 wave reflects compromise of the pathway between the optic nerve and the brain. Optical coherence tomography is a noninvasive ophthalmic imaging study performed in the clinic. Retinal nerve fiber layer (RNFL) thinning occurs due to retinal axon loss. While it is more pronounced in patients with a history of optic neuritis, RNFL thinning has been detected early in the disease process of patients without visual complaints. The differential diagnosis of MS is broad. Many different conditions can mimic MS because of primary or secondary demyelination of CNS pathways. However, the clinical history, physical examination, and diagnostic studies are fundamental in distinguishing these conditions from MS. To rule out other conditions, consider sending screening laboratory studies such as vitamin B12 level, treponemal antibody testing, Borrelia burgdorferi serology, antiphospholipid antibodies, and inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], antinuclear antibody [ANA]).

CLINICAL COURSE There are different clinical patterns or types of MS: 1. Relapsing-remitting MS is the most common form of MS, accounting for 80% to 90% of cases. It is characterized by sudden onset (over hours or days) of neurologic symptoms that usually last several weeks and then resolve, often leaving few or no deficits. The frequencies of these relapses are highly variable but average about one in every 2 years. Some degree of disability is usually present over time. Between attacks, fatigue and sensitivity to heat is common. 2. Secondary progressive MS is seen in most but not all patients with an initial relapsing-remitting course. Patients will develop neurologic decline that is

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not related to the discrete attacks in addition to incomplete recovery from attacks. MS can continue to worsen for many years and then level off with moderate to severe permanent disability. 3. Primary progressive MS is slowly progressive without any clearing of symptoms or relapses and accounts for 10% to 20% of cases. Diagnosis requires 1 year of clinical progression and two of the following: one or more MRI lesions in the brain, two or more MRI lesions in the spinal cord, and CSF with oligoclonal bands and/or elevated IgG index. 4. Progressive-relapsing MS is seen in 5% of patients, with progression at the onset but with subsequent acute relapses as well. 5. Clinically isolated syndrome is characterized by the first demyelinating event that is suggestive of MS. It places the patient at risk for further relapses. Common presentations include optic neuritis, internuclear ophthalmoplegia, sixth nerve palsy, cerebellar symptoms, and partial transverse myelitis. Some patients will go on to develop relapsing-remitting MS and suffer from multiple attacks, whereas others will have no further evidence of demyelinating disease. It is difficult to predict whether a given individual will develop MS following symptom onset, but risk is increased if there are any lesions on MRI or oligoclonal bands in the CSF. After 20 years, 82% of clinically isolated syndrome (CIS) patients with an abnormal MRI progressed to MS, compared to only 21% of those with a normal MRI. 6. Radiologically isolated syndrome, or preclinical MS, is the evidence of demyelinating disease on imaging in patients with no history of a clinical attack. Patients typically underwent imaging for an unrelated issue. One in three will experience an attack within 5 years.

TREATMENT Treatment of patients with MS needs to be individualized for each specific patient and tailored to his or her problems and needs. The treatment should be focused on both the disease and the associated symptoms.

Acute Management For acute flares, the standard treatment is intravenous steroids for about 5 days. Steroids have not been shown to decrease the risk of future attacks or change the natural history of the disease. The goal is to hasten recovery from the acute attack.

Maintenance Therapy Immunomodulating agents or disease-modifying therapies can be used to modify the course of MS and thus are used on a chronic, ongoing basis. These agents can impact the relapse rate, slow progression of disability, and prevent the accumulation or burden of MRI lesions. Since axonal damage leading to irreversible neurologic disability is already present at the onset of the disease, immunomodulatory therapy should start as soon as possible.

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The interferon medications are injectable therapies that may work by altering T cells and sealing the blood-brain barrier against their entry into the CNS. Glatiramer acetate is another injectable therapy. The molecule mimics myelin basic protein and interferes with antigen presentation. It is the only immunomodulator for MS that is pregnancy class B and thus is the treatment of choice in a pregnant patient. Natalizumab is an IV infusion therapy that prevents migration of activated T cells across the blood-brain barrier. It can decrease disease exacerbations and enhancing lesions, but its use is limited by the risk of JC virus reactivation, which can lead to progressive multifocal leukoencephalopathy. Mitoxantrone is an antineoplastic intravenous therapy that is used as a second-line treatment due to its cardiotoxicity and myelosuppressive effect. In recent years, the most significant breakthrough in MS therapy has been the development of oral therapies. While the older therapies have more long-term surveillance data, the newer agents are attractive not only for their effectiveness but also for their convenience. Fingolimod was the first approved oral agent in 2010. It is a sphingosine analog that inhibits lymphocytes from leaving the lymph node. Side effects include bradycardia, so the first dose must be given in a monitored setting. Teriflunomide is another oral therapy that acts as a pyrimidine synthesis inhibitor to decrease T-cell and B-cell proliferation and activation. It is pregnancy class X, and men must use birth control as well because levels can be detected in the semen. It can remain in the circulation for up to 2 years if accelerated clearance protocols (ie, activated charcoal or cholestyramine) are not used. Dimethyl fumarate promotes anti-inflammatory and cytoprotective activities mediated by activation of the Nrf2 antioxidant response pathway. It is given in twice-daily oral doses, and patients frequently complain of flushing and gastrointestinal (GI) upset. Another immunomodulatory treatment option is alemtuzumab, a humanized monoclonal antibody that binds CD52 on T cells and B cells to cause cellular and complement-mediated lysis. It is administered via IV infusion in two doses separated by 1 year. It is FDA approved for relapsing patients who have failed at least two other disease modifying agents. There is an increased risk of thyroid diseases, autoimmune disorders, and idiopathic thrombocytopenia. Ocreluzimab is a CD20 B cell monoclonal antibody which has been shown beneficial in patients with PPMS compared to placebo. It is the first therapy receiving FDA approval for this subset of MS patients.

Symptomatic Therapy Symptomatic therapy for MS can include physical and emotional rest, physical therapy, amantadine or modafinil for fatigue, anticholinergic medication for bladder dysfunction, baclofen or tizanidine for spasticity, selective serotonin reuptake inhibitors (SSRIs) for mood disorders, and clonazepam or valproic acid for cerebellar tremor. Dalfampridine is a prescription medication that blocks potassium channels to enhance conduction in damaged nerves. It has been shown to improve walking in MS patients, and patients report improved fatigue as well.

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CASE CORRELATION šš

See also Case 23 (Optic Neuritis) and Case 22 (Subacute Combined Degeneration of the Spinal Cord)

COMPREHENSION QUESTIONS 24.1  A 28-year-old man is noted to have double vision and leg weakness. A suspicion of MS is entertained. Which of the following findings would be consistent with the diagnosis? A. Oligoclonal bands in CSF B. Onset of symptoms was preceded by a febrile illness C. Abnormal peripheral nerve conduction by electromyography (EMG)/ nerve conduction velocity (NCV) studies D. Meningeal enhancement on contrast MRI of the brain 24.2 A 33-year-old man is noted to have recurrent episodic weakness. He is diagnosed with MS. Which of the following findings is consistent with the diagnosis? A. The diagnosis of MS is based on clinical lesions separated by time and space. B. Oligoclonal bands in the CSF are specific for MS. C. Steroids are effective in improving the course of disease. D. This is a genetic disorder well characterized on chromosome 11. 24.3 The same patient in Question 24.2 is noted to another episode of acute weakness. What is the best treatment option? A. Fingolimod B. Corticosteroid therapy C. Dalfampridine D. Interferon

ANSWERS 24.1 A. Oligoclonal bands are present in the CSF of over 95% of MS patients but are not specific to the disease. Onset of symptoms following a viral illness would raise concern for an acute post-infectious demyelinating syndrome. The acute post-infectious demyelinating syndromes can be differentiated from MS by their single phase, whereas MS requires evidence of disease occurring over time. An abnormal nerve conduction study is more consistent with a peripheral demyelinating process as opposed to the central demyelinated process that occurs in MS. While an MS patient could also have a peripheral neuropathy, it is not part of the MS disease process. Meningeal enhancement is not seen with MS.

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24.2 A. Clinical exacerbations separated by time and space are the hallmark of the diagnosis of MS. Steroids are used in acute exacerbations only and not for long-term disease-modifying therapy. MS is not due to a specific genetic defect. 24.3 B. Steroids remain the standard of care for acute MS exacerbations, despite the development of many new immunomodulatory medications. Fingolimod and interferon are used for long-term maintenance therapy. Dalfampridine provides symptomatic relief but does not treat the underlying disease.

CLINICAL PEARLS »»

MS is a demyelinating disease with lesions separated over time and space.

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MS patients can have lesions on brain MRIs without associated clinical complaints directly related to those lesions.

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Visual compromise and weakness are frequent presenting symptoms in MS.

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The symptoms of MS seem to worsen with elevation of temperature or fever, known as Uhthoff phenomenon.

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While acute relapses are managed with steroids, the long-term management of the disease is through disease-modifying agents. There are now oral therapies in addition to subcutaneous, intramuscular, and intravenous options.

REFERENCES Carrithers MD. Update on disease-modifying treatments for multiple sclerosis. Clin Ther. 2014; 36(12):1938-1945. Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269-290. Genzyme, Inc. Lemtrada (alemtuzumab) prescribing information. Issued November 2014. http://products. sanofi.us/lemtrada/lemtrada.pdf. Accessed February 13, 2015. Katz Sand IB, Lublin FD. Diagnosis and differential diagnosis of multiple sclerosis. Continuum (Minneap Minn). 2013;19(4):922-943. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et. al. For the ORATORIO Clinical Investigators. N Engl J Med. 2017;376:209-220. Popescu BF, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis: where do we stand? Continuum (Minneap Minn). 2013;19(4):901-921.

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CASE 25 A 20-year-old college student presents with a 2-day history of headache, nausea, confusion, weakness in both legs, and urinary incontinence. He had a viral illness 3 weeks earlier, but his symptoms had resolved and he was otherwise healthy. His roommate called 911, and he was taken to the emergency department. On examination, the patient was lethargic, and his speech was slurred. His vitals were stable, he was afebrile, and his general examination was normal. Neurologic evaluation was significant for weakness in his lower extremities. He was able to stand, but his gait was unsteady and he required assistance with walking. His reflexes were diffusely increased, and he had upgoing toes bilaterally. He additionally had a subjective sensory level at the level of his navel. The patient was admitted for evaluation and management. »» »» »»

What is the most likely diagnosis? What is the prognosis for this condition? What is the next step in therapy?

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ANSWERS TO CASE 25: Acute Disseminated Encephalomyelitis Summary: A 20-year-old man has developed multiple neurologic symptoms 3 weeks after the resolution of a viral illness. He complains of headache and had symptoms of spinal cord compromise (ie, weakness in lower extremities, urinary incontinence, sensory level). šš

Most likely diagnosis: Acute disseminated encephalomyelitis (ADEM).

šš

Prognosis: Fairly good.

šš

Next step in therapy: Consider intravenous corticosteroids, plasmapheresis, and intravenous immunoglobulin.

ANALYSIS Objectives 1. Understand the differential diagnosis of ADEM. 2. Understand the evaluation for ADEM. 3. Understand the prognosis of ADEM. 4. Understand when and how to treat ADEM.

Considerations ADEM is a monophasic, demyelinating illness associated with multiple neurologic symptoms secondary to involvement of the brainstem, spinal cord, optic nerves, cerebrum, and/or cerebellum. ADEM usually follows infection or vaccination, especially in children. One-quarter of patients with ADEM will develop multiple sclerosis (MS), often causing difficulty differentiating the first attack of MS from ADEM. However, ADEM is usually uniphasic and has a favorable long-term prognosis.

APPROACH TO: Acute Disseminated Encephalomyelitis DEFINITIONS ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM): ADEM is an acute, uniphasic syndrome caused by an immune-mediated inflammatory demyelination. It often is associated with recent vaccination or viral illness. ACUTE NECROTIZING HEMORRHAGIC ENCEPHALOMYELITIS (ANHE): ANHE is a hyperacute form of ADEM with similar symptoms and etiology. It can rapidly progress to coma and death.

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CLINICAL APPROACH Etiologies and Clinical Presentation ADEM can occur as a postinfectious complication in 1:400 to 1:2000 patients with measles, 1:600 patients with mumps, 1:10,000 patients with varicella, and 1:20,000 rubella patients. It is a postvaccination complication in 1:63 to 1:300,000 patients following vaccinia (smallpox vaccine) and can also occur following other immunizations, including diphtheria (tetanus), pertussis, and rubella. ADEM is a monophasic illness characterized by multiple neurologic signs and symptoms reflecting compromise of the brainstem, spinal cord, cerebrum, optic nerves, and cerebellum. The symptoms appear suddenly 1 to 3 weeks following the infection and can include headache, nausea, vomiting, and confusion. It may progress to obtundation and coma. The etiopathogenesis of ADEM is multifactorial. In a subset of patients who are genetically susceptible to these disorders, the immune system is triggered to react to myelin by an environmental trigger, either by a vaccine or by a virus, and that sets up a cascade of events that causes ADEM. In addition to the above-noted symptoms of ADEM, patients can have hemiparesis, hemisensory compromise, ataxia, optic neuritis, transverse myelitis, seizures, myoclonus, and memory loss. When ADEM follows mumps, the disease usually presents with cerebellar ataxia. ADEM is likely a T-cell–mediated autoimmune disease targeting myelin/ oligodendrocyte antigens, including myelin basic protein. Viral infection may lead to ADEM by causing downregulation of CD4+ suppressor T cells and activation of myelin-reactive T-helper cells. Neuropathology of ADEM consists of perivenular inflammatory myelinopathy, with engorgement of veins in the white matter of the brain. There is perivascular edema with significant mononuclear infiltration, primarily lymphocytes and macrophages. The primary finding is perivenular demyelination with relative sparing of axons. The diagnosis of ADEM primarily focuses on the clinical presentation of a uniphasic illness with multifocal central nervous system (CNS) involvement and encephalopathy. The most challenging aspect of its diagnosis is in distinguishing it from a first attack of MS. Clinically, the encephalopathy distinguishes ADEM from typical MS. Cerebrospinal fluid (CSF) findings can be abnormal but are not specific for ADEM (eg, mononuclear pleocytosis, mildly elevated protein), although oligoclonal bands, which are found in MS, should be absent. Magnetic resonance imaging (MRI) of the brain reveals hyperintense white matter T2-weighted signals and enhancement on T1-weighted images. The lesions vary in size because of the significant associated edema. The lesions described are rather extensive, poorly defined, and more often located in the peripheral subcortical cerebral white matter. Lesions in the thalami are more often described in ADEM than MS and can be a useful finding that suggests ADEM. Conversely, periventricular lesions are less common in ADEM than in MS. The differential diagnosis of ADEM is the same as that noted in Case 24 for MS. The fact that ADEM is monophasic, whereas MS is usually not, and the clear

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time frame of feeling well for several weeks following a viral illness, respectively, help differentiate ADEM from MS and an acute viral episode. The prognosis of ADEM is fairly good. However, approximately one-quarter (up to one-third) of these patients will subsequently relapse following the acute illness. If relapse occurs, the physician should suspect MS.

TREATMENT If there is any suspicion of encephalitis, empiric acyclovir should be started until an infectious cause such as herpes simplex virus encephalitis is excluded. Immune suppression is the main treatment for ADEM. High-dose steroids can be used to shorten the duration of illness, and patients who do not respond to steroids can be treated with intravenous immunoglobulin (IVIg) or plasmapheresis. In severe cases, it is important to maintain vital functions, maintain fluid and electrolyte balance, and avoid pneumonia, urinary infection, and decubitus ulcers.

CASE CORRELATION šš

See also Case 24 (Multiple Sclerosis)

COMPREHENSION QUESTIONS 25.1 Select the combination of signs and symptoms that best help to distinguish ADEM from a first attack MS. A. Oligoclonal bands in CSF, recurrent symptoms, positive vaccination history B. Positive vaccination history, lesions of the thalami, mental confusion C. Pleocytosis in CSF, recurrent symptoms, positive vaccination history D. Recent viral exposure, mental confusion, late ataxia 25.2 A 43-year-old woman is diagnosed with acute lower extremity weakness caused by ADEM. Which of the following is the best therapy for this condition? A. Interferon 1b B. Corticosteroid therapy C. Amantadine D. Immunoglobulin therapy

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25.3 A 33-year-old man presents to his physician with complaints of weakness in both of his legs and urinary incontinence of 2 days’ duration. Approximately 2 weeks previously, he had a “flu-like” illness. Which of the following is most likely to be present? A. Sensorineural hearing loss B. Ataxia C. Facial nerve palsy D. Tinnitus

ANSWERS 25.1 B. In the absence of a biological marker, the distinction between ADEM and MS cannot be made with certainty at the time of first presentation. However, certain features are more indicative of ADEM, including a viral prodrome or recent vaccination exposure, early-onset ataxia, high lesion load on MRI, involvement of the deep gray matter, especially thalami, and absence of oligoclonal bands. 25.2 B. Corticosteroids can help to reduce the duration and severity of symptoms in patients with ADEM. Intravenous gamma globulin therapy remains controversial, although it has been used. Standard of care for patients with MS are immune-modulating agents Food and Drug Administration (FDA) approved for MS, such as interferon beta-1b therapy. Amantadine is an antiviral agent helpful for influenza and also has slight therapeutic value for Parkinson disease A and for MS. 25.3 B. This patient has a typical presentation of ADEM. While ADEM patients can have hemiparesis, hemisensory compromise, ataxia, optic neuritis, transverse myelitis, seizures, myoclonus, and memory loss, sensorineural hearing loss, facial nerve paralysis, and tinnitus are not a complication of the disease.

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CLINICAL PEARLS »»

Acute disseminated encephalomyelitis (ADEM) is a “rare disease” affecting less than 200,000 people in the US population.

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The etiopathogenesis of ADEM is multifactorial and may include genetic susceptibility and environmental triggers (ie, vaccine or virus).

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Although ADEM is generally thought of as a monophasic disease, episodes of recurrent ADEM have been described, which are usually triggered by infections. It is possible that episodes of recurrent ADEM are multiple episodes of MS, and one should tailor management accordingly.

»»

In the absence of a biological marker, differentiation of ADEM from the initial presentation of MS may not be possible.

REFERENCES Minagar A, Sheremata WA. Acute disseminated encephalomyelitis. In: Evans RW, ed. Saunders Manual of Neurologic Practice. Philadelphia, PA: Saunders/Elsevier; 2003:241-243. Sadiq SA. Multiple sclerosis. In: Rowland LP, ed. Merritt’s Neurology. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:941-961. Wingerchuk DM. Acute disseminated encephalomyelitis, transverse myelitis, and neuromyelitis optica. Continuum (Minneap Minn). 2013;19(4):944-967.

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CASE 26 A 28-year-old man presents to the emergency department with a headache for 2 days. The headache is located in the frontal and occipital regions and is associated with mild nausea. He has taken various over-the-counter analgesics without an improvement in the headache. His headache has gradually increased in intensity, prompting an evaluation, as he could no longer tolerate it. Besides nausea, he complains of a sense of tightness in his shoulders and neck. He does not have a history of head or neck trauma and is not known to have any other medical problems. On examination, he is noted to have a temperature of 32.8°C (100.8°F), a blood pressure of 110/68 mm Hg, and pulse of 100 beats/min. He is awake, alert, and oriented. His Mini-Mental State Examination (MMSE) is normal; however, he takes a while to respond to questions. On general physical examination, no skin rashes are noted. He is noted to have a Kernig sign but no Brudzinski sign. Cranial nerves are normal except for a bilateral horizontal nystagmus. His motor, sensory, and cerebellar examinations are normal, with bilaterally downgoing toes (absent Babinski signs). His deep tendon reflexes are hyperreflexic throughout. A computed tomography (CT) of the brain without contrast is read as normal. His headache is now much worse than when he presented to the emergency department. »» »» »»

What is the most likely diagnosis? What is the best next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 26: Viral Meningitis Summary: A 28-year-old man without a history of known medical problems presents with a 2-day history of a progressively worsening headache. Associated symptoms include nausea, stiffness of the neck and shoulders, and slowness in responding to questions. Physical examination is notable for a Kernig sign, horizontal nystagmus, and generalized hyperreflexia. šš

Most likely diagnosis: Meningitis

šš

Best diagnostic step: Lumbar puncture (LP), usually done after CT imaging

šš

Next step in therapy: Start intravenous (IV) antibiotics and IV acyclovir

ANALYSIS Objectives 1. Know the clinical presentation of meningitis. 2. Learn to develop a diagnostic strategy for the diagnosis of meningitis and understand the cerebrospinal fluid (CSF) findings in bacterial and viral meningitis. 3. Know the treatment strategy for meningitis in the emergency department.

Considerations Any patient presenting with a progressively worsening headache associated with fever and nausea must prompt a clinician to suspect the possibility of an acute infective meningitis or encephalitis. Signs that further support our suspicion in this patient are a history of shoulder and neck tightness and the presence of a Kernig sign. An LP and CSF study is the best way to diagnose and determine the etiology of meningitis, that is, whether it is bacterial or viral. But why did we choose to do a CT scan first? It is crucial to consider the long list of causes with the above presentation—of them, the most common are conditions that lead to increased intracranial pressure, either by impairing CSF drainage or due to a space-occupying lesion. Performing an LP first in these patients could potentially lead to cerebral herniation and death. CT scan or magnetic resonance imaging (MRI) of the brain are the imaging modalities of choice in these patients. However, although the MRI offers a better resolution of the brain than a CT scan does, the CT is chosen to be done first as it is quicker and generally more readily available. The presence of focal neurologic findings or papilledema are absolute indications to perform an imaging study before performing an LP.

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Once it is determined that the risk of herniation is low, an LP is performed. LP analysis should include the following: 1. Opening and closing pressures. 2. CSF studies for glucose, protein, total and differential white cell count, Gram stain and culture, and fungal stains. 3. Latex particle agglutination, herpes simplex virus–polymerase chain reaction (HSV-PCR), enteroviral reverse transcriptase (EV RT-PCR), and Venereal Disease Research Laboratory for CSF (CSF-VDRL). 4. Extra CSF should be retained for additional studies. Other tests to consider include chemistry panel, complete blood count (CBC) with differential and platelets, international normalized ratio (INR)/prothrombin time (PT)/partial thromboplastin time (PTT), human immunodeficiency virus (HIV), and blood cultures. However, if there is a delay in obtaining an imaging study, treatment should not be deferred. Blood samples must be drawn and sent off for cultures, and empiric IV antibiotics should be started immediately. The initial choice of empiric therapy is customarily a third-generation cephalosporin (such as ceftriaxone or cefotaxime) plus vancomycin, IV dexamethasone; additionally, IV acyclovir is added if herpes simplex is suspected. The usage of antibiotics may confound the blood and CSF study findings and therefore should ideally be administered after the samples have been collected.

APPROACH TO: Suspected Meningitis DEFINITIONS MENINGITIS: Inflammation of the meninges (membranes surrounding the brain and the spinal cord) caused by various pathogenic organisms—typically bacterial and viral in nonimmunocompromised individuals. KERNIG SIGN: Pain and resistance to complete extension of the knee when the hip is flexed in the supine position. This is caused by a severe and usually painful spasm in the hamstring muscles due to an inflammation of the lumbosacral roots. BRUDZINSKI SIGN: An involuntary flexion of the hips and knees upon flexion of the neck, which may indicate meningeal irritation. LATEX PARTICLE AGGLUTINATION: A test utilizing the principle of antigenantibody reactions: the surface of latex particles is coated with specific antigens or antibodies, thereby forming “sensitized latex.” When a sample containing complementary antigens or antibodies are mixed with the milky-appearing sensitized latex, visible agglutination is noted. It is used to detect Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis A, B, and C.

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ENTEROVIRAL REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION (EV RT-PCR): EV RT-PCR is a technique in which complementary DNA (cDNA) is made from RNA via reverse transcription. The cDNA is then replicated and amplified through standard PCR protocols. Various viruses belonging to the enterovirus family can be detected using this technique. HERPES SIMPLEX VIRUS POLYMERASE CHAIN REACTION (HSV PCR): PCR is a molecular technique that allows a small amount of DNA to be replicated and amplified. HSV is a possible viral cause for meningitis, and PCR can be used to detect HSV DNA in the CSF. HSV-PCR for CSF has an estimated sensitivity of 95% and specificity of almost 100%. NYSTAGMUS: A rapid involuntary oscillatory movement of the eyes.

CLINICAL APPROACH Etiology Meningitis is typically bacterial or viral in etiology in nonimmunocompromised individuals. Bacterial meningitis is typically more severe and carries a higher morbidity and mortality rate as compared to viral meningitis. The incidence of bacterial meningitis is approximately 3 to 5 per 100,000 people per year in the United States. Annually, approximately 2000 deaths are reported in the United States from bacterial meningitis. The relative frequency of specific bacterial species as a cause of meningitis varies with age. During the neonatal period Escherichia coli, Listeria monocytogenes, and group B streptococci account for most of the causes of neonatal meningitis. Following the neonatal period, H. influenzae, S. pneumoniae, and N. meningitidis account for 80% of cases. In 1987, widespread vaccination against H. influenzae type b led to a marked reduction in this pathogen causing meningitis in children. Streptococcal pneumonia and Neisseria meningitis are now the principal causes of meningitis following the neonatal period. Of the viruses, Enteroviridae are the most common cause of viral meningitis in the United States. Approximately 75,000 cases of enteroviral meningitis occur in the United States each year. Coxsackie A9, B3 to B5, and echovirus 4, 6, 7, 8, 11, 18, and 30 are the most common causative strains. The infection primarily spreads by fecal-oral route, although a spread through the respiratory route may rarely be noted. Outbreaks may be associated with pharyngitis or gastroenteritis and typically occur in the late summer and early fall. A viral exanthem may be present. Other causes of viral meningitis include HSV, Arboviridae (St. Louis encephalitis virus, West Nile virus, Japanese encephalitis virus, Western equine encephalitis virus, Eastern equine encephalitis, and La Crosse virus), Arenaviridae, and Retroviridae. The Arboviridae are viruses that are transmitted to humans via arthropods, most commonly mosquitoes or ticks.

Clinical Presentation and Evaluation Typical symptoms of meningitis include the classic triad of headache, fever, and neck stiffness. Other commonly associated symptoms include photophobia (eye

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pain or sensitivity to light), nausea, vomiting, myalgia, and confusion. Focal neurologic deficits (eg, cranial nerve palsies, hemiparesis, or dysphasia), seizures, and declining levels of consciousness (ranging from lethargy to coma) may occur in severe cases as a result of an ensuing encephalitis or ischemic strokes caused by secondary thrombosis or inflammation of cerebral vessels. When evaluating patients with meningitis, it is critical to differentiate between bacterial and viral meningitis. Certain findings on clinical examination can point toward a bacterial infection rather than a viral infection. For example, the presence of a very high fever, a widespread maculopapular rash, or the presence of purpura/ ecchymosis suggests a bacterial infection such as Neisseria meningitis. CSF studies, however, are more definitive and help differentiate between viral and bacterial meningitis (Table 26–1). Blood cultures pick up the causative organism of bacterial meningitis in 50% of cases. This emphasizes the fact that bacteremia is present early on, and it also explains why bacterial meningitis is a true medical emergency. Antibiotics administered up to 2 hours before an LP do not decrease the sensitivity of the CSF culture when done in conjunction with latex particle agglutination and blood cultures. Antibiotics administered more than 2 hours before an LP may decrease the chances of finding a positive CSF Gram stain or culture by 5% to 40%. Viral CSF cultures have a relatively low sensitivity and a poor ability to grow. Furthermore, the clinical utility of this is limited by the amount of time required for the Enteroviridae to grow (days to weeks). On the other hand, the EV RT-PCR for CSF has 100% specificity and 95% sensitivity, and results are often available within 4 hours. Neuroimaging studies in bacterial meningitis are often normal but can also reveal complications such as infarction, venous sinus thrombosis, communicating or noncommunicating hydrocephalus, and increased intracranial pressure.

Table 26–1  •  BACTERIAL VS VIRAL MENINGITIS CSF CHARACTERISTICS  

Bacterial

Viral

Opening pressure

Elevated opening pressure, >200 mm of H2O

May reveal an elevated opening pressure

Protein

Elevated protein, 100-500 mg/dL

Normal to moderately increased, 120% of baseline at stimulation rates >10 Hz), and absence of posttetanic exhaustion are supportive for the diagnosis of infantile botulism.

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Treatment Any infant with clinical findings suspicious for infantile botulism should be hospitalized, closely monitored, and given supportive care including mechanical ventilation, nasogastric tube feedings, etc. Most will require ICU care because 70% of infants experience respiratory depression and may require intubation and mechanical ventilation. Treatment is with antitoxin and should be administered as soon as possible. Treatment should not be delayed while awaiting confirmatory tests. The botulinum immunoglobulin has been shown to shorten hospital stay, reduce severity of illness, and decrease total cost of hospitalization. Botulinum immunoglobulin is a human-derived antitoxin that is effective against types A and B toxins; however, in cases where human botulinum immunoglobulin is inaccessible due to cost, equine botulinum antitoxin is an effective and safe alternative. Antibiotics are not indicated in infantile botulism because of the concern for increased lysis of bacteria causing increased release and availability of toxin for gastrointestinal absorption. The infant case fatality rate is less than 2%, and on average, infants will spend 44 days in the hospital. Rare cases of relapse have been reported with no known predictors identified. Most relapses occur within 2 weeks of being discharged from the hospital. For suspected infant botulism occurring in any state, the California Department of Health Services, Infant Botulism Treatment and Prevention Program should be contacted at www.infantbotulism.org or 510-231-7600.

COMPREHENSION QUESTIONS 27.1 A newborn infant has a history of poor suck, poor oral intake, diffusely decreased muscle tone and strength. He responds to noxious stimuli with a weak cry. He is also noted to have external ophthalmoplegia, reactive pupils, facial weakness, and absent DTR’s. What is the likely diagnosis? A. Infantile botulism B. Neonatal myasthenia gravis C. GBS D. Meningitis 27.2 A 5-month-old baby girl just admitted to the ICU presents with a history of constipation, poor feeding, decreased spontaneous movement, and reduced DTRs. Which of the following diagnostic tests is useful in evaluating this patient with suspected infantile botulism? A. Serum test for botulinum toxin B. CSF studies for botulinum toxin C. EMG with repetitive nerve stimulation studies D. Pharyngeal culture for botulinum toxin

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27.3 A 73-year-old man presents to the emergency room complaining of diplopia, blurred vision, dysphagia, and xerostomia. His examination reveals ptosis, impaired ocular motility, dilated pupils, symmetrical weakness in the arms and legs, and normal cognitive function. Which of the following would be most consistent with his presentation? A. Antecedent gastrointestinal disease with nausea, vomiting, and diarrhea B. Loss of sensation in a glove and stocking distribution C. A history of eating honey from California D. Normal EMG with repetitive nerve stimulation studies

ANSWERS 27.1 B. This is likely a case of transient neonatal myasthenia gravis. This is due to transplacental IgG antibodies against ACh receptors. Mothers typically have a history of myasthenia gravis however, may be asymptomatic themselves. The vast majority of the patients with transient myasthenia gravis are symptomatic at the time of birth. Detection of ACh receptor blocking, binding, or modulating antibodies can be helpful. Treatment is typically supportive but may need intramuscular neostigmine to help with strength and feeding for a few days/weeks. Prognosis is excellent barring any complications of the transient blocking of the ACh receptors. The presence of reactive pupils and normal DTRs points away from infantile botulism. Likewise, the presence of normal DTRs is unlikely in GBS. The absence of fever makes it unlikely that this is meningitis. 27.2 C. Fecal cultures and not pharyngeal cultures are the best way to diagnose infantile botulism. EMG with repetitive nerve stimulation studies are key in making the diagnosis of infantile botulism. 27.3 A. This case is illustrative of food-borne botulism, which is known to have normal sensation and normal cognitive function. Nausea, vomiting and diarrhea are common antecedent complaints. EMG with repetitive nerve stimulation studies will be abnormal. Botulism from spores in honey occurs primarily in infants. Glove and stocking sensory loss (B) is more likely with diabetes, whereas botulism-related symptoms usually progress from the head and eyes downward. Eating honey from California (C) is not a risk factor for botulism in adults.

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CLINICAL PEARLS »»

Infantile botulism is the most common cause of botulism in the United States.

»»

Infantile botulism is proven to be acquired from spores in soil or in honey in only 15% of cases.

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Classic presentation for infantile botulism includes antecedent constipation with descending paralysis, ptosis, dilated or unreactive pupils, and weakness in the arms and legs.

»»

The best way to test for infantile botulism is through stool samples via a mouse bioassay.

»»

More than 70% of infants with botulism will eventually require mechanical ventilation.

REFERENCES Arnon SS, Schecter R, Maslanka SE, et al. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med. 2006;354(5):462-471. Chalk CH, Benstead TJ, Keezer M. Medical treatment for botulism. Cochrane Database Syst Rev. 2014;(2):CD008123. Cherington M. Clinical spectrum of botulism. Muscle Nerve. 1998;21:701-710. Hodowanec A, Bleck TP. Botulism (Clostridium botulinum). In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:2763. Thompson JA, Filloux FM, Van Orman CB, et al. Infant botulism in the age of botulism immune globulin. Neurology. 2005;64:2029-2032. Vanella de Cuetos EE, Fernandez RA, Bianco MI, et al. Equine botulinum antitoxin for the treatment of infant botulism. Clin Vaccine Immunol. 2011;18(11):1845-1849. Wigginton JM, Thill P. Infant botulism. A review of the literature. Clin Pediatr (Phila). 1993;32: 669-674.

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CASE 28 A 52-year-old man is referred for further evaluation of mild forgetfulness, poor concentration, and withdrawal from friends. His wife who has accompanied him feels that he is clumsier, noting that he frequently trips and stumbles. The patient has also noticed that he is clumsier and that he is more forgetful and is having difficulty focusing at work. He reports a recent reduction in libido. His physical examination is notable for an abnormal Montreal Cognitive Assessment (MoCA) score. He had difficulty drawing a clock, following a sequence, and copying a cube. He also had difficulty with delayed recall and attention and was slow in answering questions. Cranial nerves and motor strength are normal. He had difficulty with fine hand movements, and mild ataxia is noted. Deep tendon reflexes are slightly increased. He is concerned because he has been losing weight and is currently awaiting the results of a second human immunodeficiency virus (HIV) test. A previous HIV test 4 weeks ago was positive. »» »»

What is the most likely diagnosis? What is the next diagnostic step?

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ANSWERS TO CASE 28: HIV-Associated Dementia Summary: A 52-year-old man with weight loss has been experiencing mild forgetfulness, poor concentration, clumsiness, difficulty focusing at work, reduced libido, and withdrawal from friends. His examination shows abnormal cognitive function by MoCA and mental slowness in answering questions. Mild ataxia and poor coordination of his hands are noted. Additionally, he has mild hyperreflexia. His HIV test 4 weeks ago was positive. šš šš

Most likely diagnosis: Dementia/HIV-associated dementia (HAD). Next diagnostic step: Neuropsychological testing; obtain results of his last HIV tests, magnetic resonance imaging (MRI) of the brain, and lumbar puncture for cerebrospinal fluid (CSF) studies.

ANALYSIS Objectives 1. Be familiar with the diagnosis of HAD. 2. Recognize the treatment strategies for HAD. 3. Describe the differential diagnosis of HAD.

Considerations This 52-year-old man with a positive HIV test presents with poor concentration, mild forgetfulness, difficulty focusing, withdrawal from friends, clumsiness, and reduced libido. The classic findings of behavioral changes, difficulty with coordination, and mild impaired intellect in the setting of a positive HIV test are likely to be associated with HAD. Depression could also present this way; however, one would not expect there to be problems with coordination. Encephalitis, neurosyphilis, frontal temporal dementia, and HIV-associated opportunistic infections are also in the differential diagnosis. These can be distinguished from HAD by performing an MRI of the brain, lumbar puncture, and neuropsychological testing. Neurologic complications from HIV can be seen from opportunistic infections, drug-related complications, tumors secondary to HIV, and HIV itself. The pathophysiology of HAD is likely multifactorial. First, there is invasion of HIV into the central nervous system (CNS). HIV-infected monocytes are thought to enter the brain and infect microglia, astrocytes, neurons, and oligodendrocytes. Additionally, the virus may replicate in the cells. Viral toxins or HIV proteins may be directly toxic to neurons or may cause damage by activating macrophages, microglia, and astrocytes, which in turn release chemokines, cytokines, or neurotoxic substances. Finally, there is evidence to support oxidative stress and increases in excitatory amino acids and intracellular calcium.

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APPROACH TO: HIV-Associated Dementia DEFINITIONS ATAXIA: A neurologic sign demonstrated as incoordination or unsteady motion of the limbs and trunk. DEMENTIA: A disorder characterized by a general loss of intellectual abilities involving memory, judgment, abstract thinking, and changes in personality. NEUROPSYCHOLOGICAL TESTING: A battery of tests used to evaluate cognitive impairment more extensively than the Mini-Mental State Examination (MMSE). HAART: Highly active antiretroviral therapy consisting of multi-agent anti-viral therapy designed to lower viral counts to near undetectable levels.

CLINICAL APPROACH HAD has an incidence of 10.5 cases per 1000 person-years in the United States. This incidence has decreased since HAART was introduced, as before HAART (before 1992) the incidence was 21 cases per 1000 person-years. Nevertheless, there remains a population of patients presenting with this complication, as well as other HIVassociated diseases, who are unaware of their HIV status at the time of diagnosis. In fact, in a retrospective study of a population over 20 years, most patients who developed a neurologic complication during the HAART era were untreated or not known to be HIV-infected. Older patients with HIV have a higher likelihood of having HAD. A poor prognosis has been associated with low CD4 counts, high HIV RNA levels, low body mass index, lower educational levels, and anemia. Most patients with HAD have developed an AIDS-defining systemic illness. A few patients, however, present only with immunosuppression by laboratory criteria. In fact, a recent study of cognitive disorders in newly diagnosed HIV patients found a high prevalence of HIV-associated neurocognitive disorders (47.1%): particularly, asymptomatic neurocognitive impairment in 30.6%, mild neurocognitive disorder in 15%, and HAD in 1.5%. Male gender, low degree of education, AIDS diagnosis, and hepatitis B virus (HBV) coinfection were factors independently associated with these disorders. The earliest symptoms of HAD include difficulty with concentration, attention, and mentation. Forgetfulness is present early on, and patients have increasing difficulty performing complex tasks. Personality changes begin to appear such as apathy, social withdrawal, and quietness. Dysphoria and psychosis are rare. Psychomotor dysfunction, manifested by poor balance and lack of coordination, follows cognitive dysfunction, although rarely it can be the initial symptom of HAD. Tripping or falling, along with poor handwriting, are the more common motor symptoms due to involvement of the basal ganglia and cerebellum. As the disease progresses, the ataxia worsens and can become disabling. Myoclonic jerks, postural tremor, and bowel and bladder dysfunction can be present in the later stages of the disease. Patients at the end stage of the disease are unable to ambulate, are incontinent, and are almost in a vegetative state. Importantly, focal neurologic deficits tend to be absent.

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Early in the disease course, neuropsychological testing may be normal; however, as time progresses, there is evidence of subcortical dementia. Typical abnormalities include difficulty in concentration, motor manipulation, and motor speed. Mild problems with word finding and impaired retrieval can be present. Eventually, severe psychomotor slowing and language impairment occur. Initially, the neurologic examination is normal, and at this time, subtle impairment in rapid limb and eye movements can be found. As the disease progresses, hyperreflexia, spasticity, and frontal release signs can be found. Additionally, apraxia (inability to perform previously learned tasks) and akinetic mutism (severely decreased motor-verbal output) can develop. Neuroimaging (MRI brain) studies are essential in evaluating patients with AIDS and cognitive impairment. Diffuse cerebral atrophy is typical in HAD. Some patients have white matter changes and abnormalities in the thalamus and basal ganglia (Figure 28–1). Other conditions that can mimic or cause dementia can be excluded by MRI. CSF studies are nonspecific and are performed primarily to exclude other diagnoses. These nonspecific findings include a mildly elevated CSF protein (60% of cases) and mild mononuclear pleocytosis (25%). Quantitative HIV polymerase chain reaction (PCR) that evaluates CSF in viral load is the best parameter that relates to HAD. Improvement in CSF viral load leads to improvement in the clinical status of HAD.

Differential Diagnosis 1. CNS lymphoma 2. Progressive multifocal leukoencephalopathy

Figure 28–1.  T2-weighted MRI in AIDS dementia complex. Arrows show diffuse symmetric hyperintensities in the hemispheric white matter. (Reproduced, with permission, from Aminoff MJ, Simon RR, Greenberg D. Clinical Neurology. 6th ed. New York, NY: McGraw-Hill; 2005:58.)

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3. CNS infections such as cryptococcal meningitis, toxoplasmosis, cytomegalovirus encephalitis, neurosyphilis, histoplasmosis, and Coccidioides 4. Toxic metabolic states such as vitamin B12 deficiency, thyroid disease, alcoholism, medication effect, and illicit drug abuse

Treatment The management of HAD depends on viral suppression by means of HAART. HAART not only protects against but also leads to remission of HAD. Selective retroviral drugs that enter the CSF can be helpful and include zidovudine, indinavir, and lamivudine.

CASE CORRELATION šš

See also Case 20 (Alzheimer Dementia) and Case 21 (Lewy Body Dementia)

COMPREHENSION QUESTIONS 28.1 A 29-year-old man with a history of illicit drug abuse in the past presents with complaints of mild forgetfulness, social withdrawal, and difficulty concentrating. He has a good appetite and has not experienced alteration in his sleep cycle. His neurologic examination is nonfocal; however, his MoCA is abnormal, 23/30. His girlfriend has commented that she has seen him stumble more frequently. What is the next step in evaluating this individual? A. Obtain neuropsychological testing to evaluate for personality disorder. B. Obtain an MRI of the brain. C. Obtain a STAT lumbar puncture for CSF studies to exclude meningitis/ encephalitis. D. Clinically observe and follow the patient. 28.2 Which of the following has not been associated with a poor prognosis in HAD? A. A history of multiple AIDS-defining illnesses B. Low CD4 counts and low body mass index C. Head trauma with loss of consciousness prior to becoming HIV positive D. Low CD4 counts, anemia, and low HIV RNA 28.3 A 32-year-old HIV-positive man is noted to have forgetfulness, gait disturbance, and confusion. A lumbar puncture is performed, and the India ink preparation is positive. Which of the following is the most likely diagnosis? A. HAD B. Cryptococcal meningitis C. Toxoplasmosis D. CNS lymphoma

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ANSWERS 28.1 B. The first test to request in evaluating this patient is an imaging study. This will determine whether there is increased intracranial pressure so that a lumbar puncture can be safely performed. Although neuropsychological testing should be performed, it is appropriate to perform neuroimaging to evaluate for a structural or vascular lesion. 28.2 B. A history of multiple AIDS-defining illnesses would be a poor prognostic factor for HAD. Prior head trauma, anemia, and low HIV RNA are not poor prognostic factors. 28.3 B. India ink–positive stain is highly suggestive of cryptococcal meningitis. Cryptococcosis, a round or oval yeast, is the most common fungal infection of the CNS in HIV-infected individuals. Cryptococcus neoformans is spread hematogenously from the lungs, typically when the CD4 count falls below 100 cells/mm3. Its thick capsule is very distinctive when stained with India ink.

CLINICAL PEARLS »»

HIV-associated dementia (HAD) typically presents with forgetfulness, difficulty concentrating, slowness in thinking, and loss of coordination.

»»

HAD is more commonly seen in individuals with low CD4 counts, high HIV RNA, low body mass index, anemia, and low levels of education.

»»

The best way to prevent and reduce the severity of HAD is by using HAART.

REFERENCES Dorland’s Illustrated Medical Dictionary. 27th ed. Philadelphia, PA: WB Saunders; 1988. Focà E, Magro P, Motta D, et al. Screening for neurocognitive impairment in HIV-infected individuals at first contact after HIV diagnosis: the experience of a large clinical center in Northern Italy. Int J Mol Sci. 2016;17(4):434. Gibbie T, Mijch A, Ellen S, et al. Depression and neurocognitive performance in individuals with HIV/ AIDS: 2-year follow-up. HIV Med. 2006;7(2):112-121. Kaul M, Lipton SA. Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr HIV Res. 2006;4(3):307-318. Matinella A, Lanzafame M, Bonometti MA, et al. Neurological complications of HIV infection in pre-HAART and HAART era: a retrospective study. J Neurol. 2015;262(5):1317-1327. McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol. 2004;157(1-2):3-10.

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CASE 29 A 53-year-old woman presents with loss of balance, mood swings, and memory loss. She had not noticed these symptoms until her coworkers and family pointed them out to her. Although these symptoms presented 4 months ago, she did not seek medical attention until now, when these began interfering with her daily activities. Her ataxia has progressed to the point that she is stumbling and falling. She has noticed difficulty with problem-solving, and her boss has witnessed inappropriate behavior. Her family reports that over the past month her memory has quickly deteriorated to the point that she is unable to recognize friends, unable to drive, unable to work, and forgets if she has eaten. She has also developed slurred speech and has been witnessed to “jerk” during the day. The neurologic examination reveals a Mini-Mental State Examination (MMSE) score of 17/30, and she had difficulty with orientation, object recall, calculations, naming, concentration, and drawing the intersecting polygons. There is horizontal nystagmus, moderate dysarthria, and anomia. Her strength appears to be normal; however, she has dysmetria and a wide-based gait. Her deep tendon reflexes (DTRs) are hyperreflexic, and she has evidence of myoclonus. A computed tomography (CT) scan of the brain is performed and shows no abnormalities. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 29: Sporadic Creutzfeldt-Jakob Disease Summary: A 53-year-old woman presents with a 4-month history of rapidly progressive memory loss, ataxia, mood swings, inappropriate behavior, and dysarthria. Her examination is notable for a markedly abnormal MMSE with global abnormalities, moderate dysarthria, and anomia. She additionally has nystagmus, dysmetria, ataxia, myoclonus, and hyperreflexia. šš šš

šš

Most likely diagnosis: Sporadic Creutzfeldt-Jakob disease (CJD). Next diagnostic step: Serologic studies including comprehensive metabolic panel (CMP), complete blood count (CBC), HIV, erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), vitamin B12, rapid plasma reagin (RPR), international normalized ratio (INR), magnetic resonance imaging (MRI) of the brain, lumbar puncture for protein, glucose, cell count with differential, Gram stain and cultures, and 14-3-3 protein. Additionally, an electroencephalograph (EEG) may be requested. Next step in therapy: Supportive and symptomatic therapy since there is no specific treatment.

ANALYSIS Objectives 1. Be familiar with the clinical presentation of sporadic CJD and its variants. 2. Recognize the differential diagnosis for CJD. 3. Identify the recommended evaluations to make the diagnosis of CJD.

Considerations This 53-year-old woman presents with a rapidly progressive set of neurologic symptoms including memory loss, ataxia, behavioral changes, poor coordination, and myoclonus. These abnormalities are consistent with a rapidly progressive dementia and typical for CJD. Initially, patients experience problems with muscular coordination, personality changes including impaired memory, judgment, and thinking, and impaired vision. The CT scan rules out a structural etiology such as a stroke or brain tumor. Most other causes of dementia are insidious in onset and progression. Nevertheless, in this patient, treatable causes of dementia should be sought with the laboratory studies and neuroimaging mentioned previously.

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APPROACH TO: Creutzfeldt-Jakob Disease CLINICAL APPROACH Clinical Features and Epidemiology CJD is a rare, neurodegenerative, invariably fatal brain disorder. It affects approximately 1 person in every 1 million people per year worldwide; in the United States, there are approximately 200 cases per year. CJD usually appears later in life and has a rapid course. Typically, the onset of symptoms occurs at approximately 60 years, and about 90% of patients die within 1 year. In the early stages of disease, patients can have failing memory, behavioral changes, lack of coordination, and visual disturbances. As the illness progresses, mental deterioration becomes pronounced, and involuntary movements, blindness, weakness of extremities, and coma can occur. There are four major categories of CJD: šš

šš

šš

šš

In sporadic CJD, the disease appears even though the person has no known risk factors for the disease. This is by far the most common type of CJD and accounts for at least 85% of cases. In hereditary CJD, the person has a family history of the disease and/or tests positive for a genetic mutation associated with CJD. Approximately 5% to 10% of cases of CJD in the United States are hereditary. In acquired CJD, the disease is transmitted by exposure to the brain or nervous system tissue, usually through certain medical procedures. There is no evidence that CJD is contagious through casual contact with a CJD patient. Since CJD was first described in 1920, fewer than 1% of cases have been acquired CJD. In variant CJD, the disease is likely transmitted by ingestion of meat products from cattle infected with bovine spongiform encephalopathy (BSE). It presents at a younger age compared to sporadic CJD and has a more protracted course. Psychiatric disturbances are more likely to be the initial presentation compared to rapidly progressing dementia in sporadic CJD.

CJD belongs to a family of human and animal diseases known as the transmissible spongiform encephalopathies (TSEs). Spongiform refers to the characteristic appearance of infected brains, which become filled with holes until they resemble sponges under a microscope. CJD is the most common of the known human TSEs. Other human TSEs include kuru, fatal familial insomnia (FFI), and GerstmannStraussler-Scheinker (GSS) disease. Kuru was identified in people of an isolated cannibalistic tribe in Papua, New Guinea, and has now almost disappeared. FFI and GSS are extremely rare hereditary diseases found in just a few families around the world. Other TSEs are found in specific kinds of animals. These include BSE, which is found in cows and is often referred to as “mad cow” disease; scrapie, which affects sheep and goats; mink encephalopathy; and feline encephalopathy. Similar diseases have occurred in elk, deer, and exotic zoo animals.

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CJD is characterized by rapidly progressive dementia. Initially, patients experience problems with muscular coordination, personality changes including impaired memory, judgment, thinking, and vision. Affected patients also can experience insomnia, depression, or unusual sensations. CJD does not cause a fever or other flu-like symptoms. As the illness progresses, the patients’ mental impairment becomes severe. They often develop involuntary muscle jerks called myoclonus and may lose vision. They eventually lose the ability to move and speak and enter a coma. Pneumonia and other infections often occur in these patients and can lead to death. Some symptoms of CJD can be similar to symptoms of other progressive neurologic disorders, such as Alzheimer or Huntington disease. However, CJD causes unique changes in the brain tissue that can be seen on autopsy. It also tends to cause more rapid deterioration of a person’s abilities than Alzheimer disease or most other types of dementia.

Etiology and Pathogenesis CJD and the other TSEs are caused by a type of protein called a prion. Prion proteins occur both in a normal form, which is a harmless protein found in the body’s cells, and in an infectious form, which causes disease. The harmless and infectious forms of the prion protein have the same sequence of amino acids (the “building blocks” of proteins), but the infectious form of the protein takes a different folded shape than the normal protein. Sporadic CJD may develop because some of a person’s normal prions spontaneously change into the infectious form and then alter the prions in other cells in a chain reaction. Once they appear, abnormal prion proteins aggregate, or clump together. Investigators think these protein aggregates may lead to the neuron loss and other brain damage seen in CJD. However, they do not know exactly how this damage occurs. Approximately 5% to 10% of all CJD cases are inherited. These cases arise from a mutation in the gene that controls formation of the normal prion protein. Although prions themselves do not contain genetic information and do not require genes to reproduce themselves, infectious prions can arise if a mutation occurs in the gene for the body’s normal prion protein. If the prion protein gene is altered in a person’s sperm or egg cells, the mutation can be transmitted to the person’s offspring. Several different mutations in the prion gene have been identified. The particular mutation found in each family affects how frequently the disease appears and what symptoms are most noticeable. However, not all people with mutations in the prion protein gene develop CJD. CJD cannot be transmitted through the air, through touching, or through most other forms of casual contact. Spouses and other household members of sporadic CJD patients have no higher risk of contracting the disease than the general population. However, exposure to brain tissue and spinal fluid from infected patients should be avoided. In some cases, CJD has spread to other people from grafts of dura mater, transplanted corneas, implantation of inadequately sterilized electrodes in the brain, and injections of contaminated pituitary growth hormone derived from human pituitary glands taken from cadavers. Since 1985, all human growth hormone used in the United States has been synthesized by recombinant DNA procedures, thereby eliminating the risk of transmitting CJD by this route.

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DIAGNOSIS There is currently no single diagnostic test for CJD. CJD is distinguished from the more common forms of dementia by its rapid progression, presence of myoclonus, and gait disorder. When CJD is suspected, the first concern is to rule out treatable forms of dementia, such as encephalitis (inflammation of the brain); meningitis; autoimmune disorders such as paraneoplastic syndrome, demyelinating disease, sarcoidosis, or vasculitis; malignancy; metabolic disorders such as B12 deficiency or folate deficiency; or endocrine disorders such as hypothyroidism or Hashimoto encephalopathy. Standard diagnostic tests will include a spinal tap to rule out more common causes of dementia and measure biomarkers of neuronal damage and an EEG to record the brain’s electrical pattern. The EEG often shows periodic sharp wave complexes, which has a sensitivity of 66% and a specificity of 74% for CJD (Figure 29–1). CT of the brain can help rule out the possibility that the symptoms result from other problems such as a stroke or brain tumor. MRI scans of the brain can also reveal characteristic patterns of brain degeneration that can help diagnose CJD, such as hyperintense lesions in the brain cortex, caudate nucleus, and putamen on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI). The only way to confirm a diagnosis of CJD is by brain biopsy or autopsy. Because a correct diagnosis of CJD does not help the patient, a brain biopsy is discouraged unless it is needed to rule out a treatable disorder. In an autopsy, the whole brain is examined after death. Both brain biopsy and autopsy pose a small but definite risk that the surgeon or others who handle the brain tissue can become accidentally infected by self-inoculation. Special surgical and disinfection procedures can minimize this risk. A fact sheet with guidance on these procedures is available from the National Institute of Neurological Disorders and Stroke (NINDS) and the World Health Organization. Investigations are being conducted to create laboratory tests for CJD. One such test, developed at NINDS, is performed on a person’s CSF and detects a protein marker, 14-3-3 protein, which indicates neuronal degeneration. 14-3-3 proteins in the CSF have been found to correlate with the clinical diagnosis with a 94% sensitivity and a specificity of 84%. The protein assay in combination with EEG findings further increases the sensitivity but decreases the specificity. However, these tests can help diagnose CJD in people who already show the clinical symptoms of the disease. CSF analysis for the protein is much easier and safer than a brain biopsy. The false-positive rate is approximately 5% to 10%. Scientists are working to develop this test for use in commercial laboratories. They are also working to develop other tests for this disorder.

Treatment and Prevention There is no treatment that can cure or control CJD. Researchers have tested many drugs, including amantadine, steroids, interferon, acyclovir, antiviral agents, and antibiotics. Studies of a variety of other drugs are now in progress. However, so far none of these treatments has shown any consistent benefit in humans. Current treatment for CJD is aimed at alleviating symptoms and making the patient as comfortable as possible. Opiate drugs can help relieve pain if it occurs, and the

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Fp2-F4 F4-C4 C4-P4 P4-O2 Fp2-F8 F8-T4 T4-T6 T6-O2 Fp1-F3 F3-C3 C3-P3 P3-O1 Fp1-F7 F7-T3 T3-T5 T5-O1 200 µV

1s

Figure 29–1.  EEG of a patient with Creutzfeldt-Jakob disease. (Reproduced, with permission, from Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. 6th ed. New York, NY: McGraw-Hill; 2005:53.)

drugs clonazepam and sodium valproate can help relieve myoclonus. During later stages of the disease, changing the person’s position frequently can keep him or her comfortable and helps prevent bedsores. A catheter can be used to drain urine if the patient cannot control bladder function, and intravenous fluids and artificial feeding also can be used.

CASE CORRELATION šš

See also Case 20 (Alzheimer Dementia) and Case 21 (Lewy Body Dementia)

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COMPREHENSION QUESTIONS 29.1 A 61-year-old woman presents to the emergency room (ER) for several days of jerking limb movements. Her daughter notes 2 months of progressive memory loss. Assuming the patient has a degenerative disease, which of the following is most likely? A. Alzheimer disease B. Lewy body dementia C. Progressive supranuclear palsy D. CJD 29.2 For the patient in Question 29.1, which of the following methods is the most accurate for diagnosing her condition? A. Serum serology B. Serum polymerase chain reaction (PCR) C. Serum viral culture D. Brain biopsy 29.3 The patient’s daughter asks if there is any disease-modifying treatment available for her mother. Which of the following should be offered? A. Acyclovir B. Plasma exchange C. Donepezil D. None of the above

ANSWERS 29.1 D. The scenario describes a rapidly progressing cognitive impairment (over 2 months). CJD is the only rapidly progressive condition listed. The other answer choices are of slower onset, usually years. 29.2 D. Brain biopsy and histologic analysis is the only definitive method of diagnosis. Although there are investigational laboratory tests being evaluated, at this time, none are available. 29.3 D. There is no known treatment to reverse or slow progression of CJD; only supportive treatment can be offered.

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CLINICAL PEARLS »»

Ninety percent of patients diagnosed with CJD die within 1 year.

»»

The annual rate of CJD is approximately 3.4 cases per million. In recent years, the United States has reported fewer than 300 cases of CJD a year.

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CJD is caused by a prion, which is a misfolded protein.

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CJD is distinguished from the more common forms of dementia by its rapid progression, presence of myoclonus, and gait disorder.

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Elevated 14-3-3 proteins in the CSF and periodic sharp waves on the EEG in a patient with rapidly progressive dementia are supportive of CJD.

»»

Treatment of CJD consists of supportive care.

REFERENCES Collie DA, Summers DM, Sellar RJ, et al. Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases AJNR Am J Neuroradiol. 2003;24:1560-1569. Duhamel A, Solomon E. Role of the biomarkers for the diagnosis of Creutzfeldt-Jakob disease. J Med Life. 2016;9(2):211-215. Geschwind MD. Rapidly progressive dementia: prion diseases and other rapid dementias. Continuum (Minneap Minn). 2010;16(2 Dementia):31-56. Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22(2):510-537. National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. http:// www.ninds.nih.gov/disorders/cjd/detail_cjd.htm. Accessed Jan 1, 2017. Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14–3-3 proteins as aids to the diagnosis of Creutzfeldt–Jakob disease. Neurology. 2000;55:811-815.

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CASE 30 A 58-year-old man is referred for evaluation of severe lancinating pain in the legs and loss of balance over a period of 3 years. He has recently developed impotence, and his grandchildren have started to tease him about how his eyes are looking droopy. He reports that his balance is worse in the dark or when he closes his eyes. He has a history of gastroesophageal reflux disease and migraine headaches. He is only taking over-the-counter famotidine (Pepcid) and a multivitamin each day. He has been married for 35 years and is a retired structural engineer. He has not been exposed to toxins and does not smoke or drink alcohol. The only other pertinent information is that he served as a natural disaster relief volunteer overseas before getting married and contracted a “venereal disease.” He thinks he contracted syphilis and received oral antibiotics. The neurologic examination reveals a Mini-Mental State Examination (MMSE) score of 30/30 with intact cranial nerves except for Argyll Robertson pupils and ptosis bilaterally. His strength is normal; however, he has impaired proprioception in the toes with diminished temperature sensation in the legs. Additionally, he has loss of pinprick sensation in a glove-and-stocking distribution. A Romberg sign is present. Cerebellar examination is normal; however, his deep tendon reflexes are diminished (1+/2) in the legs. His gait is wide-based with marked ataxia. »» »» »»

What is the most likely diagnosis? What is the next step to confirm diagnosis? What is the treatment plan?

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ANSWERS TO CASE 30: Tabes Dorsalis Summary: A 58-year-old man with a history of syphilis more than 20 years ago, gastroesophageal reflux disease, and migraine headaches presents with a 3-year history of lancinating pain in the legs, loss of balance, and recent impotence and ptosis. His examination is notable for cranial nerve impairment with Argyll Robertson pupils and ptosis. Other findings include impaired posterior column function with loss of proprioception in the feet and impaired lateral spinothalamic tract function (loss of temperature and pinprick). His deep tendon reflexes are diminished in the legs, and he has a sensory ataxia. The Romberg test is positive. šš šš

šš

Most likely diagnosis: Tabes dorsalis (spinal form of syphilis). Next diagnostic step: Lumbar puncture for Venereal Disease Research Laboratory (VDRL). Next therapeutic step: High-dose intravenous aqueous penicillin G at a dose of 2 to 4 million units every 4 hours for 10 to 14 days. If there is a penicillin allergy, doxycycline at a dose of 200 mg twice a day for 28 days and ceftriaxone at a dose of 2 g intravenously per day for 14 days should be administered.

ANALYSIS Objectives 1. Be familiar with the clinical presentation of tabes dorsalis and other neurologic syndromes caused by syphilis. 2. Know how to diagnose tabes dorsalis and differentiate it from other late forms of neurosyphilis. 3. Know how to treat tabes dorsalis.

Considerations The presentation of an individual with a history of syphilis who presents with neurologic symptoms should alert the clinician to possible neurosyphilis. Other etiologies need to be excluded, as other sexually transmitted diseases such as human immunodeficiency virus (HIV) or hepatitis B or C can cause similar neurologic symptoms. Lancinating pain with associated sensory ataxia, cranial nerve abnormalities, and impotence or bowel and bladder dysfunction is a classic presentation for tabes dorsalis. In this case, tabes dorsalis is the most likely diagnosis; however, to diagnose it, confirmation from laboratory studies must be obtained. The most common serologic studies requested are a rapid plasma reagin (RPR) assay or VDRL test. These are quite sensitive for primary and secondary syphilis but are less sensitive for neurosyphilis. A negative RPR does not exclude neurosyphilis. Importantly, the RPR assay can frequently have a false-positive result. If these tests are positive, proceed in confirming the diagnosis

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with cerebrospinal fluid (CSF). The following indicates the typical CSF findings in neurosyphilis: šš

Elevated CSF protein (up to 200 mg/dL)

šš

Lymphocytic pleocytosis less than 400/μL

šš

CSF VDRL positivity in most individuals

šš

Elevated immunoglobulin G (IgG) synthesis

If, however, the RPR or VDRL studies are negative and neurosyphilis is still clinically suspected, serum studies for Treponema pallidum–specific antibodies should be performed. These include fluorescent treponemal antibody absorption (FTA-ABS) test, T. pallidum hemagglutination (TPHA) test, or microhemagglutination assay–T. pallidum (MHA-TP). These studies are much more expensive than the reaginic assays but are much more sensitive for neurosyphilis. In fact, if these studies are nonreactive, neurosyphilis is excluded. Detection of T. pallidum by polymerase chain reaction in the CSF is quite low. Importantly, the serologic studies cannot distinguish between syphilis, pinta, and yaws (nonvenereal treponemal endemic diseases) due to cross-reactivity. HIV or hepatitis B and C can present with very similar symptoms of sensory ataxia, cranial mononeuropathies, and pain. A distinguishing feature between these infections and neurosyphilis is the type of pain. Classic lancinating pain is seen with neurosyphilis, whereas a burning-type pain is associated with the others. Nevertheless, laboratory studies are the only way to distinguish these conditions definitively.

APPROACH TO: Tabes Dorsalis DEFINITIONS ARGYLL ROBERTSON PUPILS: Small pupils that constrict when focusing but fail to constrict when exposed to bright light (accommodate but do not react). ELECTROMYOGRAPH (EMG)/NERVE CONDUCTION STUDIES: An electrophysiologic examination that evaluates the integrity of the peripheral nerve and evaluates various electrical muscle properties, allowing the clinician to determine the presence of either a muscle or nerve disorder. This test is primarily useful in evaluating the peripheral nervous system. H REFLEX: The H reflex is the electrical equivalent to a monosynaptic stretch reflex. It often reflects pathology along the afferent and efferent fibers and/or the dorsal root ganglion. LANCINATING PAIN: A sensation of piercing, stabbing, or cutting. PTOSIS: Droopiness of the eyelids. ROMBERG SIGN: Falling over when a person is standing with eyes closed, feet together, and hands in the outstretched position.

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CLINICAL APPROACH Neurosyphilis is an infection of the nervous system by the spirochete T. pallidum, the organism responsible for syphilis. It is estimated that up to 10% of patients with primary syphilis who have not received treatment will develop neurosyphilis. In the HIV population, the percentage is higher. Risk factors for syphilis include drug consumption, sexual habits, and social background. It is well recognized that HIV patients with syphilis are at increased risk for developing neurosyphilis and may do so earlier than HIV-negative individuals. Importantly, syphilis is a risk factor for acquiring HIV. Neurosyphilis is twice as common in men as it is in women. T. pallidum can first be detected clinically approximately 3 weeks after infection by the presence of a primary lesion on the skin or mucous membranes (primary syphilis). Secondary syphilis results from a second bacteremic stage with generalized mucocutaneous lesions. Although neurosyphilis (tertiary syphilis) may not present until many years after a primary infection, T. pallidum enters the central nervous system (CNS) at the same time individuals develop primary and secondary syphilis. Pathogenic changes consist of endarteritis of terminal arterioles with resultant inflammatory and necrotic changes. In the CNS, T. pallidum causes meningeal inflammation, arteritis of small- and medium-sized vessels with subsequent fibrotic occlusion, and eventually direct neuronal damage. The clinical features of neurosyphilis are dependent on the time period after infection (Table 30–1). Hyporeflexia is the most common finding on clinical examination,

Table 30–1  •  NEUROLOGIC FORMS OF SYPHILIS Clinical Syndrome

Time Period After Initial Infection

Syphilitic meningitis

1-2 y

Cranial mononeuropathies, hydrocephalus, and focal hemispheric signs

Cerebrovascular and meningovascular disease

5-7 y

Ischemia, particularly along the middle cerebral artery territory, and meningeal inflammation. Can also present with stroke in evolution.

General paresis

10 y

Impairment of higher cortical functions, dementia, frontotemporal encephalitis, pupillary abnormalities, cerebellar dysfunction, optic atrophy, pyramidal tract dysfunction and features suggesting psychiatric illness

Tabes dorsalis

10-20 y

Lancinating pain, sensory ataxia, bowel dysfunction, bladder dysfunction, and cranial nerve abnormalities

Gummatous neurosyphilis

Any time after infection

Features are directly related to the location of the gummas causing compression

Asymptomatic neurosyphilis

Any time after infection

Absence of symptoms despite abnormal CSF findings seen with neurosyphilis

Clinical Features

CSF, cerebrospinal fluid.

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with up to 50% of patients with neurosyphilis having this finding. Other clinical findings include sensory impairment (48%), pupillary changes (43%) including Argyll Robertson pupils, cranial neuropathy (36%), dementia or psychiatric symptoms (35%), and a positive Romberg test (24%). The Argyll Robertson pupil is almost pathognomonic for neural syphilis. Tabes dorsalis is caused by the syphilitic involvement of the posterior spinal cord, leading to intermittent pain of the arms and legs, ataxia and gait disturbance as a result of loss of position sense, and impaired vibratory and position sense. The diagnosis of neurosyphilis is made on clinical grounds and confirmed by CSF serology (RPR or VDRL). Usually the CSF protein and cell count are abnormal. The differential diagnosis of neurosyphilis is based on clinical features. For example, the differential for gummatous neurosyphilis consists of the differential diagnosis for space-occupying lesions (metastatic brain tumors, primary brain tumors, etc). Meningovascular syphilis presenting like a stroke merits the differential diagnosis of cerebral vascular accident (vasculitis, hemorrhage, etc). Three disorders should be considered in the differential diagnosis of tabes dorsales: subacute combined degeneration from vitamin B12 deficiency, multiple sclerosis, and Lyme disease. Other less common diagnoses in the differential include sarcoidosis, herpes zoster, and diffuse metastatic disease. The finding of an Argyll Robertson pupil is highly suggestive of tabes dorsalis but can also be seen with multiple sclerosis, diabetes mellitus, sarcoidosis, Lyme disease, and Wernicke encephalopathy. Tabes dorsalis is a slow and progressive disease that causes demyelination in the posterior columns and inflammatory changes in the posterior roots of the spinal cord. Nerve conduction studies can show impaired sensory nerve conduction studies with normal motor nerve conductions. EMG is normal, but absent H reflexes are common due to the damage of the dorsal root ganglion. Abnormalities in motor nerve conduction studies should raise doubt as to the diagnosis of tabes dorsalis. The treatment of neurosyphilis consists of high-dose intravenous aqueous penicillin G at a dose of 2 to 4 million units every 4 hours for 10 to 14 days. If there is a penicillin allergy, doxycycline at a dose of 200 mg twice a day for 28 days and ceftriaxone at a dose of 2 g intravenously per day for 14 days should be administered. Although there are alternative regimens that have been tried in treating patients with neurosyphilis, these have not been found to be as effective as the use of aqueous penicillin G. Use of intramuscular procaine penicillin at a dose of 2.4 million units intramuscularly every day plus oral probenecid for 10 to 14 days has been tried in those individuals who cannot receive intravenous preparations. This has typically been combined with intramuscular benzathine penicillin G at a dose of 2.4 million units weekly for 3 weeks. If treatment fails to improve symptoms (for early neurosyphilis) or there is continued progression of symptoms (late neurosyphilis), re-treatment should be considered. CSF studies should be reexamined after the completion of therapy for a drop in white blood cell count, protein, and IgG synthesis.

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COMPREHENSION QUESTIONS 30.1 A neurologist performs an examination on a 19-year-old man and diagnoses him with an Argyll Robertson pupil. Which of the following statements is most likely to be accurate? A. The pupil likely constricts to light. B. The patient may have multiple sclerosis. C. The pupils fail to constrict when focusing up close. D. The patient is diagnosed with subacute combined degeneration. 30.2 All of the following are true regarding neurosyphilis except: A. T. pallidum infects the CNS at the time of the primary infection. B. HIV-positive individuals are at increased risk for developing neurosyphilis. C. Tabes dorsalis occurs 10 years after initial infection. D. Stroke-like symptoms may occur any time after infection. E. General paresis may present as a psychiatric illness. 30.3 The differential diagnosis of tabes dorsalis consists of all of the following except: A. Toxoplasmosis B. Lyme disease C. Sarcoidosis D. Multiple sclerosis E. Subacute combined degeneration 30.4 A 30-year-old man who abuses intravenous (IV) drugs presents to your office complaining of left-sided weakness for the past 6 weeks. His examination is notable for Argyll Robertson pupils, hyporeflexia in the legs, and left hemiparesis. He is healthy otherwise except for having developed syphilis while serving in the military at age 27. His last HIV test was 18 months ago. Which of the following is most accurate? A. He does not have neurosyphilis, as the time period from primary infection to development of symptoms is too short. B. He has definite tabes dorsalis and requires magnetic resonance imaging (MRI) of the spine and CSF analysis. C. He has neurosyphilis, and should be written up in a medical journal as a novel case presenting after a short incubation time following primary infection. D. He has possible neurosyphlis, so an HIV test and RPR should be obtained and if they are positive, treatment with IV aqueous penicillin G should be started.

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ANSWERS 30.1 B. Argyll Robertson pupils mean accommodation but no light reflex. It is seen with multiple sclerosis. Subacute combined degeneration has not been reported to cause Argyll Robertson pupils. 30.2 D. Stroke-like symptoms occur 5 to 7 years after the initial infection in individuals who are HIV negative. 30.3 A. Toxoplasmosis usually presents with symptoms suggesting an intracranial mass lesion. 30.4 D. Based on the history of IV drug abuse and now neurological symptoms of neurosyphiliis, this patient likely is HIV infected. HIV-positive individuals are known to develop signs and symptoms of neurosyphilis much earlier than individuals who are HIV-negative. His presentation is not novel and merits treatment as soon as possible. Although patients with tabes dorsalis may have an Argyll Robertson pupil, they present with lancinating pain and not hemiparesis; thus, an MRI of the brain is indicated.

CLINICAL PEARLS »»

Tabes dorsalis classically presents with lancinating pain, sensory deficits, ataxia, and hyporeflexia.

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HIV-positive individuals can present with neurosyphilis at a much earlier time than HIV-negative individuals.

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The treatment of choice for neurosyphilis remains intravenous aqueous penicillin G. Alternative treatments consisting of intramuscular doses of penicillin have not been found to be as effective.

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Individuals who present with neurologic symptoms and have a history of syphilis should be considered to have neurosyphilis until proven otherwise.

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There are various different forms of neurosyphilis including asymptomatic, meningovascular, tabes dorsalis, and general paresis.

»»

Syphilitic aseptic meningitis occurs as a chronic infection and can involve headaches, cognitive changes, and cranial nerve abnormalities.

REFERENCES Clinical Effectiveness Group. National guideline for the management of late syphilis: Clinical Effectiveness Group (Association of Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases). Sex Transm Infect. 1999;75(suppl 1):S34-S37. Dacso CC, Bortz DL. Significance of the Argyll Robertson pupil in clinical medicine. Am J Med. 1989;86(2):199-202.

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Dorland’s Illustrated Medical Dictionary. 27th ed. Philadelphia, PA: WB Saunders; 1988. Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA. 2003;290(11):1510-1514. Marra CM. Update on neurosyphilis. Curr Infect Dis Rep. 2009;11(2):127-134. Stevenson J, Heath M. Syphilis and HIV infection: an update. Dermatol Clin. 2006;24(4):497-507.

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CASE 31 A 25-year-old man is brought to the emergency room after experiencing a generalized tonic-clonic seizure. He was getting ready for work when he apparently fell to the floor and had the seizure. His mother, who witnessed the event, states that he lost consciousness and “shook all over.” The seizure lasted approximately 30 seconds and was associated with tongue biting as well as bladder incontinence. He returned to his baseline within 20 minutes. Over the past 6 months he has been complaining of headaches and had two previous generalized tonicclonic seizures. He has also lost approximately 6.8 kg (15 lb) over 1 month. He has been healthy otherwise, and the only other pertinent history is that he has been sexually promiscuous and experimented with intravenous (IV) cocaine. His last human immunodeficiency virus (HIV) test was 12 months ago, and he did not wait for the result. On physical examination, he is afebrile with a blood pressure of 130/68 mm Hg and a heart rate of 88 beats/min. He is awake and alert and oriented to person, time, location, and situation. His cranial nerves, sensory examination, cerebellar examination, and deep tendon reflexes are normal. His motor examination is notable for increased tone on the right with intact motor strength. His gait shows decreased arm swing on the right but otherwise is unremarkable. A computed tomography (CT) scan of the head without contrast shows that he has a solitary mass lesion measuring 15 mm over the left motor strip region with surrounding edema. Additionally, there is a 12-mm lesion in the left basal ganglia. With the administration of IV contrast, these lesions show enhancement. »» »» »»

What is the most likely diagnosis? What is the best way to confirm the diagnosis? What is the next step in therapy?

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ANSWERS TO CASE 31: Intracranial Lesion (Toxoplasmosis) Summary: A 25-year-old previously healthy man presents to the emergency room after experiencing a generalized tonic-clonic seizure that lasted 30 seconds. He has been experiencing headaches over the past 6 months but no other associated symptoms. His mother states she has witnessed him have two previous seizures. The history is notable for being sexually promiscuous and using IV illicit drugs. The result of his last HIV test is unknown. On neurologic examination, he is noted to have increased tone on the right and decreased right arm swing when walking. The remainder of his neurologic examination is normal. A CT scan of the head with contrast reveals that he has a ring-enhancing lesion measuring 15 mm over the left motor strip region and a 12-mm ring-enhancing lesion in the left basal ganglia. šš šš

šš

Most likely diagnosis: Cerebral toxoplasmosis. Best way to confirm diagnosis: Serum immunoglobulin M (IgM) and IgG titers for Toxoplasmosis gondii, and lumbar puncture to evaluate for polymerase chain reaction (PCR) of T. gondii. Next step in therapy: Start anticonvulsants to prevent further seizures and then start treatment for toxoplasmosis. Therapy consists of a combination of medications including pyrimethamine, sulfadiazine, and folinic acid.

ANALYSIS Objectives 1. Know the diagnostic approach to toxoplasmosis, including the use of imaging studies and cerebrospinal fluid (CSF) studies. 2. Describe the clinical features of toxoplasmosis. 3. Describe how to treat toxoplasmosis and what precautions are necessary.

Considerations This 25-year-old healthy man has been experiencing headaches for the past 6 months and just experienced his third generalized tonic-clonic seizure. His examination suggests a left-sided brain lesion, as he has right-sided motor findings (decreased right arm swing and increased tone on the right). The fact that he seems to have constitutional symptoms of weight loss and has risk factors for an HIV infection narrows the differential diagnosis significantly. This individual is most likely now HIV positive. This is based on the fact that he has been experiencing weight loss and has continued to participate in behavior placing him at high risk for HIV infection. Primary central nervous system (CNS) lymphoma, syphilitic gummas, tuberculomas, abscesses, neurocysticercosis, or metastatic brain tumors should be considered in the differential diagnosis. The presentation of headache, weight loss, generalized tonic-clonic seizures, and a focal neurologic examination suggests an

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intracranial lesion. An individual who is young and HIV positive should be evaluated for toxoplasmosis, primary CNS lymphoma, syphilitic gummas, tuberculomas, and brain abscesses. A CT scan of the head with and without contrast usually confirms the clinical suspicion but cannot differentiate each entity. Serologic studies in addition to CSF studies will help best determine the diagnosis. Besides the diagnostic tests described previously, other CSF studies include protein, glucose, cell count with differential, Gram stain, cytology, and Venereal Disease Research Laboratory (VDRL) testing. Other serologic studies include chemistry 20, complete blood count (CBC), HIV and CD4 count, erythrocyte sedimentation rate (ESR), rapid plasma reagin (RPR), and international normalized ratio (INR).

APPROACH TO: Infections in Immunocompromised Hosts: Toxoplasmosis DEFINITIONS GENERALIZED TONIC-CLONIC SEIZURE: It is often referred to as a grand mal seizure and involves loss of consciousness, violent muscle contractions, and rigidity. FOLINIC ACID: The reduced form of folic acid that does not require reduction reaction by enzyme for activation. RADICULOMYELOPATHY: A process affecting the nerve root and spinal cord. RING-ENHANCING LESION: A lesion that shows peripheral enhancement with central hypodensity on CT imaging after IV contrast is administered, unlike other lesions that have uniform/homogeneous enhancement.

CLINICAL APPROACH Toxoplasmosis is caused by the single-celled parasite, T. gondii, which is found throughout the world. It was discovered in 1908 in the gondi, a small rat-like animal from North Africa, and causes CNS toxoplasmosis in immunocompromised hosts. Toxoplasmosis has multiple hosts including humans, cats, and other warm-blooded animals. Toxoplasmosis is a common opportunistic infection in the HIV population. In fact, it is the leading cause of focal CNS disease in AIDS patients and is most frequently seen during the later phases of the disease. It is a fairly common infection, with approximately 33% of all humans having come in contact with this parasite during their lifetime. In immunocompetent adults, exposure to toxoplasmosis is asymptomatic; however, in immunocompromised patients, it can lead to severe disease and death. Toxoplasmosis acquired in pregnancy can cause various congenital anomalies in the fetus including hydrocephalus, intracerebral calcification, retardation, chorioretinitis, hearing loss, and even death. Toxoplasmosis is frequently seen in advanced AIDS when the CD4+ counts are less than 200 cells/mm3. Up to 5% of patients initially diagnosed with AIDS in

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the United States will present with toxoplasmosis. Fortunately, the incidence of toxoplasmosis has significantly declined because of the use of highly active antiretroviral therapy (HAART). In Africa and Europe as many as 50% of patients with AIDS will develop CNS toxoplasmosis.

TRANSMISSION There are three primary ways of transmission: by ingesting uncooked meat containing cysts, ingesting food and water contaminated with oocysts from infected cat feces, and by vertical transmission. The parasite can also be transmitted by transplantation of infected organs and blood transfusions. Although CNS toxoplasmosis occasionally results from a primary infection, it is more commonly caused by hematogenous spread of a previous infection.

Clinical Presentation and Diagnosis The most common clinical presentation in HIV-infected patients is encephalitis as a result of multiple brain lesions (Table 31–1). Usually, the patient experiences a deterioration in mentation over days to weeks, including headaches, seizures, or cognitive impairment; motor or sensory deficits can also be seen. T. gondii can also affect other organs such as the eyes or lungs. Diagnostic studies used to diagnose CNS toxoplasmosis include T. gondii IgG and IgM titers. An IgM antibody response is associated with newly acquired toxoplasmosis. However, antibody levels can be very low in AIDS patients. It has been reported that up to 22% of patients diagnosed with toxoplasmosis by histologic confirmation had absent antibody levels. If there are no signs of increased intracranial pressure, then a lumbar puncture may be obtained. CSF studies consistently show an elevated protein level. There is a great degree of variability when it comes to other CSF studies. PCR for T. gondii in CSF has moderate sensitivity and high specificity. The typical findings on CT scan of the brain are single or multiple hypodense lesions in the white matter and occasionally in the basal ganglia with mass effect. Lesions are usually ring enhancing. Typically, patients will present with multiple rather than solitary lesions (Figure 31–1). In fact, a solitary lesion favors CNS lymphoma over toxoplasmosis. Brain biopsy that reveals the organism should only be performed if there is no response to empiric treatment within 2 weeks or if there is a solitary lesion and negative serologic studies. Microscopic examination is notable if it shows lymphocytic vasculitis, microglial nodules, and astroglial nodules. Cases that show marked increased intracranial pressure and herniation are best handled with the aid of neurosurgeons. Table 31–1  •  CLINICAL FEATURES OF INTRACRANIAL TOXOPLASMOSIS Headache and constitutional symptoms early on Confusion, drowsiness, focal weakness, aphasia, and seizures later in the course Coma possible within days to weeks if no treatment is started Radiculomyelopathy occasionally present Other features: ataxia, cranial nerve palsies, hemianopia, personality changes

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Figure 31–1.  CT brain image with ring-enhancing toxoplasmosis. (Reproduced, with permission, from Roos KL. Principles of Neurologic Infectious Diseases. New York, NY: McGraw-Hill; 2005:80.)

TREATMENT The main treatment for CNS toxoplasmosis consists of pyrimethamine at a dose of 100 mg orally twice a day on the first day followed by 25 to 100 mg/d, usually continued for 6 weeks. Because of its selective activity against dihydrofolate reductase, it is imperative that folic acid be given concomitantly. This is often in the form of folinic acid. Sulfadiazine, which acts synergistically with pyrimethamine, should be given concomitantly at a dose of 1 to 2 g orally four times a day. If there is significant cerebral edema, corticosteroids such as dexamethasone (Decadron) should be given. Almost 75% of patients will improve within 1 week of receiving antibiotic therapy. The prognosis for full recovery is guarded, as there may be frequent relapses.

Prophylaxis Trimethoprim/sulfamethoxazole is effective prophylaxis against T. gondii and is indicated for HIV-infected individuals with CD4 counts less than 200 cells/mm3. Precautions include cooking meats completely, hygiene when handling uncooked or undercooked meat, and avoiding exposure to cat feces, such as cleaning litter boxes.

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CASE CORRELATION šš

See also Case 30 (Tabes Dorsalis)

COMPREHENSION QUESTIONS 31.1 A 22-year-old man is suspected to be infected by T. gondii. In which of the following routes is he most likely to have been infected? A. Ingesting uncooked vegetables B. Congenital C. Fecal-oral route D. Inhalation of spores 31.2 A 34-year-old HIV-infected man is being evaluated by his physician. His findings are suspicious for CNS toxoplasmosis. Which of the following clinical feature would support that diagnosis? A. Bladder retention B. Aortic dilation C. Argyll Robertson pupil D. Hemiparesis 31.3 Which of the following is true regarding CNS toxoplasmosis? A. Brain biopsy is the only reliable method of diagnosis. B. It is frequently seen in early cases of AIDS. C. Treatment consists of penicillin. D. Multiple ring-enhancing lesions as opposed to solitary lesions are suggestive of CNS toxoplasmosis.

ANSWERS 31.1 C. Spores are not part of the life cycle of T. gondii; instead, cysts can be spread via airborne contact. The documented routes of being infected by toxoplasmosis include ingesting uncooked or undercooked meats, vertical transmission (congenital) infection, and the fecal-oral route. Ingestion of uncooked meat (especially pork, lamb, and venison) is much more common than uncooked vegetables.

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31.2 D. Only 10% to 20% of toxoplasmosis-infected patients are symptomatic; however, immunocompromised patients have up to a 50% incidence of CNS involvement. The most common manifestations are seizures, cranial nerve defects, altered mental status, headache, and focal neurologic deficits such as hemiparesis. Argyll Robertson pupil has not been reported with CNS toxoplasmosis. Bladder incontinence, although uncommon, is part of an underlying myelopathy. Aortic root dilation is seen in syphilis but not toxoplasmosis. 31.3 D. Brain biopsies are deferred unless patients are not responsive to empiric therapy or if serologic studies are negative, and there is a solitary lesion on imaging studies.

CLINICAL PEARLS »»

Imaging studies suggestive of CNS toxoplasmosis show multiple ringenhancing lesions as opposed to a solitary ring-enhancing lesion, which is more suggestive of CNS lymphoma.

»»

The diagnosis of CNS toxoplasmosis can be made by positive serologic studies, although these may be undetectable in patients with AIDS.

»»

One-fourth to one-half of the world’s population is infected (most are asymptomatic), and infection is most common in places with warm, moist climates.

»»

Infection in the unborn child, called congenital toxoplasmosis, is the result of an acute, usually asymptomatic infection acquired by the mother in pregnancy and transmitted in utero.

REFERENCES Agarwal A, Banderudrappagari R. Intracranial lesion with fever and headaches. Toxoplasmic encephalitis. Am Fam Physician. 2013;87(12):877-879. Garcia LS, Bruckner DA. Diagnostic Medical Parasitology. 3rd ed. Washington, DC: American Society of Microbiology; 1997:111-121; 423-424; 577-589. Jones JL, Kruszon-Moran D, Wilson M, McQuillan G, Navin T, McAuley JB. Toxoplasma gondii infection in the United States: seroprevalence and risk factors. Am J Epidemiol. 2001;154:357-365. Remington JS, Thulliez P, Montoya JG. Recent developments for diagnosis of toxoplasmosis. J Clin Microbiol. 2004;42(3):941-945.

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CASE 32 You are paged to the emergency center (EC) to evaluate a 38-year-old woman for blurry vision. She first noticed the vision change when she woke up this morning, but it was not overly concerning for her. However, when she arrived at work, her coworker noted that her eyelid seemed to be drooping and that her pupils were not the same size. She contacted her primary care physician, who recommended that she should proceed directly to the emergency room (ER) for evaluation. She denies any other symptoms and has a past medical history significant only for migraine headaches. These headaches have not changed in character or frequency. On examination, her left eyelid is slightly lowered and the left pupil is larger than the right. The left eye is also slightly deviated laterally and downward and exhibits reduced adduction and vertical movements. She denies any eye pain. The rest of the neurologic and physical examination is normal. A computed tomography (CT) scan without contrast is normal. On further questioning, she mentioned that her mother had an aneurysm repaired years ago. »» »»

What is the most likely diagnosis? What is the next diagnostic step?

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ANSWERS TO CASE 32: Posterior Communicating Artery Aneurysm Summary: A 38-year-old woman presents with symptoms of ptosis, dilated pupil, and blurry vision. She is noted to have restricted extraocular movements on examination. These findings all localize to the third cranial nerve. CT of the head is normal. šš

šš

Most likely diagnosis: Third nerve palsy due to posterior communicating artery aneurysm. Next diagnostic step: Magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) of the brain.

ANALYSIS Objectives 1. Be familiar with common etiologies for anisocoria and how to differentiate them. 2. Understand the physiology of pupillary reaction. 3. Understand the diagnostic evaluation of third nerve palsy, including imaging studies.

Considerations This 38-year-old woman presents with acute ptosis, dilated pupil, and restricted extraocular movements, which are all findings that localize to the third cranial nerve. Parasympathetic fibers that constrict the pupil are located on the outside surface of the nerve, and therefore pupillary involvement in a third nerve palsy suggests a compressive lesion. Any acute-onset third nerve palsy with pupillary involvement is considered a neurologic emergency due to the possibility of an aneurysm, most commonly of the posterior communicating artery. Motor fibers controlling extraocular movements run in the body of the nerve. Therefore, with a microvascular ischemic lesion to the nerve, deeper nerve fibers are affected, and pupil involvement is less common. Furthermore, if a lesion occurs in a distal branch of the third nerve, the patient may only have a “partial third nerve palsy.” Suspicion for a life-threatening etiology of third nerve palsy is low when the pupil is spared or the signs of a partial third nerve palsy clearly localize to a particular branch of the nerve.

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APPROACH TO: Anisocoria DEFINITIONS ANISOCORIA: Unequal pupil size. MIOSIS: Constriction of the pupil. MYDRAISIS: Dilation of the pupil. ADIE PUPIL: Tonic pupil that has poor reaction to light but will accommodate on near gaze. It is slow to dilate after constriction. This is due to damage to the parasympathetic ciliary ganglion or short ciliary nerves followed by aberrant reinnervation. Idiopathic cases of tonic pupil are referred to as Adie pupil.

CLINICAL APPROACH Physiology The size of the pupil depends on a balance between parasympathetic and sympathetic tone. Both of these subsets of the autonomic nervous system interface with antagonistic muscles, which determine the size of the pupil. The pupillary sphincter muscle is innervated by the parasympathetic nervous system, and its activation results in pupillary constriction or miosis. The dilator muscle, on the other hand, is innervated by the sympathetic nervous system, and its activation results in pupillary dilation, otherwise known as mydriasis. The cell bodies for the parasympathetic preganglionic neurons are located in the Edinger-Westphal nucleus of the upper midbrain. These axons join the ipsilateral oculomotor nucleus motor fibers to form the third cranial nerve. Throughout the course of the oculomotor nerve, the parasympathetic fibers are situated superficially (immediately internal to the epineurium) and are susceptible to compressive injury. These parasympathetic axons eventually synapse in the ciliary ganglion, which houses the cell bodies of the postganglionic neurons. Postganglionic nerve axons then emerge to form the short ciliary nerves, which innervate the sphincter muscle. The sympathetic preganglionic neurons originate within the intermediolateral gray matter of the spinal cord, segments C8 to T2 (also known as the ciliospinal center of Budge-Waller), and receive indirect innervation from the ipsilateral hypothalamus. These preganglionic neurons exit the spinal cord via the dorsal roots and ascend in the sympathetic chain to synapse in the superior cervical ganglion in the distal neck. Postganglionic neurons then travel superficially on the internal and external carotid arteries. The axons on the external carotid artery innervate sweat glands in the skin, and the plexus on the internal carotid eventually joins the ophthalmic division of the trigeminal nerve. These fibers all pass through the ciliary ganglion without synapsing, enter the orbit with the nasociliary nerve, and innervate the dilator muscle via the long ciliary nerves (Figure 32–1).

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Ciliary ganglion Internal carotid artery

Trigeminal ganglion Superior cervical ganglion

Figure 32–1.  Sympathetic nerve pathway of the eye.

Physical Examination The first step in the pupillary examination is to note whether any anisocoria exists. If one pupil is smaller or larger than its counterpart, this can signify an autonomic nervous system disturbance. More specifically, an abnormally small pupil may signify a lesion in the sympathetic branch of the nervous system, while a large pupil may suggest a lesion affecting the parasympathetic branch. Pupil size should be assessed both in a well-lit room and a dark room. Worsening anisocoria in darkness suggests that the small pupil is the abnormal one because it is unable to dilate as well as the contralateral pupil to adjust to the darkness. Conversely, anisocoria that is more pronounced in the light suggests that the larger pupil is abnormal, as it is unable to constrict as well as the contralateral pupil in the presence of light. After assessing for anisocoria, it is important to observe the pupillary light reflex in each eye, both simultaneously and individually, using a strong light source. When light is shone in both pupils simultaneously, each should constrict to a similar degree.

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While assessing pupils individually, each should constrict to direct as well as consensual stimulation in the contralateral eye. If reaction to light is impaired, assess for intact accommodation by looking for pupillary constriction with near gaze. A pupil that accommodates but does not react is exhibiting a phenomenon called light-near dissociation. The final step in the pupillary examination is to perform the swinging-flashlight test to assess for presence of a relative afferent pupillary defect. When one eye has decreased afferent function relative to the other, the affected pupil will constrict when light is shone in the contralateral eye, but it will not constrict well in response to ipsilateral light stimulus. Because the affected eye is not sensing light properly, both pupils will appear to dilate when the light is swung toward the affected eye. Extraocular motion is also an important part of the neuro-ophthalmic examination. Cranial nerves III, IV, and VI, as well as extraocular muscles, can be assessed by testing visual tracking in the six cardinal gaze directions. Recall that the lateral rectus is innervated by cranial nerve VI, the superior oblique is innervated by cranial nerve IV, and cranial nerve III supplies all other extraocular muscles, as well as the levator palpebrae superioris muscle. Parasympathetic fibers also travel with the inferior branch of cranial nerve III before they enter the ciliary ganglion (Table 32–1). The pattern of extraocular motor deficits combined with the pupillary examination and the rest of the cranial nerve examination, mental status, neck examination, and vitals can help localize and define the etiology of the lesion.

Differential Diagnosis Third nerve palsy: The oculomotor nerve has multiple functions, as detailed in Table 32–1. A compressive lesion of the nerve will typically result in pupillary dilation as a result of parasympathetic fiber compression. Depending on the extent of compression, motor fibers may also be involved. When some function of the nerve remains, this is termed a “partial third nerve palsy.” When the entire nerve is compromised as in a “complete third nerve palsy,” the lesion is most likely microvascular. The most common third nerve compressive lesion is an aneurysm, usually of the posterior communicating or basilar arteries. While less common, the nerve can also be compressed by a tumor. In either case, third nerve compression can present as a “blown pupil,” which can be one of the first signs of impending uncal herniation. This would likely be associated with declining mental status and is a neurologic emergency. Table 32–1  •  EXTRAOCULAR MUSCLE INNERVATION Nerve

Somatic Motor

Visceral Motor

Oculomotor nerve (CN III) Superior branch Inferior branch

Levator palpebrae superioris Superior rectus Inferior rectus Medial rectus Inferior oblique

Parasympathetic input to ciliary and pupillary constrictor muscles

Trochlear nerve (CN IV)

Superior oblique

Abducens nerve (CN VI)

Lateral rectus

CN, cranial nerve.

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In this case, the patient’s pupillary dilation suggests parasympathetic involvement. The presence of multiple extraocular movement deficits and ptosis suggests that both branches of the nerve are compromised, likely from a lesion occurring proximal to their bifurcation. These findings are consistent with a partial third nerve palsy resulting from an aneurysm-related compression. Horner syndrome is the presentation of ptosis, miosis, and anhidrosis that results from ipsilateral insult to the sympathetic pathway (runs from hypothalamus to the eye). Ptosis may be subtle and is a result of the paresis of Muller muscle. The palpebral fissure can also be diminished and is referred to as an “upside-down” ptosis of the lower lid. Anhidrosis occurs when the lesion is proximal to the carotid artery bifurcation and ipsilateral sweat glands are impaired. Miosis and “dilation lag” are a result of impaired sympathetic input to the pupillary muscles. This is especially evident after roughly 5 seconds in the dark, as the normal eye will already be fully dilated. However, after 12 to 15 seconds, the abnormal pupil will have slowly dilated to full diameter, decreasing the degree of anisocoria. Congenital Horner syndrome can cause “heterochromia iridis,” a presentation where denervated areas of the iris remain lighter in color than the rest of the iris because sympathetic input is required for growth of the pigmented melanocytic cells. One iris may be a lighter color than that of the other eye, or a single iris may have areas of varied pigmentation. Historically, cocaine drops were used to test for Horner syndrome due to the drug’s indirect sympathomimetic effects. In healthy patients, cocaine drops would cause a rapid dilation of the pupil, while patients with sympathetic lesions would exhibit no such response. Because cocaine is a controlled substance, apraclonidine is now used to assess suspected Horner syndrome. Apraclonidine is a weak alpha-1 agonist and a strong alpha-2 agonist. In a normal pupil, apraclonidine has only weak alpha-1 agonist activity and will cause no change of pupil size (due to dominating alpha-2 activity). However, patients with a lack of sympathetic input to the eye have an upregulation of alpha-1 adrenergic receptors on the dilator muscle, and as a result, they have a denervation hypersensitivity to alpha-1 agonists. Thus, when apraclonidine is applied to a patient with Horner syndrome, the eye is hypersensitive to the effects of the drug and exhibits dilation of the eye and reversal of anisocoria. Of note, apraclonidine only reverses the anisocoria if the lesion is a third-order neuron because first- and second-order neuron lesions do not leave the pupil dilator muscle denervated. Pharmacologic anisocoria: There are multiple medications that can affect pupil size. Pilocarpine and organophosphates can both cause pupillary constriction, while medications such as atropine, tropicamide, and phenylephrine are routinely used to induce mydriasis in ophthalmology clinics. Similarly, scopolamine can also cause mydriasis, as can some plants. A detailed history that elicits potential exposures is key to the diagnosis of anisocoria, miosis, and mydriasis, and can help to avoid unnecessary and expensive workups for more serious intracranial lesions. For example, a patient may develop anisocoria after a breathing treatment if the face mask leaks on one side or if they touch their eye after touching their scopolamine patch (used for motion sickness, nausea, and hypersalivation).

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Physiologic anisocoria, defined as a pupillary difference of 0.4 mm or more, is the most common cause of anisocoria, occurring in 20% of the general population. This phenomenon is speculated to be due to a sympathetic imbalance in innervation and is slightly more pronounced in the dark. The degree of anisocoria often changes over time and can even switch eyes. The condition is often a long-standing one that can be confirmed on review of old photographs. It is differentiated from Horner syndrome by the fact that there are no other associated symptoms, and there will never be dilation lag in the dark. No further evaluation is needed for this condition. Light-near dissociation: Phenomenon in which pupils accommodate but have decreased or absent reaction to direct or consensual light. This can be caused by either optic neuropathy (ie, blindness), lesions of the dorsal midbrain (ie, Argyll Robertson pupil) or injury, and regeneration of oculoparasympathetic fibers (ie, tonic pupil). Optic neuropathy is the most common cause of light-near dissociation, as few light impulses reach the pretectal olivary nucleus; however, it is not often observed in clinic because accommodation is inconsistently assessed in blind patients. In patients with lesions of the dorsal midbrain (such as neurosyphillis), the light reflex pathway is interrupted, but the ventral fibers of the accommodation reflex are spared. Light-near dissociation in the setting of other neurologic symptoms is almost pathognomonic for Argyll Robertson pupil. Finally, in the setting of trauma or a compressive lesion, a light-near dissociation may develop as a result of aberrant regeneration of oculomotor nerve fibers (tonic pupil). Light-near dissociation can present as a component of various other syndromes, though less frequently than the above. Tonic pupil (Adie pupil): Tonic pupil is characterized by poor or absent reaction to light, preserved accommodation on near gaze, and slowed/tonic redilation to near stimuli following constriction. This is due to postganglionic parasympathetic denervation of the sphincter muscle followed by aberrant reinnervation with accommodative fibers. Tonic pupil presenting with decreased deep tendon reflexes may be part of a syndrome known as Adie syndrome. A unilateral tonic pupil in an otherwise healthy individual is usually benign. Adie tonic pupils exhibit light-near dissociation in that accommodation is more pronounced than reaction to light. It can be distinguished from Argyll Robertson pupils by its sluggish reaction and its usual unilateral presentation (Argyll Robertson pupils are often bilateral). Argyll Robertson pupil: A phenomenon associated with neurosyphilis, and a classic presentation of light-near dissociation where pupils will accommodate on near gaze but will not react to light. It can be differentiated from a tonic pupil in that the reactions are brisk instead of slow (or tonic). Argyll Robertson pupil has been attributed to lesions of the intercalated neurons in the midbrain or damage to inhibitory fibers of the oculomotor nucleus. It usually is a bilateral finding but may be asymmetric. The prevalence of Argyll Robertson pupils dropped significantly after the advent of penicillin therapy, but syphilis rates have risen in recent years. Structural lesions: Congenital iris defects can lead to anisocoria. Acquired ocular lesions such as iris trauma (including surgery), inflammatory changes, or even angle-closure glaucoma can also cause pupil asymmetry. If an etiology is not clear in the history, an ophthalmologic examination should identify the cause.

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Imaging Any new-onset, complete or partial third nerve palsy with pupillary involvement is considered a neurologic emergency until proven otherwise, due to the possibility of aneurysm. Imaging must be performed immediately. Imaging should also be performed in patients who are younger than 50 years, have a history of cancer, have other neurologic signs or symptoms, or who have no resolution of a suspected microvascular ischemic neuropathy after 3 months. The gold standard to assess for an aneurysm is still 4 vessel catheter angiogram; however, most patients will receive noninvasive imaging with a CT/CT angiogram (CTA) or MRI/MRA first. MRA and CTA each have a small number of false-negative studies, but the combination of MRI/MRA/CTA approaches 100%.

CASE CORRELATION šš

See also Case 23 (Optic Neuritis)

COMPREHENSION QUESTIONS 32.1 to 32.4.  Match the following (A to G) to the clinical scenario. A. Third nerve palsy B. Horner syndrome C. Pharmacological effect D. Physiologic anisocoria E. Argyll Robertson pupils F. Tonic pupil G. Structural defect 32.1 A 32-year-old man presents with anisocoria and mild left ptosis 2 days after being in a motor vehicle accident. Apraclonidine drops applied to the left eye reverse the anisocoria. 32.2 A 58-year-old pharmacy technician presents to the emergency department after her shift because she noticed that her right pupil is much larger than her left pupil. She denies any other symptoms. 32.3 A 54-year-old man with large right middle cerebral hemisphere stroke 1 day ago admitted to the intensive care unit (ICU) for monitoring is noted to be lethargic. His right pupil appears larger and less briskly reactive than the contralateral pupil. 32.4 A 27-year-old woman presents to clinic for evaluation of her migraine headaches. She is noted to have 0.5-mm asymmetry of the pupils, but both react well to light and accommodate. She has no other neurologic deficits.

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32.5 Which of the following patients is at the least risk for a life-threatening intracranial process and could be observed without imaging? A. A 48-year-old man with history of diabetes, hypertension, and hyperlipidemia who presents with an enlarged right pupil, right-sided ptosis, and diplopia. B. A 67-year-old man with a history of diabetes and hypertension who presents with diplopia, inferolateral eye deviation, and significant ptosis. C. A 77-year-old man with a history of diabetes, lung cancer, and a seizure 2 months ago who presents with a partial third nerve palsy. D. A 72-year-old woman with history of diabetes, hypertension, and polymyalgia rheumatica with third nerve palsy diagnosed 4 months ago who returns to clinic without any sign of improvement. 32.6 A 24-year-old woman with a visual disturbance is being evaluated by her physician. The physician is concerned about a possible sympathetic lesion affecting the right eye. Which of the following evaluations is most likely to uncover this lesion? A. Check for pupillary constriction in light. B. Check for pupillary dilation in dark. C. Check for upward eye gaze. D. Check for lateral eye gaze. E. Check for medial eye gaze. F. Check for accommodation.

ANSWERS 32.1 B. This man most likely has Horner syndrome induced by a carotid dissection. The apraclonidine confirms the third-order sympathetic neuron lesion. He needs angiographic evaluation of the neck vasculature. 32.2 C. Pharmacologic anisocoria is strongly suspected in this patient due to her risk of workplace exposure to mydriatic agents. Depending on the rest of her history and examination, she likely can be safely discharged without extensive workup. 32.3 A. Third nerve palsy. This patient is at risk for cerebral edema due to his large stroke. Because he is relatively young, he will have less brain atrophy and therefore less room to accommodate swelling within the cranium than would an elderly patient. The mass effect causes downward herniation of the uncal portion of the temporal lobe, compressing the third nerve in the process. He needs emergent CT and neurosurgical consultation for possible hemicraniectomy. 32.4 D. Physiologic anisocoria is the most common cause of pupil asymmetry. It is often small (age 50) with vascular risk factors and no other symptoms is likely suffering from a microvascular ischemic lesion in the deep fibers of the third nerve. This condition almost always resolves within 3 months and can often be observed for a time before proceeding with imaging. Poor resolution of symptoms over time, however, would decrease the likelihood of microvascular ischemic neuropathy, and further workup would be recommended. Patients who are younger, have a history of cancer, or have any other neurologic symptoms need imaging. Imaging should be performed in patients with pupil involvement, partial nerve palsy, or with poor resolution. The 48-year-old man is rather young for an ischemic neuropathy, and pupil involvement is less common with microvascular insults. A new cranial nerve lesion in a 77-year-old man with a history of lung cancer and recent seizure raises concern for metastatic disease. Cranial neuropathy may be a presenting sign of giant cell arteritis in a subset of patients, and polymyalgia rheumatica has a strong association with this vasculitis. 32.6 B. Sympathetic lesions will also cause abnormal constriction of the pupil, which will be most obvious in the dark because the impaired pupil will dilate much more slowly. However, after waiting 12 to 15 seconds, the pupil will reach its final diameter, and the anisocoria will be less apparent. Sympathetic lesions do not affect extraocular movements or accommodation.

CLINICAL PEARLS »»

A third nerve palsy involving the pupil is considered a medical emergency, as it may be a sign of an intracranial aneurysm (most commonly of the posterior communicating artery or basilar artery).

»»

Aneurysm is the most common compressive cause of an isolated oculomotor nerve palsy.

»»

When anisocoria is identified, additional examination findings such as ptosis and extraocular motion deficits can help determine which pupil is abnormal.

»»

Sympathetic lesions will be more obvious in the dark and will localize to the smaller pupil. Parasympathetic lesions will be more apparent in the light and localize to the larger pupil.

»»

Physiologic anisocoria is the most common cause of asymmetric pupils.

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REFERENCES Bruce BB, Biousse V, Newman NJ. Third nerve palsies. Semin Neurol. 2007;27(3):257-268. Colby K. Anisocoira. The Merck Manual Professional Edition. 2014 Aug. http://www.merckmanuals. com/professional/eye_disorders/symptoms_of_ophthalmologic_disorders/anisocoria.html. Accessed February 16, 2015. Cooper-Knock J, Pepper I, Hodgson T, Sharrack B. Early diagnosis of Horner syndrome using topical apraclonidine. J Neuroopthalmol. 2011;31(3):214-216. Dorland’s Illustrated Medical Dictionary. 27th ed. Philadelphia, PA: WB Saunders; 1988. Kawasaki A. Physiology, assessment, and disorders of the pupil. Curr Opin Ophthalmol. 1999;10(6): 394-400. Kawasaki AK. Diagnostic approach to pupillary abnormalities. Continuum (Minneap Minn). 2014; 20(4 Neuro-ophthalmology):1008-1022. Kedar S, Biousse V, Newman NJ. Approach to the patient with anisocoria. UpToDate. 2014 Jan. http:// www.uptodate.com/contents/approach-to-the-patient-with-anisocoria. Accessed February 16, 2015. Loewenfeld IE. The Pupil: Anatomy, Physiology and Clinical Applications. Ames, IA: Iowa State University Press and Detroit, MI: Wayne State University Press; 1993. Murchison AP, Gilbert ME, Savino PJ. Neuroimaging and acute ocular motor mononeuropathies: a prospective study. Arch Ophthalmol. 2011;129(3):301-305. Wilhelm H. Disorders of the pupil. Handb Clin Neurol. 2011;102:427-466. Wilson-Pauwels L, Akesson EJ, Stewart PA. Cranial Nerves: Anatomy and Clinical Comments. Philadelphia, PA: B.C. Decker; 1988.

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CASE 33 A 26-year-old obese woman presents to the emergency room with a severe headache and blurred vision. She has been experiencing headaches over the past 2 to 3 weeks. Her headaches are described as an aching sensation encompassing the entire head. She has been able to remain functional until today, when the severity of the headache acutely worsened to the point she could not tolerate it. She has taken acetaminophen without improvement in her symptoms. She has not experienced nausea, vomiting, or any other symptoms besides visual impairment. Over the past 2 weeks, she has experienced transient graying out of her vision, most noticeably when she gets up from a chair. Her temperature is 37.2°C (98.9°F), blood pressure 134/72 is mm Hg, heart rate is 78 beats/min, weight is 108.8 kg (240 lb), and height is 155 cm (5 ft 1 in). As the emergency room physician, you notice the following on examination: there are no cranial bruits, and her cardiovascular examination is normal. Her neurologic examination is notable for bilateral disc edema with intact visual acuity and full extraocular muscle movements. Her visual fields are normal on bedside confrontation examination. The remainder of her neurologic examination, including mental status, is completely normal. A comprehensive metabolic panel, complete blood count (CBC), urinalysis, and computed tomography (CT) scan of the head are all normal. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 33: Pseudotumor Cerebri/Idiopathic Intracranial Hypertension Summary: A 26-year-old obese woman presents with blurred vision and a severe headache. She provides a history of experiencing transient graying out of her vision over the past 2 to 3 weeks. She has no other associated symptoms. Her physical examination is notable for bilateral papilledema and obesity. The serum laboratory tests, urinalysis, and CT scan of the head are normal. šš šš

šš

Most likely diagnosis: Increased intracranial pressure. Next diagnostic step: Emergent CT imaging followed by lumbar puncture (if safe), and ophthalmic evaluation with formal visual field testing. Next step in therapy: A lumbar puncture is the first step in therapy in the acute setting.

ANALYSIS Objectives 1. Describe the diagnostic approach to pseudotumor cerebri. 2. Describe the differential diagnosis of papilledema. 3. Be familiar with emergent treatment of elevated intracranial pressure.

Considerations The presentation of headache with blurred vision and papilledema is a medical emergency. Papilledema denotes a serious neurologic problem and most commonly occurs bilaterally. When acute, vision for the most part is well preserved. Papilledema is defined as swelling of the optic disc from elevated intracranial pressure (Figure 33–1). It can be a sign of an underlying brain mass, which, even if benign, can cause increased intracranial pressure, placing patients at risk for irreversible neurologic dysfunction or even death. Depending on the size of the brain mass and the extent of its associated edema, patients are at risk for herniation syndromes, which eventually can lead to death. In general, all patients with increased intracranial pressure with papilledema require emergent neuroimaging studies. The study of choice in emergent situations remains a CT scan of the head with contrast. Conditions that can cause papilledema include meningitis, hydrocephalus, spaceoccupying lesions, dural sinus thrombosis, and pseudotumor cerebri (also known as idiopathic intracranial hypertension). Pseudotumor cerebri is a diagnosis of exclusion. It tends to affect women of childbearing age, and affected women are often obese.

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A

B Figure 33–1.  Fundus photographs from a patient with bilateral papilledema due to pseudotumor cerebri. A is the right eye and B is the left eye. (Reproduced, with permission, from Sushma Yalamanchili, MD.)

APPROACH TO: Papilledema DEFINITIONS PAPILLEDEMA: Disc edema from raised intracranial pressure, commonly bilaterally. HYDROCEPHALUS: Abnormal excessive accumulation of cerebrospinal fluid (CSF) in the brain.

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LUMBAR PUNCTURE: A test that evaluates CSF and opening pressure. It is performed under local anesthesia and involves placing a needle into the spinal canal, typically at L4-L5, for collection of spinal fluid.

CLINICAL APPROACH Pathophysiology Papilledema results from axoplasmic flow stasis in the slow axoplasmic transport system. Increased intracranial pressure is transmitted to the subarachnoid space, which in turn encompasses the entire optic nerve and is continuous with the optic nerve sheath. As intracranial pressure increases, the pressure in this sheath also increases, resulting in a blockage at the nerve and preventing normal axoplasmic transport. The collection of components involved in axonal transport leads to marked distension of optic axons, which in turn results in edema of the nerve and optic disc. Disc edema can be caused from many different etiologies, including inflammation, tumors, infections, and ischemia. However, papilledema refers only to the disc edema caused by increased intracranial pressure.

Evaluation The finding of papilledema on clinical examination in the setting of recent neurologic symptoms such as headaches or visual disturbances should alert the clinician of a possible space-occupying lesion in the brain. The history and physical examination can sometimes help localize a mass lesion. For example, right-sided weakness associated with headaches, papilledema, and visual disturbances would place the mass lesion in the left cerebral hemisphere. However, the etiology of this spaceoccupying lesion cannot be determined by examination alone. In the emergent setting, a CT scan of the head with and without contrast is helpful in trying to determine if this mass lesion is a tumor, hemorrhage, abscess, and so forth. Importantly, it will assist in diagnosing associated cerebral edema and impending cerebral herniation. When time allows, magnetic resonance imaging (MRI) of the brain with and without contrast provides greater detail to assess for tumors or infections. An MR venogram can exclude a dural venous sinus thrombosis. In the absence of a mass lesion, a lumbar puncture is the next step to evaluate the cause of increased intracranial pressure. Opening pressure of the CSF is measured and recorded with the patient in the recumbent position. Lumbar punctures performed in an upright position do not allow for accurate pressure measurements. If the CSF pressure is elevated greater than 20 cm of water, the clinician can choose to remove a large amount of CSF (>40 mL), otherwise known as a high-volume tap. The CSF should be sent for culture and analyzed for protein, glucose, cell count with differential, immunoglobulin G (IgG) synthesis panel, and cytology. Additionally, a note should be made of the color and clarity of the fluid. This analysis will help evaluate for conditions such as meningitis or other infections, hemorrhage, or inflammation. Visual disturbances can become permanent if the edema persists, as patients experience a progressive loss of peripheral vision. All patients need a formal ophthalmologic examination, including visual field testing, in addition to their neurologic evaluation.

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PSEUDOTUMOR CEREBRI Epidemiology Pseudotumor cerebri also is referred to as idiopathic intracranial hypertension or benign intracranial hypertension. It is often seen in young obese women and has an incidence rate in the United States of approximately 1 per 100,000 in the general population. The incidence is slightly higher in women who are overweight. The diagnosis is one of exclusion and requires the findings of increased intracranial pressure (papilledema), nonfocal neurologic signs (with the exception of a possible sixth cranial nerve palsy), normal imaging studies (except for slit-like ventricles), and normal CSF studies except for an elevated opening pressure. Although this can present at any age, most patients present in the third decade of life.

Pathophysiology The pathophysiology of pseudotumor cerebri is unclear; however, it is presumed that there is a resistance to absorption of CSF across the arachnoid villi. Others believe that the cerebral circulation is abnormal and that cerebral venous outflow is impaired, which results in increased water content in the brain. It has been suggested that obesity leads to increased intra-abdominal pressure, which raises cardiac filling pressures, which in turn leads to impaired venous return from the brain. This leads to an elevation in intracranial venous pressure. Whatever the cause, the resultant increased intracranial pressure is relayed to anatomic structures in the brain cavity, resulting in neurologic signs and symptoms.

Clinical Evaluation Typical symptoms for pseudotumor cerebri include headache, transient visual obscuration, dizziness, nausea, vomiting, pulsatile tinnitus, and horizontal diplopia from a sixth nerve palsy. The classic headache associated with pseudotumor cerebri is diffuse, worsens in the morning, and worsens by Valsalva maneuver. Patients often report transient visual obscuration or graying out/dimming of vision that is exacerbated after bending over or standing up quickly. The most common abnormality on clinical examination is bilateral disc edema. Disc edema can be asymmetric, and there can be associated subretinal hemorrhages. If untreated, it can lead to irreversible optic nerve damage. Risk factors for pseudotumor cerebri include obesity, recent weight gain, female gender, being in the reproductive age group, and menstrual irregularity. Some cases have been associated with hypothyroidism, Cushing disease, adrenal insufficiency, chronic renal failure, systemic lupus erythematosus, lithium, tamoxifen, tetracycline, cimetidine, and retin-A–containing medications. Discontinuation of corticosteroids has also been associated with the development of pseudotumor cerebri. In the evaluation process, imaging studies should be performed to exclude mass lesions, infections, hemorrhage, and dural venous sinus thrombosis. Typically, neuroimaging studies are normal in patients with pseudotumor cerebri. However, enlarged optic nerve sheaths, flattening of the posterior portion of the globe, small slit-like ventricles, or an empty sella may be seen. If imaging studies are normal, a lumbar puncture is performed to evaluate opening pressure. CSF studies

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as described earlier should be performed. In pseudotumor cerebri, all CSF studies should be normal, except for an elevated opening pressure. Additionally, visual fields should be evaluated by an ophthalmologist to clearly document any subtle abnormalities. The presence of objective deficits on formal examination can significantly impact the treatment plan.

Treatment Treatment of pseudotumor cerebri includes a high-volume lumbar puncture performed at the time of the initial evaluation. This, however, is only temporary. Long-term treatment includes the use of a carbonic anhydrase inhibitor such as acetazolamide or topiramate, which lowers the intracranial pressure through decreased CSF production. In addition, these medications have a side effect of weight loss that can be beneficial in these patients. Furosemide has also been used alone and in combination with carbonic anhydrase inhibitors. If the patient is experiencing significant or progressive visual loss, the next step is to perform optic nerve sheath fenestrations. This involves cutting patches in the dura surrounding the optic nerve, allowing efflux of CSF, which in turn reduces pressure. If medical management is insufficient, a lumbar peritoneal shunt or ventriculoperitoneal shunt is performed by neurosurgeons. Weight reduction is essential to the long-term management of the disease, and bariatric surgery may need to be considered in some patients.

COMPREHENSION QUESTIONS 33.1 An emergency room physician has found what appears to be papilledema on examination in a 40-year-old woman. The intracranial pressure is noted to be normal. Which of the following conditions is most likely to be causative? A. Metastatic breast cancer B. Intracerebral hemorrhage C. Hydrocephalus D. Idiopathic intracranial hypertension E. Optic nerve trauma 33.2 Which of the following is a risk factor for pseudotumor cerebri or idiopathic intracranial hypertension? A. Thin physique B. Hyperthyroidism C. Recent weight loss D. Female gender

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33.3 A 25-year-old woman with recent weight gain presents with headaches. She is diagnosed with pseudotumor cerebri. Other than mild papilledema, her examination is normal. Which of the following is the best next step in therapy? A. Acetazolamide B. Optic nerve sheath fenestration C. Lumbar peritoneal shunt D. Bariatric surgery

ANSWERS 33.1 E. The physician is observing findings suggestive of papilledema such as swelling of the optic margins and elevation of the optic disc. In this patient, the intracranial pressure has been measured and is normal; thus, the optic nerve disc findings is not due to a “pressure” process. Optic nerve trauma can cause the swelling and optic nerve changes. It is not due to intracranial pressure and thus is not referred to as papilledema. In summary, all the answer choices are options that can cause optic disc edema, but optic nerve trauma was the only option that would not be secondary to increased intracranial pressure. 33.2 D. Female gender places the patient at higher risk for benign intracranial hypertension. 33.3 A. Acetazolamide decreases the intracranial pressure and would be a good initial treatment option for this patient. Many pseudotumor cerebri patients do undergo shunt placement, but only if they do not tolerate or respond to medical management. Optic nerve sheath fenestration would only be indicated if she were having rapid and/or progressive visual loss. Bariatric surgery should only be considered in obese patients who fail to lose weight by diet and exercise. Medical management should always be attempted before invasive surgical options unless there is an emergent indication (eg, rapid visual loss).

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CLINICAL PEARLS »»

“Papilledema” is a term that should only be used for optic disc swelling secondary to increased intracranial pressure.

»»

Papilledema associated with visual dysfunction is a medical emergency requiring immediate neuroimaging studies.

»»

The neurologic examination in patients with pseudotumor cerebri should be normal except for papilledema, visual loss, and a possible sixth nerve palsy.

»»

Lumbar puncture can be both diagnostic and therapeutic in patients with pseudotumor cerebri.

»»

Acute treatment of pseudotumor cerebri includes a high-volume lumbar puncture, followed by long-term treatment with a carbonic anhydrase inhibitor such as acetazolamide or topiramate.

REFERENCES Brazis PW, Lee AG. Elevated intracranial pressure and pseudotumor cerebri. Curr Opin Ophthalmol. 1998;9(6):27-32. Green MW. Secondary headaches. Continuum (Minneap Minn). 2012;18(4):783-795. Miller NR, Newman NJ. Pseudotumor cerebri (benign intracranial hypertension). In: Miller NR, Newman NJ, Biousse V, et al, eds. Walsh and Hoyt’s Clinical Neuro-Ophthalmology, Vol. 1. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:523-538. Pham L, Wall M. Idiopathic intracranial hypertension (pseudotumor cerebri). University of Iowa Ophthalmology and Visual Sciences website. Updated February 2, 2010. http://webeye.ophth. uiowa.edu/eyeforum/cases/99-pseudotumor-cerebri.htm. Accessed February 15, 2015.

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CASE 34 A 65-year-old man with a history of hypertension, coronary artery disease, and diabetes mellitus presents with a complaint of double vision that started yesterday. He has not experienced any other general or neurologic symptoms. He noticed covering up either eye corrects his double vision, and has resorted to wearing an eye patch since yesterday so that he can see and walk without falling. In fact, he was able to drive on his own on the freeway to your office, much to his family’s dismay. On further questioning, you elicit the history that his double vision is worse when he looks to the right and better with gaze to the left. He has been compliant with his medications for hypertension and coronary artery disease. On examination, his blood pressure is 124/72 mm Hg, with a heart rate of 88 beats/min. He is afebrile and has a regular rate and rhythm without murmurs on cardiac examination. There are no carotid bruits, and his peripheral pulses are normal. His neurologic examination is notable for intact orientation and intact motor strength. His cranial nerve examination is remarkable only for impaired abduction of the right eye. Sensory examination is normal, and his deep tendon reflexes are 2+ throughout. Plantar responses are downgoing. His gait is normal. Review of his daily blood pressure log shows stable pressures around 130/70 mm Hg. »» »»

What is the neurologic deficit? What is the most likely diagnosis?

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ANSWERS TO CASE 34: Sixth Nerve Palsy (Ischemic Mononeuropathy) Summary: A 65-year-old man with hypertension, coronary artery disease, and diabetes mellitus presents with a 24-hour history of binocular horizontal diplopia (double vision). He has not experienced associated symptoms such as headache. His examination is significant for a normal blood pressure and heart rate and the findings of the isolated right sixth nerve palsy. šš

Likely neurologic deficit: Sixth nerve palsy

šš

Most likely diagnosis: Ischemic mononeuropathy

ANALYSIS Objectives 1. Understand the diagnostic approach in evaluating diplopia. 2. Describe the difference between monocular and binocular diplopia. 3. Know the differential diagnosis of a sixth nerve palsy.

Considerations This 65-year-old man with known risk factors for cerebrovascular disease (hypertension, diabetes, and coronary artery disease) presents with an acute episode of binocular diplopia. The history suggests binocular diplopia, as he tells you that covering up an eye resolves the diplopia. You are given the history that he has diplopia only on horizontal gaze. Given the history of hypertension and coronary artery disease, he is at risk for cerebrovascular disease and ischemia. In this particular case, you are told that the patient’s brain magnetic resonance imaging (MRI) is normal. In this setting, the most likely cause of diplopia is microvascular ischemic mononeuropathy of the peripheral abducens nerve.

APPROACH TO: Binocular Diplopia DEFINITIONS DIPLOPIA: Double vision. ISCHEMIC MONONEUROPATHY: Isolated nerve injury from inadequate blood flow to the nerve. PTOSIS: Drooping of the eyelid.

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CLINICAL APPROACH Sixth nerve or abducens nerve palsy has a variety of causes, and a detailed history and clinical examination usually lead to an accurate diagnosis. Unilateral abducens palsy is the most common isolated ocular motor palsy. A careful review of the anatomic course of the abducens nerve can help delineate the location of the lesion. The abducens nucleus is located in the lower dorsal pons. The motor neurons of this nucleus send axons that course anteriorly in the pons and travel near the corticospinal tract and emerge in the sulcus between the pons and medulla. The abducens nerve exits the pons ventrally and ascends in the prepontine cistern via the subarachnoid space. It pierces the dura lateral to the dorsum sellae of the sphenoid bone. It then rises over the petrous apex of the temporal bone and enters the cavernous sinus lying between the carotid artery and the ophthalmic branch of the trigeminal nerve laterally. It finally passes through the medial end of the superior orbital fissure and through the tendinous ring to enter the deep surface of the lateral rectus muscle.

Etiology of Sixth Nerve Palsy After the localization of the lesion to the sixth cranial nerve, the next step is to determine the etiology of the abnormality. Vascular lesions are a common cause of sixth nerve palsy. An infarct in the basal pons can also damage the nucleus or the axons, as these travel toward the ventral surface from the nerve. Microvascular ischemia can occur at any point along the nerve’s path and may be painful. Posterior inferior cerebellar artery or basilar artery aneurysms may also compress the nerve. Masses in the fourth ventricle, skull base, and cavernous sinus can also compress the nerve. Inflammatory and infectious processes may also affect the nerve (eg, sarcoidosis, extension of a middle ear infection). It is also prone to injury with fractures of the skull base. The sixth cranial nerve is most commonly affected by elevated intracranial pressure due to impingement over the petrous temporal ridge. This is considered a “false localizing sign” because the nerve palsy suggests a focal lesion when the true problem is often diffuse elevation of intracranial pressure, and the underlying cause of the elevated pressures may or may not localize to the same side as the sixth nerve palsy.

Evaluation of Diplopia Diplopia results from lack of visual fusion. The first step in evaluating a patient with diplopia is to determine whether it is binocular or monocular. Binocular diplopia denotes double vision arising from misalignment of both the eyes and is caused by an underlying primary neurologic problem. Covering up either eye resolves the double vision. Monocular diplopia is primarily caused by an ophthalmologic disorder such as abnormalities of the lens, cornea, or vitreous humor. Only rarely is monocular diplopia caused by occipital lobe disease or seizures. Monocular diplopia arises from a primary problem within one eye and does not resolve when an eye is covered. The next step in evaluating someone with binocular diplopia is to determine if it is horizontal or vertical. Different eye muscles are involved in moving the eyes horizontally or vertically. There are only two muscles in each eye responsible for horizontal gaze, and those are the medial rectus (innervated by the third nerve) and

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the lateral rectus (innervated by the sixth nerve). Worsening horizontal diplopia on near vision could suggest a problem with the medial rectus, whereas horizontal diplopia that worsens when viewing distant and lateral objects could indicate a problem with the lateral rectus. Examining extraocular muscles in the six cardinal fields of gaze can readily point out which of the two muscles is affected. For example, if the right eye cannot cross the midline and look out laterally, the lateral rectus is affected. Conversely, if the right eye cannot cross the midline and turn inward, the medial rectus is affected. The red lens test can help determine which eye muscle is causing the diplopia. A red lens is placed over the right eye, and the patient is asked to follow the movements in six positions of cardinal gaze. The key to performing this test is to understand the following: (1) Image separation will be greatest in the direction of the weak muscle, and (2) the image that is the farthest away from the midline is a false image and corresponds to the eye with impaired motility. The other four eye muscles (superior rectus, inferior rectus, inferior oblique, and superior oblique) move the eyes vertically. Individuals that present with vertical binocular diplopia are experiencing weakness in one or several of these muscles. Vertical diplopia that worsens on near vision suggests a problem with either the inferior oblique or superior oblique. A fourth nerve palsy will have worse diplopia on downward gaze. The three-step Parks-Bielschowsky test can be used to localize the impaired muscle causing vertical diplopia. Each step assesses whether the dysconjugate gaze is worse in a particular direction. First, determine which eye is hypertrophic (elevated or “higher up” compared to the other) on primary midline gaze. If the right eye appears higher than the left, this means the right eye depressors (right inferior rectus, right superior oblique) or the left eye elevators (left superior rectus, right inferior oblique) are weak. The second step assesses whether the hypertropia increases on right or left gaze. The vertical rectus muscles have their greatest vertical action when the eye is abducted and the oblique muscles have their greatest vertical action when the eye is adducted. In the final step, determine whether the hypertropia increases on right or left head tilt. For example, a right fourth nerve palsy would have right eye hypertropia on primary gaze. The hypertropia and diplopia would be worse on left gaze and right head tilt. Left head tilt would help the diplopia, and the patient may naturally assume that position (Figure 34–1). A red lens test may be performed in conjunction with this test. Another option is to use a Maddox rod, a more advance form of red lens testing. Evaluating other aspects of the cranial nerve examination may also help localize the lesion. Special attention should be given to the eyelid, pupillary responses, symmetry of the pupillary size, and abnormalities of cranial nerves V, VII, and VIII. For example, ptosis or droopiness of the eyelid can suggest a third nerve problem. Likewise, pupillary asymmetry suggests a third nerve problem. Multiple cranial nerve involvement may indicate a lesion in the brainstem, cavernous sinus, or orbit, depending on the particular nerve’s involvement. Variable fatigability of the eyelid can suggest myasthenia gravis. The evaluation includes serologic studies including an erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibody (ANA), complete blood count (CBC), and hemoglobin A1c. An ESR, CRP, and ANA can help exclude

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RIR–

LIO–

G

F

E

LSR–

RSO–

RSO– vs LSR–

Figure 34–1.  Example of the three-step Parks-Bielschowsky test. LSO/RSO, left/right superior oblique; LIO/RIO, left/right inferior oblique; LSR/RSR, left/right superior rectus. (Reproduced, with permission, from von Noorden GK. Atlas of Strabismus. 4th ed. St Louis, MO: Mosby-Year Book; 1983.)

D

C

B

RIR– vs LIO–

A

RSO– RIR– LSR– LIO–

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inflammatory causes such as vasculitis; glycosylated hemoglobin can exclude diabetes mellitus, and a CBC can exclude infectious processes. An MRI of the brain and orbits can exclude vascular abnormalities such as an aneurysm and can exclude lesions that are inflammatory (sarcoid), demyelinating, neoplastic, or due to brainstem infarct. Imaging of the brain and vasculature must be considered in suspected third cranial nerve palsies, especially if the pupil is involved, due to the possibility of compression of the peripherally lying parasympathetic fibers by a posterior communicating artery aneurysm. Ancillary studies such as cerebrospinal fluid (CSF) analysis may be necessary in younger patients if imaging is inconclusive. Most clinicians will also obtain imaging in patients with isolated fourth or sixth nerve palsies. An ischemic process may not be readily visualized on imaging studies and is often a diagnosis of exclusion.

TREATMENT Treatment is focused on symptomatic relief and controlling the underlying medical conditions, particularly diabetes. An isolated and presumed ischemic-related sixth nerve palsy can be observed for improvement for 1 to 3 months. Patching of the involved eye can help alleviate diplopia symptoms temporarily. Eyeglasses made with prism lens can also be used to minimize or correct diplopia during recovery. Some suggest using botulinum toxin as a temporizing measure. It is injected into the antagonist muscle of the paretic muscle and the effect of a single injection can last for up to 3 to 6 months. If these measures fail, strabismus surgery on the extraocular muscles to try to correct the misalignment may be of benefit in some patients. Surgery should not be considered until adequate time has been given for recovery.

CASE CORRELATION šš

See also Case 24 (Multiple Sclerosis) and Case 32 (Posterior Communicating Artery Aneurysm)

COMPREHENSION QUESTIONS 34.1 Which of the following is most accurate regarding diplopia? A. Binocular diplopia refers to double vision occurring from intrinsic problems in both eyes. B. Monocular diplopia most commonly occurs because of extrinsic eye problems. C. On red lens testing, the false image is always the image closest to the midline. D. The key in evaluating diplopia is to start by determining if it is monocular or binocular.

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34.2 A 33-year-old woman has a 3-minute seizure episode caused by her epilepsy. There are no underlying medical disorders or brain structural lesions. Which of the following indicates a more complicated underlying neurologic problem? A. Urinary incontinence with seizure B. Confusion and lethargy after seizure C. Headache after the seizure D. Sixth nerve palsy after seizure 34.3 A 58-year-old woman suffers from an ischemic-related sixth nerve palsy, which occurred 6 months ago. Various methods have been tried with limited success, and the patient still has diplopia. Which of the following is most likely to be helpful at this stage? A. Surgery B. Eye patch C. Prisms D. Prednisone at a dose of 10 mg/d

ANSWERS 34.1 D. The key to evaluating diplopia is to assess unilateral versus bilateral. In most cases, binocular diplopia arises from a primary neurologic problem and monocular diplopia is due to a primary ophthalmologic issue. The false image on red lens testing is always the farthest from the midline. 34.2 D. Seizures have not been reported to cause sixth nerve dysfunction, and thus its presence indicates a more complex situation such as space-occupying lesion. A sixth nerve palsy can be a sign of elevated intracranial pressure. Headache, postictal confusion and lethargy, and incontinence are commonly associated with seizures. 34.3 A. Surgery may be considered in patients with persistent symptoms that have not resolved and are not controlled by less invasive methods. Surgery is not considered immediately, as many patients will recover function within a few months. Prednisone has not been used for sixth nerve palsies from ischemia but can be used for inflammatory causes of sixth nerve abnormalities.

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CLINICAL PEARLS »»

Localization of diplopia can be determined with careful interview and clinical examination. It is essential to determine if the diplopia is (1) binocular or monocular and (2) horizontal or vertical.

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Binocular diplopia typically occurs from misalignment of the eye muscles on a target and commonly denotes an underlying primary neurologic problem. Monocular diplopia results from intrinsic eye problems.

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MRI of the brain should be considered when evaluating patients with binocular diplopia, as it allows for the detection of vascular or demyelinating processes and mass lesions.

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Isolated cranial nerve palsies are often due to microvascular ischemia, especially in older patients with vascular risk factors such as diabetes mellitus.

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A sixth nerve palsy can be a sign of increased intracranial pressure but it does not necessarily help localize the causative lesion.

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A third nerve palsy involving the pupil (pupil dilation) is considered a medical emergency, as it may be a sign of a posterior communication artery aneurysm.

REFERENCES Cybersight by Project Orbis International Inc. Parks-Bielschowsky Test. http://www.cybersight.org/ bins/content_page.asp?cid=735-2858-4397-4781-5287-5289-5292. Accessed February 15, 2015. Danchaivijitr C, Kennard C. Diplopia and eye movement disorders. J Neurol Neurosurg Psychiatry. 2004;75:iv24-iv31. Patel SV, Mutyala S, Leske DA, Hodge DO, Holmes JM. Incidence, associations, and evaluation of sixth nerve palsy using a population-based method. Ophthalmology. 2004;111:369-375. Quah BL, Ling YL, Cheong PY, Balakrishnan V. A review of 5-years’ experience in the use of botulinum toxin A in the treatment of sixth cranial nerve palsy at the Singapore National Eye Centre. Singapore Med J. 1999;40:405-409. Savino PJ. Diplopia and sixth nerve palsies. Semin Neurol. 1986;6:142-146. Tamhankar MA, Biousse V, Ying GS, et al. Isolated third, fourth, and sixth cranial nerve palsies from presumed microvascular versus other causes: a prospective study. Ophthalmology. 2013;120(11): 2264-2269. Wilson-Pauwels L, Akesson EJ, Stewart PA. Cranial nerve VI: abducens nerve. In: Cranial Nerves: Anatomy and Clinical Comments. Philadelphia, PA: B.C. Decker; 1988:71-79.

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CASE 35 A 68-year-old woman presents with right facial droop. She reports waking up this morning and having trouble eating breakfast, as food slipped out of her mouth. Her husband complains that her speech is difficult to understand. She denies numbness or tingling of her face, change in vision, or weakness or sensory changes involving her extremities. Her medical history is unremarkable, although she does have a history of chicken pox as a child. Physical examination reveals right-sided facial paralysis involving the upper and lower face. She has clear nasolabial asymmetry as well as difficulty closing the right eye and elevating the right forehead. There are multiple vesicular, erythematous blisters over her right external ear. The examination of the ear canal is painful to her, but the tympanic membrane is intact. No pus is seen in the ear canal. Hearing is mildly diminished in the right ear relative to the left. The examination of the nose, oral cavity, throat, and neck is normal. The remainder of the cranial nerve (CN) examination as well as the general examination is unremarkable. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 35: Facial Paralysis Summary: A 68-year-old, otherwise healthy woman presents with sudden-onset right-sided facial paralysis and right-sided hearing loss. Facial weakness involves the upper and lower face on the right. There is a vesicular rash over the right external ear. šš šš

šš

Most likely diagnosis: Herpes zoster oticus (Ramsay Hunt syndrome) Next diagnostic test step: Tzanck smear, audiogram; consider facial nerve electrodiagnostic studies, and diagnostic imaging, if indicated Next therapeutic step: Corticosteroid and antiviral therapy

ANALYSIS Objectives 1. Describe the clinical presentation and diagnostic approach to facial weakness. 2. Compare and contrast central and peripheral causes of facial paralysis. 3. Know the differential diagnosis of facial weakness. 4. Know the treatment for Ramsay Hunt syndrome.

Considerations This patient with a history of chicken pox as a child presents with blisters on her ear, hearing abnormalities, and unilateral facial paralysis. Her upper and lower facial muscles are involved, suggestive of a peripheral facial nerve palsy, as central defects generally spare muscles of the forehead. Her right-sided hearing loss is worrisome for involvement of the right CN VIII. This constellation of findings is most consistent with Ramsay Hunt syndrome, which is reactivation of latent herpes zoster infection affecting both VII and VIII CNs. In the setting of a right-sided peripheral seventh nerve palsy alone, we might expect to find hyperacusis (increased hearing) on the right side. This is due to innervation of the stapedius muscle by branches of CN VII, which normally dampens and attenuates loud sounds.

APPROACH TO: Facial Nerve Paralysis DEFINITIONS AUDIOGRAM: A test that measures the level of hearing in each ear. BELL PALSY: Idiopathic facial paralysis due to seventh peripheral CN palsy, sometimes associated with herpes simplex virus (HSV).

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CHOLESTEATOMA: A benign tumor composed of epithelial debris from the tympanic membrane that becomes trapped in the middle ear. POSTHERPETIC NEURALGIA: Neuropathic pain resulting from resolved herpes infection. TZANCK SMEAR: Slide preparation for visualization of intracytoplasmic particles due to viral infection. VESICLES: Small fluid-filled blisters on an erythematous base.

CLINICAL APPROACH Facial weakness is among the most common neurologic presentations in the clinic or hospital setting. Understanding the anatomy and function of the facial nerve is important in narrowing the otherwise broad differential diagnosis for facial palsy. In the setting of unilateral facial weakness, the first clinical step is to distinguish central (upper motor neuron [UMN]) from peripheral (lower motor neuron [LMN]) causes. The facial nerve (CN VII) is a multimodal nerve involved with facial expression, taste (anterior two-thirds of tongue), auditory attenuation, lacrimation, salivation, and cutaneous sensory input from the outer ear canal and part of the outer ear. Efferent fibers of CN VII (LMN) originate from the facial motor nucleus in the lower pons. These fibers, in turn, supply the muscles of facial expression as well as the stapedius muscle, which attenuates loud sounds. The facial motor nucleus is organized topographically, such that fibers to the upper one-third of the face originate from the dorsal part of the nucleus, while those to the lower two-thirds of the face originate from the ventral part of the nucleus. Corticobulbar tract fibers (UMN) provide bilateral cortical input to the dorsal part of the nucleus, while the ventral nucleus receives contralateral input only. Subsequently, lesions to the corticobulbar tract (UMN) will cause lower facial weakness, generally sparing the forehead. In contrast, lesions of CN VII after it has exited the facial motor nucleus will produce weakness of the whole face, including the forehead. In addition to involvement of the forehead, other features suggestive of peripheral/LMN facial lesions include ipsilateral hyperacusis (branch to stapedius), ipsilateral loss of taste in the anterior two-thirds of the tongue, and ipsilateral sensory deficit over the outer ear (auricle). Because the facial nerve passes through the middle ear and temporal bone, examination of the ear canal and tympanic membrane is important. Otitis media and cholesteatoma can be associated with facial paralysis. Acute otitis media is a common cause of isolated facial paralysis in children. Cholesteatoma is a benign tumor of epithelial debris that is produced when the squamous layer of the eardrum is trapped and cannot exfoliate properly. Cholesteatoma usually occurs in patients who have preexisting ear problems, and physical examination may reveal either cheesy epithelial debris in the ear canal or a pearly white tumor behind the ear drum. Generally, patients with cholesteatoma will have a preexisting history of hearing loss and often a long history of intermittent foulsmelling, purulent otorrhea. Cholesteatomas grow slowly and sometimes can be present for years without producing symptoms.

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Facial neuromas (schwannomas of the facial nerve) are relatively rare benign tumors of the facial nerve that grow slowly and produce a slowly progressive (over several months, not days) form of facial paralysis. Tumors of the parotid gland and skull base can produce facial paralysis. Paralysis of an isolated branch of the facial nerve should raise suspicion for malignancy. Malignant tumors of the skin or parotid gland can produce facial paralysis either by compression or perineural invasion. Bilateral facial paralysis has a limited number of causes, including Lyme disease and sarcoidosis, which may affect multiple cranial nerves. Also, patients with Guillain-Barre’ syndrome may present with unilateral or bilateral facial paralysis. Ramsay Hunt syndrome is caused by reactivation of varicella zoster virus (VZV) in the geniculate ganglion, the main sensory ganglion of CN VII. Reactivation of the virus produces vesicles in its area of sensory innervation. For the facial nerve, this can include the posterior ear canal or postauricular skin. Reactivation can occur in the setting of immunocompromise or due to nonspecific physiology. Ramsay Hunt syndrome may also involve other CNs, including VIII, IX, V, and VI, in order of frequency. The pain from herpes zoster is often described as burning and can be intensely painful. Treatment of Ramsay Hunt syndrome involves oral acyclovir and corticosteroids, with faster resolution of symptoms if initiated within 48 hours of onset. Carbamazepine, pregabalin, or gabapentin may also be useful in treating associated neuropathic pain. Of note, patients with active vesicles are contagious and can spread the virus to susceptible individuals. Hearing loss and/or vestibular symptoms can occur in patients with Ramsay Hunt syndrome. This will produce ipsilateral sensorineural hearing loss. Proposed mechanisms for involvement of CN VIII include periganglionic spread and compression due to secondary inflammatory changes and edema. Bell palsy refers to idiopathic facial nerve palsy, often associated with viral infection with HSV. In contrast to Ramsay Hunt syndrome, which may cause ipsilateral hearing loss due to involvement of CN VIII, Bell palsy is associated with ipsilateral hyperacusis secondary to attenuation deficits from stapedius muscle involvement. With regard to treatment, corticosteroids have been shown to increase the likelihood of recovery in Bell palsy. In contrast, antiviral therapy has not been shown to improve outcomes and is not evidence-based medicine for treatment in Bell palsy. Current recommendations are for steroids alone; treatment should be initiated within the first 72 hours of symptoms. Regardless of the cause, patients with facial paralysis (particularly LMN lesions) need special care of the eye on the affected side. Because of the loss of the blink reflex and decreased lacrimation, the affected eye can dry out and produce exposure keratoconjunctivitis, which may lead to loss of vision in the affected eye. Simple eye care consisting of artificial tears every hour while awake and lubricant ointment at night with eye taping can prevent permanent loss of vision.

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CASE CORRELATION šš

See also Case 32 (Posterior Communicating Artery Aneurysm), Case 34 (Sixth Nerve Palsy [Ischemic Mononeuropathy]), and Case 36 (Ptosis [Myasthenia Gravis])

COMPREHENSION QUESTIONS 35.1 A 49-year-old woman is noted to have right-sided facial weakness of acute onset. What is the most common cause of this patient’s condition? A. Lyme disease B. VZV reactivation C. Acoustic neuroma D. HSV reactivation E. Noncaseating granulomas 35.2 What is the key indicator of Ramsay Hunt syndrome? A. Vesicles on an erythematous base found in the external ear B. Noncaseating granulomas on lower lip biopsy C. Circulating antibodies to Borrelia burgdorferi D. Uveitis and parotid gland swelling E. Loss of taste on the ipsilateral tongue 35.3 A 69-year-old man complains of acute-onset right facial droop. A close examination of his facial movements indicates loss of the nasolabial fold and inability to raise the upper lip on that side. His blink, forehead, and lower lip movement are normal. What is the most likely cause of his facial paralysis? A. Bell palsy B. Stroke C. Malignant parotid gland tumor D. Acoustic neuroma E. Lyme disease

ANSWERS 35.1 D. By far the most common cause of acute facial weakness in an adult is Bell palsy. This disorder is considered to be associated with reactivation of HSV. However, this is a diagnosis of exclusion, as no accurate serologic tests have been discovered that confirm the diagnosis.

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35.2 A. The pathognomonic feature of herpes zoster oticus (Ramsay Hunt syndrome) is a vesicular eruption on an erythematous base in an area of facial nerve sensory distribution (external ear). This disorder is caused by reactivation of VZV and is treated with antiviral medications and steroids. Inadequately treated zoster infections can lead to poor recovery of facial function and postherpetic neuralgia. 35.3 B. Strokes affecting corticobulbar pathways may present as a partial facial paralysis. Because strokes are central, there is sparing of the forehead. Incomplete facial nerve palsy or involvement of an isolated facial nerve branch(s) is also worrisome for malignancy but would likely be subacute in presentation. Bell palsy, herpes zoster oticus, and Lyme disease generally affect the entire nerve. Acoustic neuromas can cause facial paralysis when they are large, but this is very rarely seen in the modern area. Their location in the cerebellopontine angle would produce whole face weakness, not an isolated branch weakness as described.

CLINICAL PEARLS »»

Bell palsy is the most common cause of acute, unilateral facial weakness in adults.

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Facial paralysis with vesicles on an area of facial nerve sensation is pathognomonic for herpes zoster oticus (Ramsay Hunt syndrome).

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An isolated facial nerve branch weakness should prompt evaluation for malignant tumor compressing the nerve if stroke workup is negative.

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Patients with facial paralysis or paresis should be given instructions regarding eye care and moisturization to avoid exposure keratopathy.

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Steroid and antiviral medications should be given to patients with Ramsay Hunt syndrome. Treatment for Bell palsy is steroids alone and should be initiated within 72 hours of symptom onset.

REFERENCES Ahmed A. When is facial paralysis Bell palsy? Current diagnosis and treatment. Cleve Clin J Med. 2005;72(5):398-401, 405. Alberton DL, Zed PJ. Bell’s palsy: a review of treatment using antiviral agents. Ann Pharmacother. 2006;40(10):1838-1842. Austin JR, Peskind SP, Austin SG, et al. Idiopathic facial nerve paralysis: a randomized double-blind controlled study of placebo versus prednisone. Laryngoscope. 1993;103(12):1326-1333. Gilden DH, Cohrs RJ, Hayward AR, et al. Chronic varicella-zoster virus ganglionitis—a possible cause of postherpetic neuralgia. J Neurovirol. 2003;9(3):404-407. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg. 1985;93(2): 146-147.

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Kuhweide R, Van de Steene V, Vlaminck S, et al. Ramsay Hunt syndrome: pathophysiology of cochleovestibular symptoms. J Laryngol Otol. 2002;116(10):844-848. Ohtani F, Furuta Y, Aizawa H, et al. Varicella-zoster virus load and cochleovestibular symptoms in Ramsay Hunt syndrome. Ann Otol Rhinol Laryngol. 2006;115(3):233-238. Overell JR, Willison HJ. Recent developments in Miller Fisher syndrome and related disorders. Curr Opin Neurol. 2005;18(5):562-566. Redaelli de Zinis LO, Gamba P, Balzanelli C. Acute otitis media and facial nerve paralysis in adults. Otol Neurotol. 2003;24(1):113-117. Ronthal M. Bell’s palsy: prognosis and treatment in adults. UpToDate. http://www.uptodate.com/ contents/bells-palsy-prognosis-and-treatment-in-adults#references. Accessed December 1, 2016. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry. 2001;71(2):149-154.

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CASE 36 A 30-year-old woman presents with a 1-month history of intermittent ptosis (droopiness of the eyelids) and fatigue. She is a surgery resident and has been on call every third night over the past 2 months and has been attributing her fatigue to her hectic call schedule. However, she became concerned when she acutely developed ptosis last month after an exhausting night on call. The next morning after sufficient rest, her ptosis had resolved. Since her first episode, she has experienced three more episodes of ptosis over the past month. They all have occurred while she has been postcall or fatigued and have improved by the morning. Her children have pointed out to her that she can’t keep up with them when they’re riding their bicycles. Today, she developed ptosis while assisting in a complicated abdominal surgery. Her attending asked her to scrub out of the surgery and immediately seek medical evaluation. She has not experienced diplopia, dysarthria, dysphagia, difficulty walking up the stairs, difficulty blowdrying her hair, or shortness of breath. She has no other medical issues. Her neurologic examination is notable for normal mental status and speech. Her cranial nerve examination reveals bilateral ptosis on primary gaze, which worsens with sustained upward gaze for 90 seconds. Extraocular muscles are intact, as is her facial strength. Her motor strength is normal with the exception of 4+/5 in the deltoid muscles bilaterally. On repetitive testing of the right iliopsoas muscle, fatigability is elicited, which improves after 2 minutes of rest. Her sensory examination and deep tendon reflexes (DTRs) are normal. »» »» »»

What is the most likely diagnosis? What is the best test to confirm the diagnosis? What is the next step in therapy?

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ANSWERS TO CASE 36: Ptosis (Myasthenia Gravis) Summary: A 30-year-old woman with no significant medical history presents with a 2-month history of fatigue and a 1-month history of intermittent ptosis. She does not complain of proximal muscle weakness, dysarthria, shortness of breath, or dysphagia. Her examination is notable for ptosis on primary gaze, which worsens with sustained upward gaze, weakness of the deltoid muscles, and fatigability of the iliopsoas muscle, which improves with rest. šš

Most likely diagnosis: Myasthenia gravis

šš

Best confirmatory test: Antiacetylcholine (anti-ACh) receptor antibodies

šš

Next step in therapy: Acetylcholinesterase inhibitors (pyridostigmine) and immunosuppression

ANALYSIS Objectives 1. Know a diagnostic approach to ptosis and understand how associated symptoms are helpful in determining the etiology. 2. Be familiar with the differential diagnosis of ptosis. 3. Understand the basic pathophysiology of myasthenia gravis and the rationale for treatment.

Considerations This 30-year-old woman developed fatigue and ptosis over a short period of time. The most concerning symptom is ptosis, as it has already interfered with her ability to perform her duties as a resident. In this particular case, the patient complained only of fatigue in addition to the ptosis, but findings on examination show fatigability and proximal muscle weakness. Based on this, the cause of ptosis can be pinpointed to either a neuromuscular junction transmission disorder or myopathy. Electromyography (EMG)/nerve conduction study (NCS) can help differentiate between the two, and if indicative of a neuromuscular junction issue, then the diagnosis of myasthenia gravis is most likely. Forced vital capacity and negative inspiratory force are very important in evaluating patients with suspected neuromuscular disease associated with diaphragmatic weakness. In this particular case, the patient does not complain of shortness of breath; however, the history of fatigue and having difficulty keeping up with her children while bike riding should raise the concern. Forced vital capacity and negative inspiratory force are simple bedside tests that can provide further information on the respiratory status of an individual.

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APPROACH TO: Ptosis DEFINITIONS ANTI-MUSK ANTIBODIES: Muscle-specific receptor tyrosine kinase (MuSK) antibodies. MuSK is a surface membrane enzyme that is critical for aggregating ACh receptors during neuromuscular junction development. It is seen in approximately 40% of myasthenics who are seronegative for ACh receptor antibodies. BULBAR WEAKNESS: Weakness in muscle groups innervated by cranial nerves IX, X, XI, and XII that most often results in dysphagia, dysphonia, dysarthria, and slurring of speech. ANTI-Lrp4 ANTIBODIES: Low-density lipoprotein receptor–related protein 4 (Lrp4) antibodies. Lrp4 is a protein that binds to MuSK, which is critical for the aggregation of ACh receptors and neuromuscular junction development. Anti-Lrp4 antibodies are seen in some double-seronegative (patients without anti-MuSK or anti-ACh antibodies) myasthenic patients. MYOPATHIC: A disorder of muscle or muscle tissue. NEUROPATHIC: A disorder affecting the anterior horn cell, nerve root, plexus, or peripheral nerves.

CLINICAL APPROACH Ptosis is associated with multiple conditions. As noted in Table 36–1, the differential diagnosis will be based on the patient’s symptoms and the clinical findings. Ptosis results from weakness of the levator palpebrae superioris muscle and can occur unilaterally or bilaterally. It becomes evident when the eyelid partially or completely covers the pupil, iris, or other parts of the eye. In some instances, the upper eyelid may only cover the entire pupil, resulting in impaired vision. Acquired ptosis is a sign of an underlying neurologic problem that requires urgent medical evaluation. The possible etiologies of ptosis include local mechanical lid abnormalities, myopathy, diseases of the neuromuscular junction such as myasthenia gravis, oculosympathetic lesions, third nuclear pathology, and supranuclear lesions in the contralateral hemisphere along the territory of the middle cerebral artery. Associated clinical findings such as miosis, hemiparesis, or other cranial nerve abnormalities will indicate if this is a supranuclear problem, nuclear problem, oculosympathetic problem, third nerve dysfunction, neuromuscular junction transmission disorder, myopathic disorder, or local infiltrative process. The associated symptoms and findings on neurologic examination are critical to establish the cause of ptosis. Isolated ptosis without other symptoms suggests local mechanical factors as a cause. Conversely, ptosis along with proximal muscle weakness (difficulty climbing up stairs, difficulty arising from a chair, difficulty blow-drying hair, difficulty reaching over the head) suggests an underlying myopathy. Fatigability of muscle (repetitive use of the same muscle leading to loss of strength) with

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Table 36–1  •  ETIOLOGIES OF PTOSIS Location of Lesion

Etiologies

Local mechanical lid abnormalities

Thyroid disease, ocular surgery, infiltrative processes (sarcoid, amyloid), orbital cellulitis, primary or metastatic tumors

Myopathy

Mitochondrial cytopathies (Kearns-Sayre), congenital myopathies (centronuclear myopathy), oculopharyngeal muscular dystrophy

Neuromuscular junction

Myasthenia gravis, botulism

Oculosympathetic

Horner syndrome; associated miosis

Third nerve palsy

Ischemic, metabolic (diabetes mellitus), uncal herniation syndrome, posterior communicating artery aneurysm, cavernous sinus; associated with other cranial nerve abnormalities

Third nucleus

Ischemic

Supranuclear

Midbrain neoplasms (bilateral ptosis), contralateral middle cerebral artery ischemia

improvement after a short period of rest associated with ptosis suggests an underlying neuromuscular junction transmission disorder. Contralateral hemiparesis or hemitremor accompanying ptosis suggests ischemic lesions in the midbrain affecting the third nerve. Ptosis from a third nerve palsy associated with other cranial nerve dysfunction such as IV, V, and VI is seen with cavernous sinus syndrome. The history and clinical examination are key to evaluate patients with ptosis. In this particular case, the patient gives a history of fatigue and ptosis, and her examination is also notable for proximal muscle weakness and fatigability. These features are suggestive of an underlying neuromuscular junction transmission disorder or, less likely, a myopathy. The evaluation of a patient with ptosis should be guided by associated symptoms and findings on clinical examination. Serologic studies consisting of a comprehensive metabolic panel and complete blood count (CBC) with differential are helpful in ascertaining metabolic processes such as diabetes mellitus, hypokalemia, infections, or even malignancies. A vasculitis screen with antinuclear antibody (ANA) and erythrocyte sedimentation rate (ESR) can be helpful in evaluating for inflammatory processes such as systemic lupus erythematosus. Thyroid function studies evaluate for thyroid disease. Serum creatine phosphokinase (CPK) is helpful in evaluating for myopathies. Serum lactate can be helpful in screening for mitochondrial cytopathies. Specifically, ACh receptor antibodies are used to evaluate for myasthenia gravis. If there is evidence of multiple cranial nerve involvement or of contralateral hemiparesis on physical examination, magnetic resonance imaging (MRI) of the brain should be obtained, as these findings are suggestive of cavernous sinus or brainstem pathology. If ptosis is associated with an isolated third nerve palsy, both an MRI of the brain and magnetic resonance angiogram (MRA) should be obtained, as this may suggest a possible posterior communicating artery aneurysm.

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An EMG/NCS is one of the most important studies in evaluating patients with suspected neuromuscular diseases. It can be helpful in differentiating between a neuropathic process, myopathic process, and disorder of the neuromuscular junction. Additionally, it provides information as to the severity and chronicity of the process. It is a two-part study consisting of NCS and EMG. NCSs evaluate conduction velocity of a nerve between two different points. It evaluates both motor and sensory nerves. Repetitive nerve stimulation uses a 2- to 5-Hz train of stimulations to a nerve innervating a symptomatic muscle. An amplitude decrement of 10% or greater between the first and fourth stimulations is suggestive of a postsynaptic neuromuscular junction defect. Repetitive nerve stimulation studies are done before and after brief exercise and then repeated after 5 minutes of rest. EMG evaluates the electrical properties of the muscle at rest and on contraction, and can help distinguish a myopathy from a neuropathy.

MYASTHENIA GRAVIS Myasthenia gravis is an uncommon autoimmune disorder affecting the neuromuscular junction postsynaptically. It is characterized by skeletal muscle weakness and fatigability. The prevalence of myasthenia gravis in the United States is approximately 14.2 cases per 100,000. It is estimated that the annual incidence of myasthenia gravis in United States is 2:1,000,000. Women are affected more than men at a ratio of 3:2. Although myasthenia gravis can occur at any age, it tends to peak in females during the second and third decades of life and in males during the sixth and seventh decade of life. Women have also been noted to have a second peak during their eighth decade of life. The classic symptoms are those of skeletal muscle weakness affecting the ocular, facial, bulbar, respiratory, and limb muscles. The weakness quickly fluctuates and worsens throughout the day. Importantly, there is fatigability of the muscles with recovery to baseline strength after a short period of rest. Approximately 75% of patients will present with ocular disturbances including ptosis and diplopia. Up to 90% of patients with myasthenia gravis will eventually experience ocular symptoms. Ptosis can be bilateral or unilateral and can shift quickly from one eye to the other. Weakness of the extraocular muscles causing diplopia can be asymmetrical. Other common complaints include dysphagia, dysarthria, shortness of breath, fatigue with chewing, difficulty holding the head up, limb weakness, and torso weakness. Limb weakness is most commonly proximal and typically presents as difficulty raising the arms above the head, climbing up the stairs, or rising from a chair. Commonly affected muscles include the neck flexors, deltoids, triceps, finger extensors, wrist extensors, hip flexors, and foot dorsiflexors. Fatigability of these muscles is frequently observed on physical examination. Weakness of the pharyngeal and tongue muscles results in impaired speech and swallowing. Speech can have a nasal quality to it or be slurred. This is most noticeable when the patient continues to talk for prolonged periods of time. A snarling expression on attempted smile can be present, which denotes facial weakness. Additionally, weakness of the orbicularis oculi muscles can be present on examination when the eyelids are separated against forced eye closure. Patients do not often complain of facial weakness.

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Shortness of breath results from weakness of the intercostal and diaphragm muscles. This can become a medical emergency requiring emergent intubation. A good way of evaluating the status of respiratory muscle weakness is to perform a forced vital capacity and negative inspiratory force, as these studies can reflect neuromuscular respiratory fatigue before changes in oxygen saturation. Therefore, significant precautions should be undertaken when patients are evaluated in the emergency room, as they can decompensate very quickly and require immediate intubation.

Physiology of Myasthenia Gravis Normally, an excitatory postsynaptic end-plate potential is generated at the neuromuscular junction when ACh is released into the synaptic cleft and diffuses to the postsynaptic membrane to bind to nicotinic ACh receptors. Once the threshold for depolarization is reached, an action potential will be generated that spreads across the muscle, leading to contraction. ACh is then removed from the synaptic cleft by acetylcholinesterase or via presynaptic membrane reuptake. In myasthenia gravis, an action potential is not generated at the postsynaptic membrane (neuromuscular transmission failure), which results in weakness. Failure to generate an action potential is caused by the inability of excitatory postsynaptic end-plate potentials to reach the threshold for depolarization. This is caused by a diminished amount and availability of postsynaptic receptors. If ACh fails to bind to a sufficient number of postsynaptic ACh receptors, the end-plate potentials generated are not enough to reach threshold for depolarization. This, in essence, fails to generate an action potential and thus prevents muscle contraction and causes weakness. Circulating antibodies (ACh receptor antibodies) bind to the ACh receptor and prevent ACh from binding. This in turn allows for cross-linking of receptors, which leads to degradation and eventually receptor internalization. Postsynaptic membrane damage can also occur via complement activation. The number of ACh receptors diminishes over time because of these changes (Figure 36–1).

Diagnostic Testing for Myasthenia Gravis Laboratory studies for ACh receptor antibodies are the most specific and sensitive test for myasthenia gravis. There are three antibodies described against the ACh receptor: binding (most commonly tested), blocking, and modulating antibodies. Up to 90% of patients with generalized myasthenia gravis (affecting more than the ocular muscles) will have a positive test for one of these antibodies. However, patients with no ACh receptor antibodies can have anti-MuSK antibodies, which have also been associated with myasthenia gravis. In addition, thyroid function studies should always be performed, as concomitant thyroid disease is often seen in myasthenia gravis. The Tensilon (edrophonium bromide) test has historically been described as the classic diagnostic test. Edrophonium bromide is an acetylcholinesterase inhibitor that rapidly and transiently blocks degradation of ACh, allowing for prolonged stimulation of the muscle and temporary improvement of ptosis. However, edrophonium bromide may not be available in some hospital or clinic settings and

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B

Normal

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MG

Axon M V Nerve terminal

Release site

AChR Muscle AChE

AChR

Figure 36–1.  Diagrams of (A) normal and (B) myasthenic neuromuscular junctions. V, vesicles of acetylcholine; M, mitochondria; AChR, Acetylcholine receptor; AChE, Acetylcholine esterase. (Reproduced, with permission, from Kasper DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2004:2519.)

requires electrocardiogram (ECG) monitoring during testing for drug-related bradycardia. Another simple bedside test that can be used in patients with ptosis is the ice test. Ice is placed over the ptotic eyelid for 2 minutes. If the ptosis improves after removing the ice, a diagnosis of an underlying neuromuscular junction transmission disorder (ie, myasthenia gravis) can be made. Cooling improves neuromuscular junction transmission, whereas heat worsens it. This is the reason that many patients with myasthenia gravis typically worsen during the summer months. Electrodiagnostic studies with EMG/NCS can be performed to evaluate patients with myasthenia gravis. Classically, NCSs are normal. EMG can be normal or can show myopathic features. A more specialized study, single-fiber EMG, is the most sensitive test available for myasthenia gravis; however, it is not very specific and can be abnormal in other neurologic disease states such as neuropathies, amyotrophic lateral sclerosis, and muscular dystrophy. A computed tomography (CT) scan or MRI of the mediastinum should be performed to exclude thymic enlargement or more importantly, a thymoma. Thymectomy should always be performed in those individuals who have thymoma. An international randomized study of thymectomy in myasthenia gravis was recently completed and showed that in patients receiving a thymectomy, those patients required less steroid therapy at study completion compared to non surgical patients.

Treatment of Myasthenia Gravis Immunosuppressive agents are the mainstay of treatment for myasthenia gravis. These include corticosteroids, cyclosporine, azathioprine, mycophenolate mofetil, intravenous immunoglobulin, and plasmapheresis. There is no general agreement among experts regarding the timing or use of the other immunosuppressive treatments. Acetylcholinesterase inhibitors such as pyridostigmine only treat the

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symptoms and not the disease. However, these are routinely used in patients with myasthenia gravis, especially if the only symptoms are ocular.

CASE CORRELATIONS šš

See Case 35 (Facial Paralysis)

COMPREHENSION QUESTIONS 36.1 You evaluate a 23-year-old woman with a history of intermittent ptosis and difficulty walking up the stairs that improves with rest. You suspect a neuromuscular junction disorder. Therefore, which of the following would be most characteristic of this disorder? A. Myotonia and distal muscle weakness B. Decreased DTRs out of proportion to the degree of muscle weakness C. Fatigable proximal and symmetric muscle weakness with prominent ocular involvement D. Fatigable distal and asymmetric muscle weakness with prominent ocular involvement E. Ptosis, diplopia, and nonreactive pupils 36.2 Which of the following is a critical difference between myogenic processes and disorders of the neuromuscular junction? A. Fatigability with improvement after rest in neuromuscular junction transmission disorders B. Weakness of the ocular muscles only in neuromuscular junction transmission disorders C. Decrement of greater than 5% in myogenic disorders D. Elevated CPK in neuromuscular junction transmission disorders E. Right eye ptosis and diplopia and left-sided weakness 36.3 A 52-year-old woman presents with ptosis and ophthalmoplegia. Which study should be performed first? A. ACh receptor antibodies B. EMG/NCS C. Serologic studies for CPK D. MRI of the brain with MRA E. Thyroid function studies

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36.4 A 62-year-old man with ptosis with an abnormal brain MRI is being monitored in the intensive care unit (ICU). Which of the following conditions is the most likely cause for ptosis? A. Pituitary necrosis B. Uncal herniation C. Central herniation D. Arteriovenous (AV) malformation

ANSWERS 36.1 C. Myasthenia gravis is characterized by fatigable and symmetric proximal muscle weakness with prominent ocular involvement. If decreased, DTRs are diminished in proportion to the degree of muscle weakness, and the pupils are never involved. 36.2 A. Fatigability of muscles with improvement after rest is a hallmark of neuromuscular junction transmission disorders. 36.3 D. The presence of multiple cranial abnormalities along with ptosis is suggestive of central nervous system pathology, particularly in the brainstem or cavernous sinus. 36.4 B. Central herniation causes compression of the diencephalon, flattening the midbrain and pons; uncal herniation compresses the third cranial nerve, causing ptosis.

CLINICAL PEARLS »»

The etiology of ptosis is best determined by recognizing associated symptoms that patients present with and discerning clinical findings on examination.

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Ptosis associated with central nervous system signs and symptoms mandates an MRI of the brain.

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Fatigability of muscle with improvement after a brief period of rest is seen only with neuromuscular junction transmission disorders.

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Up to 90% of patients with myasthenia gravis will eventually have ocular symptoms.

»»

Local cooling of the eye can improve function in a ptotic eyelid, similarly to a Tensilon test, and is a rapid, simple, and inexpensive test for myasthenia gravis.

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REFERENCES Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve. 2004;29(4): 484-505. Mills KR. Specialised electromyography and nerve conduction studies. J Neurol Neurosurg Psychiatry. 2005;76:ii36-ii40. Newsom-Davis J, Cutter G, Wolfe GI, et al. Status of the thymectomy trial for nonthymomatous myasthenia gravis patients receiving prednisone. Ann N Y Acad Sci. 2008;1132:344-347. Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87(4):419-425. Saperstein DS, Barohn RJ. Management of myasthenia gravis. Semin Neurol. 2004;24(1):41-48. Zisimopoulou P, Evangelakou P, Tzartos J, et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun. 2014;52:139-145.

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CASE 37 A 63-year-old otherwise healthy man presents with a 3-month history of intermittent “dizziness.” He describes the episodes as a sensation of “room spinning” and notes that they are brought on or exacerbated by change in position, particularly when rolling out of bed in the morning. Episodes are generally self-limiting, lasting from 10 to 15 seconds on average. He denies associated nausea, vomiting, blurry or double-vision, hearing loss, tinnitus, ear pain, or headache. He does not take any medications. On examination, he is a well-nourished, healthy-appearing man. Vital signs are within normal limits, and he is afebrile. There are no lesions or masses on his face or head. His voice is normal, and speech is fluent. His ear canals and tympanic membranes are normal-appearing. His symptoms can be provoked by lying down and changing position of his head. While symptomatic, he also develops rotational nystagmus. The nystagmus is self-limiting, with the fast phase occurring counterclockwise (from patient’s perspective) as his head is tilted 45-degrees to the left (geotropic nystagmus). He improves a few seconds after sitting up, and nystagmus is no longer noted. The remainder of his general and neurologic examination is unremarkable. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 37: Vertigo, Benign Paroxysmal Positional Summary: A 63-year-old man with brief episodes of dizziness that are brought on by different positions, not associated with hearing loss, tinnitus, or headache. šš šš

šš

Most likely diagnosis: Benign paroxysmal positional vertigo (BPPV). Next diagnostic step: Perform a Dix-Hallpike maneuver (as described later) and consider neuroimaging if a central cause is suspected. Next therapeutic step: Canalith repositioning maneuvers and/or vestibular rehabilitation.

ANALYSIS Objectives 1. Define vertigo and understand its common causes. 2. Learn to discern the prominent symptoms of vertigo. 3. Learn about the important physical examination findings in patients with vestibular disorders. 4. Learn about ancillary tests that can be performed to evaluate vertigo. 5. Learn about the appropriate treatments for vertigo.

Considerations This patient has brief (3-4) of the legs and arms. He presents with a slowly progressive symmetrical weakness and sensory abnormalities of the hands and legs. This patient’s examination is consistent with a peripheral nervous system process, as reflected by weakness that is flaccid or associated with decreased or absent reflexes. The sensory deficits point toward peripheral nerve involvement, rather than that of motor neuron cells, nerve-muscle junction, or solely muscle, since disorders of these structures result in pure motor involvement. Other conditions that can cause a peripheral neuropathy include toxins such as lead, arsenic, thallium, chemotherapy drugs, and certain antiretroviral therapy; metabolic conditions, classically diabetes mellitus, with an estimated 50% of diabetics having some form of neuropathy, although many are asymptomatic. Chronic polyneuropathies without an underlying etiology are considered primary or idiopathic, although these can be associated with a number of conditions, such as malignancy and human immunodeficiency virus (HIV). Chronic acquired

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inflammatory demyelinating polyneuropathy is a neurologic disorder characterized by progressive weakness and impaired sensory function in the legs and arms caused by damage to the myelin sheath (the fatty covering that wraps around and protects nerve fibers) and is one of the treatable peripheral neuropathies. In this case, the patient’s presentation is consistent with CIDP. EMG and NCS can help confirm the diagnosis.

APPROACH TO: Chronic Inflammatory Demyelinating Polyneuropathy DEFINITIONS MYELIN: An electrically insulating phospholipid layer that surrounds the axons of many neurons. It is an outgrowth of Schwann cells, a glial cell that supplies the myelin for peripheral neurons, whereas oligodendrocytes supply it to those of the central nervous system. AXON: Nerve fiber projection of a motor or sensory neuron that conducts electrical impulses away from the neuron cell body or soma.

CLINICAL APPROACH Clinical Features and Epidemiology The prevalence of CIDP is approximately 0.9 to 8.9 per 100,000 population. The estimated annual incidence is 0.15 per 100,000 population. However, the true incidence of CIDP is likely underestimated because of stringent diagnostic criteria and clinical and pathologic variability of the disorder. In neuromuscular disease referral centers, however, CIDP represents approximately 20% of undiagnosed neuropathies and accounts for approximately 10% of all patients referred. CIDP can occur at any age, including childhood in 10% of cases. However, the mean age of onset is approximately 47.6 (median, 53.5 years). Males are more affected than females by 2:1. CIDP is an acquired peripheral neuropathy with an extremely variable clinical presentation and course. At symptom onset, patients usually present with a generalized pattern of numbness and weakness in upper and lower extremities and spontaneous pain that develops gradually over several weeks. Some patients present with a progressive sensory ataxia; in other patients motor deficits predominate. Proximal and distal limbs are commonly affected in a roughly symmetrical pattern. Yet occasionally, the demyelinating neuropathy is focal, leading to focal or multifocal motor dysfunction. Motor deficits occur in 83% to 94%, sensory deficit in 72% to 89%, loss of tendon reflexes in 86% to 94%, and facial palsy in 4% to 15% of patients. Symptoms typically develop gradually in 84% but can occur more acutely in 16% of patients, who reach maximal disability within 4 weeks. Often, these rapidly progressing patients are initially diagnosed with Guillain-Barré syndrome or acute inflammatory demyelinating polyneuropathy (see Case 39), but the diagnosis is usually changed to CIDP or CIDP-variant when symptoms progress beyond

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8 weeks. A variable proportion of cases follow a relapsing course, with many of these patients, often younger, developing a secondarily progressive course, similar to that observed in multiple sclerosis patients.

Etiology and Pathogenesis CIDP is immunologic in origin. It is characterized by long-standing multifocal demyelination that predominantly affects spinal roots, major plexuses, and proximal nerve trunks. Although no genetic susceptibility genes or factors have been identified, there are certain predisposing factors reportedly linked to the disease, including a history of vaccination or infection within 6 weeks of symptom onset, pregnancy or postpartum period, and surgery. Pathologically, lesions consist of patchy regions of demyelination and edema with variable inflammatory infiltrates of macrophages and T cells, which are diagnostic of CIDP. Both cell-mediated mechanisms and antibody-mediated responses to major glycolipid or myelin protein antigens have been implicated. CD4+ and CD8 T cells can be demonstrated in nerve biopsy specimens, but macrophages constitute the major cell component of the inflammatory infiltrate.

Diagnosis CIDP should be considered in patients with a progressive symmetrical or asymmetrical polyneuropathy that is relapsing and remitting or progresses for more than 2 months. Sensory symptoms, proximal weakness, areflexia without wasting, or preferential loss of vibration or joint position sense are especially suggestive. The major diagnostic tests for CIDP are electrophysiologic studies (EMG/NCV), CSF examination, and nerve biopsy. Increased CSF protein content in association with less than 10 cells/mm3, cytoalbuminologic dissociation, is also a feature of CIDP. EMG is useful to differentiate other causes of muscle weakness, such as myopathy, axonal neuropathies, and disorders of nerve muscle transmission. NCS will often show a reduction or block in nerve conduction velocities, which is consistent with demyelination. These studies, however, may be nonspecific. In many instances, the electrophysiologic tests for the diagnosis of a demyelinating neuropathy will provide mixed results because of the accompanying secondary nerve axon degeneration that can occur with demyelination. A nerve biopsy should be considered in patients when a clinical suspicion of an inflammatory demyelinating neuropathy remains even if they fail to meet the proposed criteria for CIDP. The nerve biopsy may show only nonspecific lesions when the demyelination and inflammation are proximal to the site of the biopsy (sampling error). MRI can be supportive in difficult diagnostic cases, can show hypertrophy and contrast enhancement of nerve roots and nerve plexi, and is helpful in ruling out infiltrative processes or spinal disease. Laboratory studies should also be performed to rule out other causes or associated conditions including a fasting glucose or glucose tolerance test to rule out diabetes or prediabetic state, thyroid dysfunction, vitamin deficiencies (B12, folate), rheumatologic disorders, leukemia or paraproteinemias, and infection (HIV). Although this patient does not have diabetes mellitus, many diabetics will develop a chronic progressive symmetric polyneuropathy. However, these patients

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usually develop a predominantly motor and ataxic polyneuropathy, and the NCSs usually show more severe axonal loss.

Treatment and Management Corticosteroids, intravenous immunoglobulin, plasma exchange, and immunosuppressive drugs are the main treatments used in this condition. Nearly all patients with CIDP will show an initial response to immunomodulatory therapy but often require long-term therapy to maintain clinical response. Historically, evaluation of response to treatment is hampered by the lack of objective measures, poor correlation with electrophysiologic data, variable incidence of axonal degeneration, which is unlikely to respond quickly to treatments, and variability of the disease course. A 5-year retrospective review of patients treated for CIDP showed subacute onset, symmetrical symptoms, and good initial response to corticosteroids as positive prognostic factors. However, a landmark study (the ICE trial 2008) showed that intravenous immunoglobulin (IVIg) therapy was effective for initial treatment of CIDP compared to placebo as well as for maintenance therapy with associated improved quality of life, motor scores, sensory perception, and electrophysiologic measures of nerve function in treated patients. Patients with very mild symptoms that do not or only slightly interfere with activities of daily living may be monitored without treatment. Urgent treatment with corticosteroids or IVIg should be considered for patients with moderate or severe disability—for example, when hospitalization is required or ambulation is severely impaired. Contraindications to corticosteroids will influence the choice toward IVIg and vice versa. For pure motor CIDP, IVIg treatment should be the first choice. If corticosteroids are used, patients should be monitored closely for adverse events related to steroid therapy. Occupational and physical therapy are often helpful in maintaining muscle conditioning and safe mobility.

CASE CORRELATION šš

See also Case 39 (Guillain-Barré Syndrome) and Case 40 (Dermatomyositis)

COMPREHENSION QUESTIONS 38.1 Which of the following test results is most supportive of the diagnosis of definite CIDP? A. Cytoalbuminologic dissociation B. Decreased nerve conduction velocities C. Hypertrophy of nerve roots D. Segmental demyelination of nerve axons 38.2 Which patient will often present with relapsing CIDP? A. Older patients B. Diabetic patients C. HIV-infected patients D. Younger patients

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38.3 Which of the following therapies is effective in treating CIDP? A. Corticosteroids, physical therapy, radiation therapy B. Corticosteroids, physical therapy, immunoglobulin C. Corticosteroids, plasma exchange, surgery D. Corticosteroids, immunoglobulin, nerve growth factor

ANSWERS 38.1 D. Segmental demyelination of nerve axons is diagnostic of CIDP. 38.2 D. Younger patients are more prone to a relapsing course. 38.3 B. Corticosteroids, physical therapy, and immunoglobulins are effective therapy in CIDP.

CLINICAL PEARLS »»

CIDP is the second most frequently diagnosed neuropathy in patients age 70 to 79.

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Clinical diversity in presentation and course is the most remarkable feature of CIDP.

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Cranial nerves can be involved, particularly cranial nerve VII resulting in diplopia.

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Papilledema with pseudotumor cerebri syndrome is rarely observed in patients with CIDP and is caused by high CSF protein levels (usually >1000 mg/mL).

REFERENCES European Federation of Neurological Societies; Peripheral Nerve Society. Guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2006;13(8):809-818. Hughes RA, Donofrio P, Bril V, et al; ICE Study Group. Intravenous immune globulin (10% caprylatechromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. Lancet Neurol. 2008;7(2):136-144. Kuwabara S, Misawa S, Mori M, Tamura N, Kubota M, Hattori T. Long term prognosis of chronic inflammatory demyelinating polyneuropathy: a five year follow-up of 38 cases. J Neurol Neurosurg Psych. 2006;77:66-70. Rajabally YA, Simpson BS, Beri S, Bankart J, Gosalakkal JA. Epidemiologic variability of chronic inflammatory demyelinating polyneuropathy with different diagnostic criteria: study of a UK population. Muscle Nerve. 2009;39(4):432-438. Said G. Chronic inflammatory demyelinating polyneuropathy. Neuromuscul Disord. 2006;16(5):293-303.

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CASE 39 A 25-year-old woman with no previous medical issues is brought into the emergency room (ER) after tripping during a volleyball match. Her teammate notes that she had been stumbling and was starting to have more difficulty with her serve. On arrival, she can no longer raise her legs and labors to adjust herself in bed. She has also begun to complain of shortness of breath. She denies fever but states that 3 weeks ago the entire team suffered from abdominal cramps and diarrhea after a championship cookout. On examination, she appears weak and slightly dyspneic. Her temperature is 36.6°C (98°F); heart rate is 50 beats/min; respiration rate is 26 breaths/min; and blood pressure is 90/60 mm Hg. Her pupils are sluggish, and she constantly clears her throat. She can only keep her arms up against gravity for 10 seconds, and her hands are limp. She has slight movement of her legs, with decreased sensation of pain and fine touch to her knees. Her reflexes are absent. She has no skin lesions. Her heart and lung examinations are unremarkable except for bradycardia and poor inspiratory effort. The abdominal examination reveals normoactive bowel sounds and no masses. Her complete blood count (CBC) is unremarkable. The pregnancy test is negative. Magnetic resonance imaging (MRI) scans of the brain and spine are normal. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 39: Guillain-Barré Syndrome Summary: A 25-year-old previously healthy woman presents to the ER with rapid progression of ascending weakness with diaphragmatic involvement. She has a history of gastroenteritis 3 weeks before presentation. She is bradycardic, tachypneic, and hypotensive. The neurologic examination is significant for areflexia, paralysis of her legs with sensory deficits, severe weakness of her arms, and some difficulty swallowing and breathing. šš

šš

šš

Most likely diagnosis: Guillain-Barré syndrome, specifically acute inflammatory demyelinating polyneuropathy (AIDP). Next diagnostic step: Lumbar puncture for elevated protein level with few cells (cytoalbuminologic dissociation). Next step in therapy: Forced vital capacity (FVC) and negative inspiratory force (NIF) with consideration of intubation and mechanical ventilation for FVC less than 20 mL/kg, or NIF worse than –30 cm H2O.

ANALYSIS Objectives 1. Know a diagnostic approach to Guillain-Barré syndrome, including historical clues and examination findings, and understand the differential diagnosis. 2. Understand that addressing respiratory failure should be the first priority in treating acute weakness caused by Guillain-Barré syndrome. 3. Be familiar with a rational workup for Guillain-Barré syndrome and know the subtypes, including the Miller-Fisher variant.

Considerations This 25-year-old woman developed acute symmetric ascending paralysis with progressive involvement of diaphragmatic muscles. Her most immediate problem is impending respiratory failure. The first priority should be to determine the progression of respiratory insufficiency, usually by serially measuring FVC. The NIF should also be followed. Oxygen desaturation occurs much too late to be a safe indicator. An FVC less than 15 to 20 mL/kg or NIF worse than –30 cm H2O usually signals imminent need for intubation and mechanical ventilation. After determining the need for intubation, the next priority is to determine the etiology of the weakness. Guillain-Barré syndrome is the most common cause of acute flaccid paralysis in the United States, occurring in 1 to 3 out of every 100,000 people with a bimodal distribution affecting patients of 15 to 35 years and 50 to 75 years. This patient has the classic history of a bacterial or viral gastrointestinal illness 2 to 4 weeks prior to onset of paresthesia and weakness. She had been exposed to poorly cooked meat, which predisposes her to Campylobacter jejuni. Forty percent of Guillain-Barré

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patients have positive C. jejuni serum antibodies and/or stool cultures. Areflexia is a hallmark examination finding, particularly in conjunction with proximal lower extremity weakness with distal sensory changes and ascending progression. Diaphragmatic and cranial nerve muscles can be affected as well, with up to onethird of patients requiring intubation, as well as autonomic involvement causing bradycardia and hypotension.

APPROACH TO: Acute Weakness DEFINITIONS ACUTE ASCENDING WEAKNESS: Ascends from legs to arms and cranial nerves over hours to days. INFLAMMATORY: Autoimmune humoral and cell-mediated response to recent infection. This response is capable of molecular mimicry to stimulate production of antiganglioside antibodies against surface molecules of peripheral nerves. DEMYELINATING: Damage to myelin surrounding the peripheral nerves, spinal roots, and cranial nerves resulting in clinical weakness and numbness, and electromyographic evidence of profoundly delayed or absent nerve conduction velocities. POLYNEUROPATHY: Symmetric damage to peripheral nerves in multiple extremities. FLACCID: Lower motor neuron weakness with hypo- or areflexia, hypotonia, and, in the case of chronic disease, muscle atrophy.

CLINICAL APPROACH Acute weakness can be associated with conditions affecting all levels of the nervous system. However, the pattern of weakness, presence of other signs (sensory loss, incoordination, altered mental status), and degree of hypo- or hyperreflexia help to distinguish the anatomic site of disease. Disorders of the brain that cause acute weakness include acute stroke, spaceoccupying lesion, or an inflammatory or infectious cause. Often, these conditions affect multiple pathways, resulting not only in motor weakness but also in sensory changes, speech changes, and altered mental status. In this case, the patient presented with a rapidly ascending, bilateral, and respiratory weakness, in the absence of speech changes. Her reflexes were absent, and her level of consciousness was intact. Therefore, it is unlikely that her condition was caused by a primary disease of the brain, as central nervous system (CNS) disease often results in unilateral involvement in association with increased reflexes. Further, those conditions that affect both sides of the brain and cause bilateral weakness are often diffuse and affect speech and mentation. The exception to this is spinal cord disease, which can result in symmetric weakness and sensory loss that can ascend from the legs, depending on the condition. Therefore, it is often worthwhile to image the spinal

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cord in such clinical presentations. In this case, the patient's spinal cord was normal and the clinical presentation was most consistent with a condition of the peripheral nervous system (PNS). The PNS is made up of the nerve root, peripheral nerve, nerve-muscle junction, and muscle. Myopathies of various etiologies often present with a subacute or chronic course associated with proximal muscle weakness, which typically does not ascend. Although muscle diseases such as inflammatory myopathies, muscular dystrophies, and metabolic myopathies can be associated with respiratory impairment, the sensory and autonomic systems are not affected. Nerve-muscle junctional disorders such as myasthenia gravis can present with acute and subacute motor weakness that fatigues with repetitive activity. However, the examination in this case did not reveal impairment or fatigue due to disorders of the neuromuscular junction. Guillain-Barré syndrome can be associated with C. jejuni as well as other bacterial etiologies, including Haemophilus influenzae, Mycoplasma pneumoniae, and Borrelia burgdorferi, and viral etiologies such as human immunodeficiency virus (HIV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Most recently, there have been reported cases of cases associated with the Zika virus, but further research to confirm this possibility is still ongoing. In addition, postvaccination disease, especially influenza, has been reported, as well as rare cases associated with systemic lupus erythematosus, sarcoidosis, lymphoma, postpregnancy, and certain medications. There are five major subtypes of Guillain-Barré syndrome; the most common in the western hemisphere is AIDP. The Miller-Fisher variant presents with the textbook triad of areflexia, ataxia (out of proportion to sensory deficits), and ophthalmoplegia, as well as predominant cranial nerve weakness rather than extremity weakness, and positive anti-GQ1b (ganglioside) antibodies. Acute motor-axonal neuropathy (AMAN) is purely motor and affects mostly children, with greater than 70% being seropositive for C. jejuni. It usually carries a better prognosis for recovery. Acute motor-sensory axonal neuropathy (AMSAN) is more common in adults and generally causes significant muscle atrophy with poor prognosis for recovery. Acute panautonomic neuropathy is the rarest subtype and is associated with high mortality from cardiovascular involvement and dysrhythmias. The differential diagnosis for acute flaccid paralysis with gastrointestinal symptoms includes two very important etiologies that carry high morbidity but, if identified and treated quickly, can be reversed: botulism and tick paralysis. Botulism is caused by the Clostridium botulinum neurotoxin and is frequently foodborne but can also present as a result of intravenous drug use, surgery, and wound complications. The difference is that patients with botulism present with a descending paralysis, beginning with the Dozen Ds of cranial nerve progression. šš

Dry mouth

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Double vision

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Dilated pupil

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Droopy eyelids

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šš

Drooping face

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Diminished gag reflex

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Dysphagia

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Dysarthria

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Dysphonia

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Difficulty lifting head

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Descending paralysis

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Diaphragmatic paralysis

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Rapid administration of botulism antitoxin halts worsening, although mechanical ventilation can still be required. Tick paralysis produces a rapidly ascending paralysis with areflexia, ataxia, and respiratory insufficiency much like GuillainBarré syndrome, particularly in children with a history of outdoor exposure. Removal of the discovered female tick can be curative by elimination of the source of the neurotoxin.

CLINICAL PRESENTATION The mean interval from onset of Guillain-Barré syndrome to the most severe degree of impairment is 12 days, with 98% of patients reaching the endpoint of clinical worsening (nadir) by 4 weeks. The mean time to improvement starts at 28 days, and clinical recovery usually occurs by 200 days. Although 85% of patients recover completely, up to 15% have permanent deficits. Three to eight percent of patients die in spite of intensive care management. A major cause of mortality in elderly victims is arrhythmia. The history should identify corroborating symptomatology and triggers as discussed above and should rule out other causes of acute flaccid paralysis. The physical examination should focus on the vital signs, reflexes, and extent of weakness in the extremities, diaphragm, and cranial nerves. Fever and mental status changes are unusual and signal hypoxic respiratory failure or a different etiology. An important diagnostic test is the lumbar puncture, which shows rising protein levels up to 400 mg/L with no associated increase in cell count (cytoalbuminologic dissociation), although protein elevation may not be seen until 1 to 2 weeks after onset, and in 10% of cases it remains normal. Antibodies and stool culture for C. jejuni are frequently checked. Other helpful tests include sedimentation rate, antiganglioside antibodies, anti-GQ1b antibodies for Miller-Fisher presentations, and a pregnancy test. The presence of anti-GM1 antibodies is typically associated with a poor prognosis. Nerve conduction studies show early changes indicative of nerve root demyelination. MRI of the brain and spine can show anterior nerve root enhancement, which is more specific for Guillain-Barré syndrome but should be obtained in all cases to rule out other secondary causes such as malignancy, vasculitides, viral infections, or spinal cord pathology. Measurement of respiratory strength (FVC) is crucial for cases with respiratory involvement. An electrocardiograph (ECG) should

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be performed to screen for atrioventricular (AV) block, ST-segment changes, and arrhythmias. The patient should be admitted for further monitoring and treatment. If the etiology is still unclear and the patient continues to deteriorate, consultation with a neurologist is indicated.

TREATMENT Intubation and mechanical ventilation should be considered for FVC less than 15 mL/kg or NIF worse than –30 cm H2O, with intensive care monitoring for the presence of arrhythmias and blood pressure instability. Because of the immune-mediated pathogenesis of the disease, the only proven therapies to date are IV immunoglobulin (IVIg) and plasma exchange, both of which can hasten recovery by 50% if initiated early in the course of the disease. There are no data to support the use of steroids. Complications of immobility, hospitalization, and respiratory insufficiency should be avoided by implementing prophylactic measures for deep venous thrombosis, decubitus ulcers, gastritis, and aspiration. Recurrence is rare but can occur in up to 5% of cases.

CASE CORRELATION šš

See also Case 38 (Chronic Inflammatory Demyelinating Polyneuropathy) and Case 40 (Dermatomyositis)

COMPREHENSION QUESTIONS Match the following etiologies (A-F) to the clinical situation 39.1 to 39.5: A. Acute inflammatory demyelinating polyneuropathy B. Miller-Fisher syndrome C. Myasthenia gravis D. Inflammatory myopathy E. Tick paralysis F. Acute stroke 39.1 A 25-year-old man presents with difficulty walking and foot numbness 2 weeks after the resolution of fever and bloody diarrhea. 39.2 An 18-year-old woman returns from a camping trip complaining of blurry vision, facial weakness, and difficulty swallowing. She subsequently develops arm and leg weakness. 39.3 A 65-year-old man with hypertension and diabetes presents with acute right face, arm, leg weakness, slurred speech, and right-sided hyperreflexia. 39.4 A 34-year-old woman presents with muscle weakness after climbing stairs or blow-drying her hair that improves with rest.

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39.5 A 28-year-old man presents with ataxia, double vision, and absent deep tendon reflexes 3 weeks following the onset of cough and fever.

ANSWERS 39.1 A. Acute inflammatory demyelinating polyneuropathy is the most common presentation of Guillain-Barré syndrome, with up to 60% of patients seropositive for C. jejuni, which is mostly found in poorly cooked meats. 39.2 E. Tick paralysis presents with ascending paralysis and resolves with removal of the tick. This patient developed her symptoms immediately after a camping trip, which makes tick bite paralysis a strong suspicion. 39.3 F. This older patient has multiple risk factors of cardiovascular disease and presents with unilateral face, arm, and leg weakness and dysarthria, which are consistent with an acute cerebrovascular event. 39.4 C. Myasthenia gravis is an acquired neuromuscular junction disorder caused by antibody-mediated impairment of the skeletal muscle acetylcholine receptor. Fatigability and improvement with rest are hallmarks of the disease. 39.5 B. Miller-Fisher syndrome typically presents with the classic triad of ataxia, ophthalmoplegia, and areflexia and is a common variant of Guillain-Barré syndrome. There is often an antecedent viral infection or Campylobacter infection.

CLINICAL PEARLS »»

The majority of Guillain-Barré cases are associated with a history of preceding C. jejuni or other flu-like or gastrointestinal syndromes.

»»

Most Guillain-Barré patients experience proximal lower extremity weakness with ascending paralysis within hours to days.

»»

One should be wary that the examination can worsen rapidly from one visit to the next, with the possibility of respiratory failure.

»»

Significant autonomic instability can accompany Guillain-Barré symptoms and require intensive care monitoring.

»»

IV immunoglobulin and plasma exchange are the two therapeutic options that have been shown to improve recovery.

REFERENCES Hughes RA, Cornblath DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666. van den Berg B, Walgaard C, Drenthen J, Fokke C, Jacobs BC, van Doorn PA. Guillain-Barre syndrome: pathogenesis, diagnosis, treatment and prognosis. Nat Rev Neurol. 2014;10:469-482.

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Winer JB, Jacob S. Guillain-Barre syndrome. BMJ Best Practice April 2015. http://bestpractice.bmj. com/best-practice/monograph/176.html. Accessed March 3, 2016. World Health Organization. Identification and management of Guillain-Barré syndrome in the context of Zika virus. http://apps.who.int/iris/bitstream/10665/204474/1/WHO_ZIKV_MOC_16.4_ eng.pdf?ua=1. Accessed September 3, 2016. Zautner AE, Johann C, Strubel A, et al. Seroprevalence of campylobacteriosis and relevant postinfectious sequelae. Eur J Clin Microbiol Infect Dis. 2014;33(6)1019-1027.

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CASE 40 A 31-year-old woman presents with a 3-month history of muscle soreness, cramps, and muscle fatigue with climbing stairs and carrying objects. The patient has recently noted a rash on her cheeks, necks, chest, and back and swelling around her eyes. Her review of symptoms is significant for recent sensitivity of her fingers to cold temperatures, difficulty swallowing certain foods and pills, and some shortness of breath with exertion. The physical examination is significant for an erythematous rash across her cheeks, neck, chest, and back and mild lid edema. The cardiac examination is significant for occasional skipped beats. The neurologic examination shows proximal muscle weakness of the patient’s deltoids, biceps, hip flexors, and knee flexors. The sensory and coordination examination is normal. Laboratory studies are normal except for elevated serum creatine kinase (CK) of 770 IU/L (normal 50-200). Electromyography (EMG) and nerve conduction studies (NCSs) reveal an irritative myopathy and normal nerve conductions. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 40: Dermatomyositis Summary: A young woman complains of a subacute onset of proximal muscle weakness and myalgias, skin rash, and a clinical history of Raynaud phenomena, dysphagia, and cardiac arrhythmia. Diagnostic studies reveal an irritative and damaging myopathy that is likely inflammatory in etiology. šš

Most likely diagnosis: Dermatomyositis

šš

Next diagnostic step: Skeletal muscle biopsy

šš

Next step in therapy: Immunomodulatory therapy; cardiac and respiratory evaluation

ANALYSIS Objectives 1. Describe the most common types of inflammatory myopathies. 2. Be familiar with the diagnostic workup of inflammatory myopathies. 3. Be familiar with the treatment and management of dermatomyositis.

Considerations The patient presented in this case has a subacute onset of proximal muscle pain and weakness, swallowing difficulties, and rash. This clinical presentation is consistent with dermatomyositis. The two most common idiopathic inflammatory myopathies are dermatomyositis and polymyositis. Both diseases share the common symptom of proximal muscle weakness. Dermatomyositis differs from polymyositis not only by its immune pathogenesis but also by the involvement of skin, with rash, discoloration, and tissue calcification. Inclusion body myositis (IBM) is another inflammatory myopathy that shares some features with polymyositis and dermatomyositis. However, IBM occurs in older patients, usually age greater than 50, and affects men more than women. It tends to present with a more gradual onset of weakness, which can date back several years by the time of diagnosis. It generally follows a more indolent course and can be refractory to therapy.

APPROACH TO: Dermatomyositis DEFINITIONS HELIOTROPE RASH: Bluish-purple discolorations on the face, lids, neck, shoulders, upper chest, elbows, knees, knuckles, and back of patients with dermatomyositis.

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GOTTRON NODULES: Flat-topped raised nonpruritic lesions found over the dorsum of the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints. ANTI-JO-1 ANTIBODY: Antibody that recognizes a cytoplasmic histidyl transfer RNA synthetase. CREATINE KINASE (CK): An enzyme found primarily in the heart and skeletal muscles, and to a lesser extent in the brain. Significant injury to any of these structures will lead to a measurable increase in CK levels. RAYNAUD PHENOMENON: A condition resulting from poor circulation in the extremities (ie, fingers and toes). In a person with Raynaud phenomenon, when his or her skin is exposed to cold temperatures or the person becomes upset, the blood vessels under the skin spasm, resulting in decreased blood flow in fingers and toes. This is called vasospasm and can cause these areas to be cyanotic and cold.

CLINICAL APPROACH Polymyositis and dermatomyositis are frequently considered together because they have similar clinical and laboratory features and because they progress at a similar rate. Although IBM shares some features with polymyositis and dermatomyositis, it generally follows a prolonged course and is more refractory to therapy.

Epidemiology and Clinical Features Dermatomyositis affects 10 people out of every 1 million, with a female-to-male predominance of about 2:1. Although there is a juvenile form of this disease that begins between the ages of 5 and 15, the peak incidence in adults occurs between the ages of 40 and 50. Dermatomyositis has a subacute onset, usually worsening over a period of days or weeks; however, it might also last for months. The distinguishing characteristic of dermatomyositis is a rash preceding or accompanying muscle weakness. The rash is described as patchy, bluish-purple discolorations on the face, neck, shoulders, upper chest, elbows, knees, knuckles, and back. Some patients might also develop hardened bumps of calcium deposits under the skin. Trouble with swallowing (dysphagia) might also occur. In approximately 25% to 50% of cases, mild myalgias and muscle tenderness occur. Polymyositis also causes varying degrees of decreased muscle function. The disease has a more gradual onset compared to dermatomyositis and generally begins in the second decade of life yet rarely occurs in isolation of contributing conditions, such as Sjogren’s or Rheumatoid arthritis. Dysphagia is more common with polymyositis, which can affect nutrition and also increase the risk of aspiration pneumonia. Approximately one-third of patients with polymyositis or dermatomyositis experience muscle tenderness and cramps. The chief clinical feature of polymyositis and dermatomyositis is progressive, painless, symmetrical proximal muscle weakness, with symptoms possibly dating back 3 to 6 months by the time of the diagnosis. Upper extremity muscle weakness manifests as difficulty in performing activities that require holding the arms up, such as hair washing, shaving, or reaching into overhead cupboards. Neck muscle weakness may lead to difficulty raising the head from a pillow or even holding it

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up while standing. Involvement of pharyngeal muscles may result in hoarseness, dysphonia, dysphagia, and nasal regurgitation after swallowing. Lower extremity proximal muscle weakness manifests as difficulty climbing stairs and rising from a seated or squatting position. Patients will often seek chairs with armrests to push off from or grab the sink or towel bar to rise from the toilet.

Other Clinical Features Weakness is a major complaint, but proximal myalgias and constitutional symptoms such as fever, fatigue, and weight loss can also occur. Interstitial pneumonitis occurs in approximately 10% of patients with polymyositis or dermatomyositis, usually developing gradually over the course of the illness. Myocardial involvement in polymyositis and dermatomyositis is well described. The reported frequency of congestive heart failure (with or without cardiomegaly) ranges from fewer than 5% of patients to 27% to 45%. Electrocardiographic (ECG) abnormalities are more common, with left anterior fascicular block and right bundlebranch block representing the most frequent conduction defects. Both polymyositis and dermatomyositis were associated with an increased risk of malignancy, with a threefold risk demonstrated in patients with dermatomyositis and a 1.4-fold risk for patients with polymyositis. The types of malignancy generally reflected those expected for age and sex, although ovarian cancer was overrepresented in women with dermatomyositis, and both groups of patients displayed a greater-than-expected occurrence of non-Hodgkin lymphoma.

Cutaneous Features of Dermatomyositis In dermatomyositis, patients can have an erythematous, often pruritic rash over the face, including the cheeks, nasolabial folds, chin, and forehead. Heliotrope (purplish) discoloration over the upper eyelids with periorbital edema is characteristic (Figure 40–1), as is the shawl sign, which describes the pattern of an erythematous

Figure 40–1.  Heliotrope rash. (Reproduced, with permission, from Wolff K, Johnson RA, Suurmond D. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 5th ed. New York, NY: McGraw-Hill; 2005:373.)

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Figure 40–2.  Gottron papules. (Reproduced, with permission, from Kasper DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2004:316.)

rash in a “V” distribution on the chest and across the shoulders. Gottron papules— flat-topped raised nonpruritic lesions found over the dorsum of the MCP, PIP, and DIP joints—are virtually pathognomonic for dermatomyositis (Figure 40–2). Often pinkish to violaceous, sometimes with a slight scale, these are distinguished from cutaneous lupus in that lupus has a predilection for the dorsum of the fingers between the joints.

Calcinosis Cutis Children with dermatomyositis are also particularly prone to calcinosis cutis, which is the development of dystrophic calcification in the soft tissues and muscles, leading to skin ulceration, secondary infection, and joint contracture. Calcinosis cutis occurs in up to 40% of children with dermatomyositis and less commonly in adults; there is no proven therapy to prevent this complication.

Inclusion Body Myositis Inclusion body myositis (IBM) tends to present with a more gradual onset of weakness, which can date back several years by the time of diagnosis. Although the muscle weakness is proximal, distal muscle groups can also be affected, and asymmetry of involvement is characteristic. Atrophy of the deltoids and quadriceps is often present, and weakness of forearm muscles (especially finger flexors) and ankle dorsiflexors is typical. Peripheral neuropathy with loss of deep tendon reflexes can be present in some patients.

DIAGNOSIS The diagnosis of polymyositis and dermatomyositis generally relies on the presence of characteristic clinical and laboratory findings, including symmetric proximal muscle weakness and elevated muscle enzymes. However, diagnosis can be complicated because of the similarity between these two diseases and other more commonly

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described disorders. Both polymyositis and dermatomyositis are often diagnosed by ruling out other conditions. Laboratory studies include a CK serum level. The laboratory hallmark of polymyositis and dermatomyositis, although not specific to either of these, is a dramatic elevation of the serum CK, often in the range of 1000 to 10,000 IU/L. Early in the disease process milder elevations can be seen. In IBM, CK elevations tend to be less striking, often increasing only to the 600 to 800 IU/L range; 20% to 30% of patients with IBM can have a normal CK at presentation. With initiation of effective treatment in dermatomyositis and polymyositis, CK levels decrease rapidly, and periodic measurements are used to follow up disease activity over the course of the long term. Caution is advised when interpreting CK elevations, as levels can remain mildly elevated with clinically quiescent disease. Therefore, the degree of elevation does not necessarily correlate with the degree of muscle weakness, although disease exacerbation is often associated with increased levels. Elevated serum levels of aldolase, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are less sensitive and specific for active myositis. Autoantibodies can be present in polymyositis, dermatomyositis, and IBM. Autoantibodies present in polymyositis and dermatomyositis include the myositis-specific autoantibodies anti-Jo-1, seen in 20% of patients, and the less commonly encountered anti-PL-7, anti-PL-12, anti-OJ, and anti-EJ. These antibodies recognize cytoplasmic transfer RNA synthetases (for transfer RNA synthetase), and they are markers of the subset of polymyositis and dermatomyositis patients described as having antisynthetase syndrome, which is characterized by fever, inflammatory arthritis, Raynaud phenomenon, and interstitial lung disease and is associated with a reduction in survival compared with uncomplicated polymyositis and dermatomyositis. The evaluation of the patient with suspected myositis should include EMG and NCSs that will show changes in muscle activity at rest and with contraction suggestive of an irritative or inflammatory myopathy. A muscle biopsy specimen demonstrating typical histologic features in the absence of markers of metabolic myopathy, infection, or drug effect establishes the diagnosis of polymyositis. Muscle biopsy may not be necessary in a patient presenting with proximal muscle weakness, CK elevation, and the classic cutaneous manifestations of dermatomyositis. When biopsy is performed, however, care must be taken not to select a muscle that is so weak or atrophic that the biopsy reveals end-stage disease. The common pathophysiologic features of polymyositis, dermatomyositis, and IBM are chronic inflammation, fibrosis, and a net loss of myofibrils. For IBM, the muscle cells exhibit a variety of abnormal inclusions, including eosinophilic cytoplasmic inclusions, vacuoles rimmed with basophilic granules, and foci that stain positively with Congo red, consistent with amyloid deposits. On electron microscopy, IBM is characterized by the presence of cytoplasmic helical filaments (tonofilaments), which contain beta-amyloid protein and a number of other proteins implicated in neurodegeneration. Often, the clinical presentation is straightforward and can help distinguish between the most common types of myositis (polymyositis, dermatomyositis, IBM,

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Table 40–1  •  IDIOPATHIC INFLAMMATORY MYOPATHIES: CLINICAL AND LABORATORY FEATURES IBM

PM

DM

Age of onset

>50 y

Adult

All ages

Gender

Males

Females

Females

Family history

Rare

No

No

Malignancy associated

No

Slight

Yes

Rash

No

No

Yes

CK level

15 headache days/month for 3 consecutive months) may be amenable to Onabotulinum toxin A, which was approved by the FDA for use in chronic migraine in adults in 2010. Although there is limited experience in pediatric patients, small unrandomized and/or retrospective studies showed benefit.

CASE CORRELATION šš

See also Case 53 (Metastatic Brain Tumor)

COMPREHENSION QUESTIONS 46.1 Which of the following would be classified as a secondary headache? A. Migraine with aura B. Cluster headaches C. Chronic sinusitis D. Migraine without aura E. Tension-type headaches 46.2 Which of the following is a criterion for pediatric migraine? A. A visual aura preceding the onset of head pain B. Pain improved by physical activity C. Moderate to severe intensity of head pain D. A family history of migraine E. Response to nonsteroidal anti-inflammatory medication

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46.3 Which of the following patients should have neuroimaging as part of the evaluation of their headache? A. An 18-year-old woman who was found unconscious at home and is now in the emergency room with the worst headache of her life B. A 14-year-old adolescent boy with acute recurrent attacks of moderateintensity throbbing hemicranial pain associated with nausea and photophobia C. A 12-year-old straight-A student who is healthy and neurodevelopmentally normal, but who complains of mild squeezing head pain when he is studying for tests D. A 17-year-old adolescent boy who develops a moderate global headache 1 day after he decides to quit drinking coffee “cold turkey” 46.4 A 9-year-old girl is newly diagnosed with pediatric migraine headaches. Which of the following is the best initial choice for abortive therapy for this patient? A. Topiramate B. Naproxen C. Rizatriptan D. Ibuprofen E. Amitriptyline

ANSWERS 46.1 C. A headache caused by a medical disorder such as sinusitis, or subarachnoid hemorrhage would be classified as a secondary headache disorder. All of the other listed possibilities are primary headaches. 46.2 C. To meet criteria, the patient must have had five or more headaches with certain characteristics including moderate-to-severe pain. A family history of migraines, while common and helpful, is not required for the diagnosis. 46.3 A. A history of “worse headache of my life” is troubling. This history is very concerning for a subarachnoid hemorrhage and requires an emergent CT scan. 46.4 D. A trial of ibuprofen at an adequate dose (10 mg/kg) would be the best initial choice. There is more evidence for the effectiveness and safety of ibuprofen and acetaminophen for pediatric migraine headaches versus other medications.

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CLINICAL PEARLS »»

Studies support that migraineurs are in a state of mitochondrial energy depletion and supplementation with mitochondrial energy stores such as coenzyme Q10 and riboflavin may have clinical benefit.

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It is not uncommon for patients with migraines to experience vertigo in association with their headaches. If associated without headache, it is termed a migraine equivalent.

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Although migraine headaches are classically described as unilateral (hemicranial), this is actually only true in approximately 60% of all headaches. It is quite common for migraines to be bifrontal.

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Asking what the patient does during a headache is a key clinical question. Patients with migraines generally report wanting to lay still in a darkened room and wanting to go to sleep.

»»

Although not all migraine headaches are severe, headaches that do not interrupt a patient’s activities are unlikely to be migrainous.

REFERENCES Damen L, Bruijn J, Verhagen A, et al. Symptomatic treatment of migraine in children: a systematic review of medication trials. Pediatrics. 2005;116:295-302. Kacperski J. Prophylaxis of migraine in children and adolescents. Pediatri Drugs. 2015;17:217-226. Lewis D. Headaches in children and adolescents. Am Fam Physician. 2002;65:625-632. Lewis D, Ashwal S, Hershey A, et al. Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology. 2004;63:2215-2224. Patniyot IR, Gelfand AA. Acute treatment therapies for pediatric migraine: a qualitative systematic review. Headache. 2016;56:49-70. Young W, Silberstein S. Migraine: spectrum of symptoms and diagnosis. Continuum Headache. 2006;12(6):67-86.

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CASE 47 A 3-year-old boy is brought to his pediatrician to be evaluated for difficulty walking and clumsiness. According to his parents, the patient began walking at the age of 18 months, but in the past year he has begun to fall more frequently and has difficulty getting up from the floor, often supporting himself with his hands along the length of his legs. Birth and developmental history until symptom onset are reportedly normal. There is no contributing family history. On physical examination, the young boy has significant muscle weakness of his hip flexors, knee extensors, deltoids, and biceps muscles. His calves are large, and he walks on his toes during ambulation. He has the presence of a Gowers sign. Laboratory studies reveal an elevated serum creatine kinase (CK) level of greater than 900 IU/L. Electromyography (EMG) of his muscles reveals a myopathy. Nerve conduction studies (NCSs) reveal relative normal nerve function. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 47: Duchenne Muscular Dystrophy Summary: A 3-year-old boy presents with regression of motor milestones with gait instability. His examination is significant for proximal muscle weakness, toe walking, and calf enlargement. Diagnostic studies are significant for a primary muscle disorder with myopathic changes on electrodiagnostic testing and significantly elevated levels of a muscle enzyme, CK. šš

šš šš

Most likely diagnosis: Muscular dystrophy (MD)/Duchenne muscular dystrophy (DMD) Next diagnostic step: Genetic testing for dystrophin mutation Next step in therapy: Supportive management of mobility and monitoring of cardiac and respiratory function

ANALYSIS Objectives 1. Know the clinical presentation of the most common childhood-onset MD. 2. Be familiar with the diagnostic workup of MD. 3. Be familiar with the treatment and management of DMD.

Considerations This previously healthy 3-year-old boy is noted to have regression of motor milestones, but other developmental milestones are normal; this is suggestive of a neuromuscular disorder. The diagnostic studies are supportive of a primary muscle disorder. An important consideration in this case is the clinical presentation. The toddler has proximal muscle weakness resulting in gait instability (toe walking) and inability to rise from a sitting position or from a fall, often requiring the child to push on his knees to upright himself. The EMG/nerve conduction velocity (NCV) studies reveal a muscle problem. The elevated muscle enzyme, CK, supports a muscle destructive process. Thus, the clinical consideration is of a primary myopathy, either acquired or inherited. In this case, the toddler presents with regression of motor milestones, enlarged calves, an elevated CK, and no family history. Although not completely specific, the presentation is highly suggestive of DMD, the most common form of MD. It is caused by the absence of dystrophin, a protein involved in maintaining the integrity of muscle. The most distinctive feature of DMD is a progressive proximal MD with characteristic enlargement (pseudohypertrophy) of the calves. The bulbar (extraocular) muscles are spared, but the myocardium is affected. There is massive elevation of CK levels in the blood, myopathic changes by EMG, and myofiber degeneration with fibrosis and fatty infiltration on muscle biopsy. DMD has an X-linked recessive inheritance pattern, affecting only males. In the absence of a family history, a patient younger than 2 or 3 is unlikely to be diagnosed. Most boys with DMD walk independently at a later age than average.

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Parents usually worry something is unusual in the way the child walks, due to frequent falling or difficulty rising from the ground or going up steps. The serum CK level is always at least five times the upper limit of normal and makes the diagnosis of DMD probable. However, the diagnosis is confirmed by genetic testing and/or muscle biopsy.

APPROACH TO: Duchenne/Becker Muscular Dystrophy DEFINITIONS MYOPATHY: Disorders in which the primary symptom is muscle weakness because of dysfunction of muscle fiber. CREATINE KINASE: An enzyme found primarily in the heart and skeletal muscles and, to a lesser extent, in the brain. Significant injury to any of these structures will lead to a measurable increase in serum CK levels. MUSCULAR DYSTROPHY (MD): Inherited disease characterized by progressive weakness and degeneration of the skeletal muscles that control movement. X-LINKED INHERITANCE: Inherited disease passed from mother to son because of a genetic abnormality on the X chromosome. DYSTROPHIN PROTEIN: Rod-shaped protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. Its gene is the longest known to date and accounts for 0.1% of the human genome. GOWERS SIGN: Clinical assessment of strength in proximal lower extremities performed by having the patient rise from a seated or lying position on the floor. A positive sign is characterized by placing the hands on the knees to aid in rising (tripod sign). This may be seen in any disease process resulting in proximal lower extremity muscle weakness.

CLINICAL APPROACH Clinical Features and Epidemiology Dystrophin-associated MDs are the most common types of inherited muscular dystrophies and are characterized by rapid progression of muscle degeneration that occurs early in life. The severe form occurs earlier and is called Duchenne, and the milder form, which can occur later, is called Becker MD (BMD). Both are caused by the same genetic mutation and follow an X-linked inheritance pattern, affecting mainly males—an estimated 1 in 3500 boys worldwide. Symptoms usually appear younger than age 6 but can appear as early as infancy. Patients present with progressive muscle weakness of the legs and pelvis, which is associated with a loss of muscle mass or muscle atrophy. Muscle weakness occurs in the arms, neck, and other areas, but it is usually not as severe or with as early an onset as the muscles of the lower extremities. Calf muscles initially grow larger because of replacement

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of muscle tissue with fat and connective tissue, a condition called pseudohypertrophy. With progressive weakness, muscle contractures occur in the hips, knees, and ankles. Thus, the muscles are unusable because the muscle fibers shorten and fibrosis (scarring) occurs in connective tissue. By age 10, braces might be required for walking, and by age 12, most patients are confined to a wheelchair. Bones develop abnormally, causing skeletal deformities of the spine (scoliosis) and other areas. Muscular weakness and skeletal deformities contribute to respiratory or breathing problems, leading to frequent infections and often requiring assisted ventilation. Cardiac muscle is also commonly affected, leading to cardiomyopathy and in almost all cases leading to congestive heart failure and arrhythmias. Intellectual impairment can occur, but it is not inevitable and does not worsen as the disorder progresses. Death usually occurs by age 25, typically from respiratory (lung) disorders. BMD is very similar to DMD and is caused by a mutation of the dystrophin gene on the X chromosome; however, BMD progresses at a much slower rate. This is because while DMD has a frameshift deletion that results in complete absence of dystrophin, BMD has an in-frame deletion that leads to a truncated protein with some function. BMD occurs in approximately 3 to 6 in 100,000 male births. Symptoms usually appear in males at approximately age 12 but can sometimes begin later. The average age of becoming unable to walk is 25 to 30. Women rarely develop symptoms. Muscle weakness is slowly progressive, causing difficulty with running, hopping, jumping, and eventually, walking. Patients may be able to walk well into adulthood, but it is associated with instability and frequent falls. Similar to DMD, patients with BMD experience respiratory weakness, skeletal deformities, muscle contractures, and calf pseudohypertrophy. Heart disease, including dilated cardiomyopathy, is also commonly associated, but heart failure is rare.

Etiology and Pathogenesis The particular gene mutation that causes Duchenne and Becker muscular dystrophies (DBMD) is found on the X chromosome and results in loss or reduction of a functional muscle protein, dystrophin. A functional copy of the gene is needed for normal muscle function. In females, one functional copy is usually enough to compensate, and a female with a DBMD mutation usually has few or no symptoms. Most boys with DBMD inherited the mutation from their mother. However, in about 30% of the patients with DBMD, it is a result of a new mutation. In these cases, it is unlikely that future children will also have DBMD. Dystrophin is considered a key structural element in the muscle fiber and the stabilization of the muscle plasma membrane, and it possibly has a role of signaling (Figure 47–1). Mechanically induced damage through muscle contractions puts a high stress on fragile membranes that could eventually lead to loss of regulatory processes leading to cell death. Altered regeneration, inflammation, impaired vessel response, and fibrosis are probably later events that take part in the MD.

DIAGNOSIS The diagnosis of DMD and BMD depends on obtaining a complete medical and family history, documentation of muscle weakness, and pseudohypertrophy on physical examination. Diagnostic tests include measurement of a muscle enzyme,

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Collagen VI

Dystroglycan α complex β

Sarcoglycan complex Extracellular

β β1 α7

δ γ α nNOS

Calpain F-Actin

Caveolin-3 Dysferlin

Integrin Intracellular complex

Dystrophin

Golgi POMT1 POMGnT1 Fukutin Fukutin-related protein

Figure 47–1.  Dystrophin and other sarcolemmal proteins in the cell membrane.

CK, in the blood. Because of the release of CK from damaged muscles, high blood levels of CK in DMD is often at least five times as high as the maximum for unaffected people. It is sometimes 50 to 100 times as high. In addition, electrodiagnostic studies of nerve and muscle function (EMG and NCSs) will confirm abnormal muscle function (myopathy) and the pattern or distribution of muscle dysfunction, in the absence of a peripheral nerve disorder. Genetic testing can establish the diagnosis of DMD or BMD and is often pursued prior to muscle biopsy. The dystrophin gene is the longest gene and therefore susceptible to genetic mutations. Approximately 60% of DMD cases are due to deletions of at least one exon in DMD, ~6% to duplications, and the rest to small mutations which results in absence of functional dystrophin protein. Other are due to in-frame mutations, generating variants able to produce functional yet truncated versions of dystrophin. This kind of deletion occurs in patients with Becker MD (BMD). Most affected males have identifiable DMD pathogenic genetic variants. If genetic testing is positive, testing for the mutation can be offered to other family members. It is also used to determine probabilities of carrier status, prenatal diagnosis, and family planning. Muscle biopsy is often diagnostic of the disease, with confirmation of muscle pathology and a loss or decrease of the dystrophin protein.

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TREATMENT AND MANAGEMENT Treatment is aimed at control of symptoms to maximize the quality of life. Modalities can include physical therapy, respiratory therapy, speech therapy, orthopedic appliances used for support, and corrective orthopedic surgery. Drug therapy includes corticosteroids to increase dystrophin expression and slow muscle degeneration, calcium and vitamin D to minimize bone loss, and vaccinations and antibiotics to fight respiratory infections. Some individuals can benefit from occupational therapy and assistive technology. Some patients might need assisted ventilation to treat respiratory muscle weakness and a pacemaker for cardiac abnormalities. Close surveillance is important to assess for development of complications. Therefore, patients require multispecialty care from pediatricians, neurologists, rehabilitative services, pulmonologists, and cardiologists. Recent advances have pointed toward gene therapy as the next step. Experimental treatments include exon-skipping, which uses oligonucleotides to skip entire exons to avoid frameshift mutations such that a truncated but still functional dystrophin protein can be expressed and insertion of the wild-type dystrophin gene using viruses, stem cell therapies, treatments targeted at membrane stabilization, and upregulation of cytoskeletal proteins.

COMPREHENSION QUESTIONS 47.1 A 3-year-old boy is brought into the pediatric neurologist’s office because of progressive weakness. The neurologist is contemplating a diagnosis between BMD and DMD. Which of the following statements is most accurate regarding these two conditions? A. BMD differs from DMD because of later onset and different inheritance pattern. B. BMD is similar to DMD because of a shared genetic mutation and inheritance pattern. C. Mothers of BMD and DMD patients are often symptomatic in late adulthood. D. BMD is a more rapidly progressive form of DMD. 47.2 A 32-year-old woman is 32 weeks pregnant and is a known carrier for DMD. She asks what the ramifications are for her unborn child. Which of the following statements is most accurate? A. Almost 25% of her daughters will be affected with the disease. B. About 50% of her daughters will be carriers. C. About 75% of her sons will be affected with the disease. D. One hundred percent of sons will either be carriers or inherit the disease.

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47.3 A 5-year-old child presents to neurology clinic for evaluation of gait difficulty and weakness. Which of the following diagnostic tests is supportive in diagnosing DMD/BMD? A. Serum CK B. Echocardiogram C. Pulmonary lung function tests D. Magnetic resonance imaging (MRI) of the brain and spine

ANSWERS 47.1 B. BMD is very similar to DMD and is due to a mutation of the dystrophin gene on the X chromosome with a male-specific inheritance pattern; however, BMD progresses at a much slower rate. 47.2 B. Because males have only one X chromosome, a male carrying a copy with a dystrophin gene mutation will have the condition. Because females have two copies of the X chromosome, a female can have one copy with a DBMD mutation and one functional copy. Thus, a mother who is a carrier has a 50% chance passing the mutation to her sons or daughters. Of those children, 50% of the boys will have the disease and 50% of the girls will be carriers. 47.3 A. CK in DMD is often at least five times as high as the maximum for unaffected people. Because it is a primary skeletal muscle disorder, the other mentioned tests are of limited value.

CLINICAL PEARLS »»

Both DMD and BMD are X-linked. When the woman is a carrier for the dystrophin mutation, half of her sons will have the disease, and half of her daughters will be carriers.

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Behavioral studies have shown that DMD boys have a cognitive impairment and a lower IQ (average 85) because of mutant dystrophin in neurons.

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Corticosteroids can be beneficial in the treatment of DMD and can be offered as a treatment option.

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Elevated CK levels are typical for DMD.

REFERENCES Darras BT, Miller DT, Urion DK. Dystrophinopathies. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® (Internet). Seattle, WA: University of Washington; 1993-2017. Deconinck N, Dan B. Pathophysiology of Duchenne muscular dystrophy: current hypotheses. Pediatr Neurol. 2007:36(1):1-7.

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Kalra V. Muscular dystrophies. Indian J Pediatr. 2000;67(12):923-928. Lim KR, Maruyama R, and Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017:11:533-545. Mah JK. Current and emerging treatment strategies for Duchenne muscular dystrophy. Neuropsychiatr Dis Treat. 2016;12:1795-1807. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74:637-647. Wu B, Xiao B, Cloer C, et al. One-year treatment of morpholino antisense oligomer improves skeletal and cardiac muscle functions in dystrophic mdx mice. Mol Ther. 2011;19:576-583.

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CASE 48 An 8-year-old boy is brought to the neurologist’s office on the recommendation of the allergist. His parents complain that their son is constantly clearing his throat and coughing and often has repetitive jerking hand movements and shoulder shrugging. These symptoms started approximately a year ago. The child has a socially disturbing habit of constantly touching his genital region and recently has been having difficulty paying attention at school. The child had a normal birth and development and no recent illnesses or exposure to medications. He suffered from night terrors when he was 4 years old and still occasionally sleepwalks but was never on any medications. The family history is remarkable for an older brother with attention deficit hyperactivity disorder (ADHD). On examination, the patient is a quiet, cooperative boy in no apparent distress. He admits to the stated behavior and reports an overwhelming desire to clear his throat, which he is unable to suppress. When reminded of this behavior, he starts to manifest it despite an obvious attempt to control it. He exhibits multiple, repetitive stereotypical jerking movements of his hand and shoulder as well as twisting of his neck. He states that he is aware of these movements and can control them only briefly with mounting tension, which results in an inevitable release with more exaggerated behavior. The child manifested an unusual insight into his behavior and appears to be highly intelligent and motivated. He is embarrassed by his habit of touching his genitals, but cannot resist an urge and instead, attempts to cover it up by adjusting his clothing. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWER TO CASE 48: Tourette Syndrome Summary: An 8-year-old boy has a 1-year history of motor and vocal/phonic tics accompanied by obsessive-compulsive behavior (OCB) that has affected his school performance. šš

šš

šš

Most likely diagnosis: Tourette syndrome with concurrent obsessive-compulsive disorder (or behavior) (OCD/OCB). Next diagnostic step: Tourette syndrome is purely a clinical diagnosis based on the history and symptoms and does not require any additional testing. Next step in therapy: Education of parents, teachers, community. Pharmacologic therapy may be started if indicated. Comprehensive behavioral intervention for tics is also available.

ANALYSIS Objectives 1. Know the diagnostic criteria for Tourette syndrome and its comorbidities. 2. Know etiology of tics other than Tourette syndrome. 3. Understand the management of tics and their accompanied behavioral symptoms.

Considerations This 8-year-old boy has been noted to have phonic/vocal and motor tics. He has OCB and is having difficulty in paying attention at school. His examination is otherwise unremarkable. This boy most likely has Tourette syndrome. Tics are the clinical hallmark of Tourette syndrome. Tics are involuntary, brief, and repetitive movements or sounds induced by internal stimuli that are only temporarily suppressible. Of note, the tics associated with Tourette syndrome are often suggestible; discussing the tics leads to an irrepressible urge to manifest the suggested tics despite attempts to control them. A full evaluation including physical examination, assessment for illicit drugs, mental status examination, and neurologic examination are important. The most important aspect of therapy is education, as it can be very distressing for both child and parents.

APPROACH TO: Suspected Tourette Syndrome DEFINITIONS TICS: Sudden, involuntary, recurrent, nonrhythmic motor movements or vocalizations generally proceeded by urge. They are the hallmark feature of

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neurodevelopmental disorders with onset in childhood called tic disorders. Tic disorders consist of Tourette syndrome, chronic tic disorder (motor or vocal type), and provisional tic disorder. TOURETTE SYNDROME: Based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) definition, the patient should have at least two or more motor tics and at least one vocal tic for at least a year. The tics should start before age 18 and the symptoms should not be secondary to taking medicine or due to other medical conditions (eg, seizures, Huntington disease, or postviral encephalitis).

CLINICAL APPROACH Although Tourette syndrome is the most common cause of childhood-onset tics, there are many other neurologic and psychiatric disorders that exhibit tics as part of their presentation. The differential is based on other accompanied symptoms. Autism spectrum disorders (ASDs) are usually manifested by impaired social interactions, poorly developed language, and variable cognitive impairment. Although symptoms of Tourette syndrome and OCD can lead to certain selfimposed social isolation and behavioral issues, children with Tourette syndrome have excellent insight into their condition and can interact and function fully with the environment in which they are accepted. There are usually no cognitive or intellectual deficits associated with Tourette syndrome. Patients with progressive neurodegenerative disorders such as neuroacanthocytosis and Huntington disease can often present with tics but rapidly develop other hyperkinetic movements that differentiate them from Tourette syndrome. Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics usually starting in childhood and often accompanied by poor impulse control, OCD, and ADHD. The cause of Tourette syndrome is unknown, but in many cases, a genetic component is seen. Environmental and developmental factors are also postulated to have a contributory role, but no specific factors have been currently identified. Current estimates of prevalence report that 1 out of every 160 children between the age of 5 and 17 has Tourette syndrome in the United States and 1 out of every 100 children (1%) has Tourette syndrome or an other tic disorder. Tics are the clinical hallmark of Tourette syndrome. Tics are involuntary, brief, and episodic movements or sounds induced by internal stimuli that are only temporarily suppressible. It is often difficult to differentiate tics from compulsive movements, which are semivoluntary and induced by unwanted feelings or compulsion. For example, in our patient, touching of the genitalia is probably not a tic but a compulsion, whereas throat clearing, coughing, and shoulder shrugging are simple phonic and motor tics, respectively. Tics are divided into simple and complex. Simple motor tics involve single groups of muscles, causing jerk-like movements in cases of clonic tics, or briefly sustained posture in cases of dystonic or tonic tics. Simple clonic tics include eye blinking, head or limb jerking, and nose twitching. Simple dystonic tics include oculogyric deviation, bruxism, blepharospasm, and torticollis-like posturing. Most common

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tonic tics include tensing of abdominal and other muscles. Simple phonic/vocal tics include coughing, sniffing, throat clearing, and grunting, among others. Complex motor tics include coordinated movements that involve multiple muscles and often resemble normal movements. They vary from head shaking to touching and hitting. A complex tic should be considered a compulsion if it is preceded by obsessive thought, anxiety, or fear. Complex tics are often camouflaged by incorporating them into seemingly planned and purposeful movement. Some patients become experts at those so-called parakinesias, confusing the clinical picture. Complex phonic tics include linguistically meaningful verbalizations. Although rare, but notoriously associated with Tourette syndrome, coprolalia, the shouting of obscenities or profanities, may be seen. More common, however, is repetition of someone else’s or one’s own words or sentences (echo or palilalia). The related complex motor tic, when a patient briefly exhibits obscene gestures, is called copropraxia. In contrast to most other hyperkinetic movement disorders, tics are involuntary, episodic, repetitive, and often stereotypic, being mistaken for mannerisms. Tics wax and wane and vary in frequency and intensity. The onset of tics is typically between 5 and 9 years, with tendency to increase in frequency and intensity between age 8 and 12. Most patients will show symptom improvement or become tic-free in late adolescence; however, some continue to have tics into adulthood. Tics are unpredictable and often change in distribution. Most patients report an ability to suppress tics with mental effort at the expense of mounting inner tension with the eventual explosive release in a more appropriate environment. Despite common belief, suppressibility is not unique to tics. Tics are often exacerbated by stress, anxiety, excitement, illness, fatigue, or exposure to heat. The unique feature of tics is suggestibility. No other movement disorder has this feature. Also in contrast to other hyperkinetic movements, motor and phonic tics can persist during all stages of sleep. In addition to tics, patients with Tourette syndrome exhibit multiple behavioral symptoms including ADHD, OCD/OCB, learning difficulties, behavioral problems, anxiety, mood problems, sleep problems, social skill deficits, and social functioning. ADHD and OCD often interfere with learning and social activities more than tics. It is essential to recognize and treat those symptoms to help an affected child. It is important to elucidate the family history of ADHD and OCD, which is well accepted as part of the spectrum of neurobehavioral symptoms of Tourette syndrome. In our case, a family history of ADHD in his older brother adds to the diagnostic certainty of Tourette syndrome in this patient. Obsessions are intense and often intrusive thoughts, which compel patients to perform mostly meaningless, time-consuming, and sometimes embarrassing rituals or compulsions. In contrast to primary OCD, in Tourette syndrome, symptoms rarely relate to hygiene and compulsive cleaning; the behaviors more commonly involve symmetry requiring constant rearrangement, forced touching; fear of harming self or family; and an overwhelming desire to do things “right” (in a very strict predetermined way). One of the most distressing symptoms of Tourette syndrome is a self-injurious behavior, which varies from minor skin damage by biting or scratching to life-threatening

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injuries. These irresistible urges are not tics, but obsessions followed by a compulsive injurious behavior.

TREATMENT The first and most important component in the management of Tourette syndrome is education of the patient and caregivers, who in turn should educate teachers, coaches, and principals. Most Tourette syndrome patients do not need medications. Reassurance and help in arranging the most productive environment for the child at school and at home are necessary. However, if education and behavioral modification are not enough, and tics interfere with daily functioning, medications can be considered to improve the child’s performance and facilitate social interactions. Priority should be given not to the most visible, but to the most disturbing symptoms, which are often related to the child’s ADHD or OCD/OCB. Tics should be treated if they interfere with school or work, cause embarrassment, disturb others to the degree that the patient avoids social interactions, or cause pain to the patient. Tics that can cause immediate or potential injury to the patient need to be treated aggressively. Most physicians prefer initiation of treatment with off-label (not Food and Drug Administration [FDA] approved specifically for treating tics) use of alpha-2 adrenergic agonists guanfacine and clonidine, which are FDA approved for hypertension. Guanfacine is generally preferred over clonidine due to less sedative effects. Newer atypical antipsychotic drugs (risperidone, olanzapine, quetiapine, aripiprazole) have been reported to demonstrate tic-suppressing effects in Tourette syndrome patients, but these seem to be less effective than the classical neuroleptics. The most effective pharmacologic agents for tic suppression are the first generation of dopamine receptor blocking agents. Haloperidol (Haldol) and pimozide (Orap) are the only neuroleptics that are approved by the FDA for the treatment of Tourette syndrome. Typical neuroleptics such as Haldol, despite being effective, are rarely used as first-line therapy because of their side effects. The most feared side effects of the long-term neuroleptic therapy are tardive dyskinesia and hepatotoxicity. In addition to dopamine receptor blockers, the dopamine depleter, tetrabenazine, has been found to be effective and more tolerable in the treatment of tics. Botulinum toxin injections have also been found to be beneficial in treating focal motor and vocal tics. A growing number of case reports and studies indicate that deep brain stimulation (DBS) can be an effective therapy for patients with severe, debilitating, or socially unacceptable tics. It remains an experimental surgical procedure, however, and no randomized control trials supporting benefit are currently available. Often, tics do not present a major concern to the patient, but behavioral symptoms that do not respond to a more conservative approach of behavioral modification and classroom adjustments require pharmacotherapy. Treating these comorbidities can improve the quality of life in patients with tics. The most effective agents for the treatment of ADHD are central nervous system (CNS) stimulants, such as methylphenidate (Ritalin), dextroamphetamine (Dexedrine), pemoline (Cylert), and many others. The problem is that according to some reports CNS stimulants can

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exacerbate or precipitate tics in up to 25% of patients. If this is the case, non-CNS stimulants like alpha-2 agonists and tricyclic antidepressants can be used instead of stimulants. However, OCB responds well to the combination of cognitivebehavioral psychotherapy and selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and sertraline (Zoloft). In this case, the child and parents were informed of the diagnosis but chose not to start pharmacotherapy. The patient’s teachers were also informed, and they modified his class environment. He improved in his school performance, and within a year his tics became less pronounced and less bothersome to the patient and his immediate family.

CASE CORRELATION šš

See also Case 2 (Huntington Disease) and Case 6 (Tardive Dyskinesia)

COMPREHENSION QUESTIONS 48.1 Which of the following behavioral abnormalities is associated with Tourette syndrome? A. ADHD B. Schizophrenia C. Trichotillomania D. Autism spectrum disorder 48.2 Which of the following statements is correct regarding Tourette syndrome? A. Motor and vocal tics remit during sleep. B. Tics in Tourette syndrome are suggestible by talking about it or demonstrating it. C. Tics and compulsions mean the same thing in Tourette syndrome. D. Risk of Tourette syndrome is associated with vaccinations as an infant. 48.3 A 12-year-old boy has been recently diagnosed with Tourette syndrome. Medications are being contemplated to help control the symptoms. Which of the following is most likely to be prescribed at initial therapy? A. Haloperidol B. Dopamine blocking agents C. Anticholinergic agents D. Tricyclic antidepressant

ANSWERS 48.1 A. In addition to tics, patients with Tourette syndrome exhibit multiple behavioral symptoms, most commonly ADHD and OCD/OCB.

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48.2 B. The tics are a characteristic aspect of Tourette syndrome and can be brought on by talking about it. This is referred to as “suggestible.” Tics are involuntary, unpredictable, and tend to increase during times of stress. 48.3 B. Dopamine blocking agents are commonly prescribed as first-line therapy for Tourette syndrome. Although haloperidol is sometimes used for this condition, it is used rarely because of side effects.

CLINICAL PEARLS »»

Tourette syndrome is the most common cause of childhood tics.

»»

Most tics are suggestible and at least temporarily suppressible.

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Poor impulse control, ADHD, and OCB are often more debilitating than tics.

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Treat tics only if they interfere with school, work, or social activities.

»»

Patients with Tourette syndrome almost always have excellent insight into their disease, even very early in life.

REFERENCES American Psychiatric Association. Obsessive-compulsive and related disorders. In: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. Feigin A, Clarke H. Tourette’s syndrome: update and review of the literature. Neurologist. 1998;4: 188-195. Hensiek AE, Trimble MR. Relevance of new psychotropic drugs for the neurologist. J Neurol Neurosurg Psychiatry. 2002;72:33, 281-285. Hirschtritt ME, Dy ME, Yang KG, Scharf JM. Child neurology: diagnosis and treatment of Tourette syndrome. Neurology. 2016;87(7):e65-e67. Jankovic J. Botulinum toxin in the treatment of dystonic tics. Mov Disord. 1994;9(3):347-349. Jankovic J, Glaze DG, Frost JD. Effects of tetrabenazine on tics and sleep of Gilles de la Tourette’s syndrome. Neurology. 1984;34(5):688-692. Jankovic J, Kurlan R. Tourette syndrome: evolving concepts. Mov Disord. 2011;26(6):1149-1156. Robertson M, Eapen V. Pharmacologic controversy of CNS stimulants in Gilles de la Tourette’s syndrome. Clin Neuropharmacol. 1992;15(5):408-425.

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CASE 49 A right hand–dominant 7-year-old boy is brought to the emergency room (ER) after having had an unusual spell at night. He came into his parent’s room looking very frightened, making gurgling noises but unable to speak, with twitching noted over the right side of his face. After approximately 30 seconds, he fell to the ground and had a 2-minute generalized tonic-clonic event. Immediately afterward he was drowsy and confused but now is completely back to his normal baseline. His vital signs are within the range of normal for his age, and his physical examination, including a detailed neurologic examination, is normal. He has never experienced any similar events, and there is no history of febrile seizures, central nervous system (CNS) infections, significant head trauma, headaches, developmental or behavioral problems, or changes in personality. He was born at 38 weeks of gestation after an uneventful pregnancy and went home on the second day of life. He has not been febrile nor had any recent illnesses. The child’s father states that he had similar episodes as a child. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 49: Benign Epilepsy with Centrotemporal Spikes Summary: This is a 7-year-old boy, full term, with no significant past medical history and normal development who is brought to the ER after a nocturnal spell involving speech arrest and hemifacial spasms, followed by an apparent secondarily generalized tonic-clonic seizure. He had brief postictal confusion, and quickly returned to his normal baseline. His examination is unremarkable. The family history is significant for similar episodes in his father when he was a child. šš

Most likely diagnosis: Benign epilepsy with centrotemporal spikes (BECTS).

šš

Next diagnostic step: Perform an electroencephalograph (EEG) as an outpatient.

šš

Next step in therapy: Reassurance as well as monitoring for subsequent events.

ANALYSIS Objectives 1. Understand the difference between partial, generalized, and secondarily generalized seizures. 2. Know the clinical characteristics of BECTS. 3. Be aware of long-term prognosis of BECTS and considerations in deciding on treatment. 4. Know when a focal seizure in childhood requires further workup and how to proceed with such an evaluation.

Considerations This 7-year-old boy experienced a nocturnal seizure with secondary generalization and was not associated with any obvious provocation. The most likely diagnosis is BECTS, also known as benign rolandic epilepsy (BRE). BECTS accounts for 6% to 10% of all childhood epilepsies, making it the most common focal epilepsy of childhood. Typically, it has its onset between 3 and 10 years with a peak onset of 7 to 8 years, resolving by age 18. BECTS has no known etiology, but because of positive family history in about one-fourth of patients, there is a presumed genetic basis that still remains to be unclear. This type of epilepsy is more common in boys. About two-thirds of patients will have only one or very few seizures. The typical seizure presentation with BECTS includes clonic or tonic activity of one side of the lower face; paresthesia of the tongue, lips, gum, and cheek; and drooling and arrest of speech or dysarthria. Hemiconvulsions are more common in young children, and evolution to bilateral convulsive activity is more frequent in sleep. Most of the seizure activity is at night, related to falling asleep or awakening from sleep. The EEG is particularly helpful in making the diagnosis of BECTS; as the name implies, patients will have epileptiform discharges in the central and temporal regions.

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The seizure description, the age of the patient, the onset during sleep, and the family history of similar episodes in his father are together highly suggestive of BECTS (see also Case 44).

APPROACH TO: Benign Epilepsy with Centrotemporal Spikes TERMINOLOGY Understanding of the terminology used to describe seizures is essential to the discussion of any specific type of epilepsy. According to the 2010 International League Against Epilepsy (ILAE) classification, the term generalized is used if the seizure onset involves both cerebral hemispheres. The term focal, also referred to previously as partial or as localization-related, is used if the seizures begins in one part of one hemisphere. Focal seizures can be further categorized into those that do not impair consciousness—simple focal seizures—and those that do impair consciousness, complex partial seizures. It is not uncommon for focal seizures to spread and involve a greater cortical region as the seizure progresses. If this abnormal activity spreads to the contralateral hemisphere, the seizure is said to be secondarily generalized. This would appear to be what happened in the case under consideration because the child initially had focal manifestations (speech arrest and right hemifacial spasm), followed by generalized motor activity (a generalized tonic-clonic seizure). A focal seizure is by definition a manifestation of a focal physiologic abnormality in the cortex. Sometimes this will be associated with an anatomic abnormality seen with a magnetic resonance imaging (MRI) scan, and sometimes the MRI will not show the lesion. Examples of common causes of such a lesion would be trauma, stroke, infection, tumor, or a congenital malformation of cortical development. If an anatomic substrate is seen in association with the region of seizure onset (the seizure focus), the disorder is classified as structural. If the patient has a metabolic condition that predisposes them to have seizures, the disorder is classified as metabolic. Alternatively, a seizure focus can exist without any obvious finding on neuroimaging. In this case, the disorder would be considered unknown (previously referred to as cryptogenic, indicating that the cause remains hidden). The final category of epilepsies is genetic, which refers to conditions in which there is a known or presumed genetic etiology. The most common focal epilepsy of childhood, BECTS, is an example of a (presumed) genetic epilepsy which is highly heritable, although the mode of that inheritance remains unclear.

CLINICAL PRESENTATION The clinical manifestations, or semiology, of focal seizures reflect the normal function of the region of the brain from which they arise. For example, an occipital lobe focus can produce visual manifestations, whereas a focus in the primary motor cortex can generate contralateral tonic and/or clonic activity. In this patient, speech

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arrest and right hemifacial spasm suggest a seizure focus near the facial aspect of the left motor strip as well as the nearby regions responsible for expressive language. This would be consistent with a perirolandic location involving the lateral aspect of the left hemisphere near the central sulcus (formerly referred to as the rolandic fissure). Information about seizure presentation is combined with the findings of MRI and electroencephalography (EEG) in an attempt to localize the focal abnormality. BECTS is labeled benign because this type of epilepsy is not typically associated with any neurocognitive or behavioral abnormalities. It resolves before reaching adulthood, in most patients it is associated with infrequent seizures, and it is typically easily treated or so mild that treatment is not necessary. Frequent seizures are seen in only 6% of the cases, while 13% to 21% will have only one single event. The number of seizures the patient experiences will play an important factor when considering whether to begin anticonvulsant therapy. Obtaining an EEG is particularly helpful in making the diagnosis of BECTS because characteristic features can be seen interictally. Typically, the interictal EEG will show centrotemporal (perirolandic) spikes, which may be bilateral or unilateral. If a period of sleep is captured during the recording session, approximately 30% of patients with BECTS will have sharp waves seen arising from the centrotemporal region. If both the history and the EEG are consistent with BECTS, and there is a normal neurologic examination without significant neurocognitive or behavioral changes, no further diagnostic workup needs to be undertaken. If the history is consistent but the EEG is unrevealing, then it can be worth obtaining a prolonged EEG to see if diagnostic abnormal activity can be captured. Certainly, if there are focal features on neurologic examination, concerning aspects to the history (such as developmental regression), or abnormalities on EEG that are inconsistent with BECTS, then neuroimaging with an MRI should be strongly considered.

TREATMENT Once the diagnosis is made, consideration must turn to treatment. Most patients experience only one or very few seizures, and all patients eventually outgrow BECTS. Also, although this is a matter of some debate, there is no evidence whether treatment should be started right away. Some studies recommend withholding treatment unless there were multiple seizures, cognitive changes, quality-of-life changes, and generalized tonic-clonic seizures. Clearly this is a decision that must be tailored to the individual patient in careful consultation with the child and the child’s parents.

PROGNOSIS Remission occurs in essentially all children: 50% by age 6, 92% by age 12, and 99.8% by age 18. The diagnosis of BECTS must be reconsidered in patients who do not respond to treatment, whose seizures persist into adulthood, or who have very frequent or otherwise atypical seizures or neurocognitive/behavioral deficits which persist or are severe.

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CASE CORRELATION šš

See also Case 44 (New-Onset Seizure, Child)

COMPREHENSION QUESTIONS 49.1 A third-year medical student observes a seizure occurring in one of the neurology intensive care unit (ICU) patients which involved isolated twitching of one hand and no impairment of consciousness. The patient’s computed tomography (CT) of the brain showed a stroke in the hemisphere contralateral to the hand twitching. Which of the following is the most appropriate description? A. Generalized seizure B. Focal, genetic seizure C. Focal, structural seizure D. Focal, metabolic seizure E. Focal seizure with secondary generalization 49.2 Which of the following is typical of seizures seen in patients with BECTS? A. Seizures occur mostly during the daytime. B. Seizures are generalized from the outset. C. Seizures primarily involve the lower extremities. D. Seizures recur frequently. E. Seizures often begin in the face or mouth. 49.3 A 9-year-old girl is brought to the clinic with a history entirely consistent with the diagnosis of BECTS. An EEG is obtained that reveals the centrotemporal sharp waves characteristic of this disorder. The patient has had one witnessed seizure 2 weeks ago and had one unwitnessed event 1 year ago, which may have been a seizure. The child’s parents are not very interested in beginning daily anticonvulsant medication. Which of the following would be the best course of treatment for this patient? A. Strongly encourage the parents to begin a low dose of daily valproic acid. B. Prescribe prophylactic diazepam in case of febrile illness. C. Reassure the family and encourage “watchful waiting” to see if further seizures occur. D. Obtain an MRI prior to making any treatment recommendations. E. Recommend twice-daily dosing of oxcarbazepine.

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ANSWERS 49.1 C. Because the patient had motor activity only in one hand, this would be focal. A focal seizure with a stroke in the region of the brain related to the observed clinical event would be considered to have a structural etiology. 49.2 E. The seizures of BECTS are usually nocturnal, infrequent, begin with orofacial involvement, and can secondarily generalize. 49.3 C. In the context of typical BECTS with infrequent seizures, “watchful waiting” is the most prudent approach. An MRI is unnecessary in this patient at this time.

CLINICAL PEARLS »»

Although BECTS is the most common focal epilepsy of childhood, the most common focal epilepsy in adults is temporal lobe epilepsy.

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A small subset of patients has been described with malignant rolandic epilepsy, in which the seizures look similar to those of BECTS but are frequent, difficult to treat, and do not remit by 16 years. It is likely that these patients have a different syndrome rather than a severe form of BECTS.

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Approximately 50% of patients with BRE are not treated with anticonvulsants because the seizures are infrequent.

REFERENCES 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. 2010;51(4):676-685. Camfield P, Camfield C. Epileptic syndromes in childhood: clinical features, outcomes, and treatment. Epilepsia. 2002;43(suppl 3):27-32. Camfield P, Camfield C. Rolandic epilepsy has little effect on adult life 30 years later. Neurology. 2014;82:1162-1166. Guerrini R, Pellacani S. Benign childhood focal epilepsies. Epilepsia. 2012;53(suppl 4):9-18. Hughes JR. Benign epilepsy of childhood with centrotemporal spikes (BECTS): to treat or not to treat, that is the question. Epilepsy Behav. 2010;19:197-203. Loiseau P. Idiopathic and benign partial epilepsies. In: Wyllie E, ed. The treatment of epilepsy: principles and practice. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:475-484. Panayiotopoulos CP. Atlas of Epilepsies. London, UK: Springer Science & Business Media; 2010. Willer E. Infantile, childhood, and adolescent epilepsies. Continuum (Minneap Minn). 2016;22:60-93. Willmore LJ. Treatment of benign epilepsy syndromes throughout life. Epilepsia. 2001;42(suppl 8):6-9.

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CASE 50 A 13-month-old baby boy is brought to the clinic by his pregnant mother after he experienced a seizure. He has had recurrent seizures since age 6 months and had generalized spasms as an infant. She expresses concern that he has not been able to sit up by himself yet and has always been a weak baby. He has not been feeding well and lately has had a wet cough with low-grade fevers. Developmentally, he has not said his first word, compared to his older sister who was able to say three words as well as “Mama” and “Dada” by the same age. His birth history is significant for intrauterine growth restriction and reduced fetal movements. After birth, he underwent surgery for cryptorchidism. On examination, his head circumference is small for his age. General examination reveals a high forehead with vertical wrinkling, bitemporal hollowing, widely spaced eyes with epicanthal folds, flattened ears, short nose with upturned nares, prominent nasal folds, a flat midface with a round philtrum and upper lip, and a small chin. He is tachycardic, and his chest sounds are diminished in the right lower lobe. A back examination reveals a sacral dimple. Neurologically, he has generalized hypotonia and is unable to support himself when sitting up. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 50: Lissencephaly Summary: A 13-month-old baby boy with history of developmental delay, dysmorphic facial features, and infantile spasms is brought for evaluation by his mother for recurrent seizures. He has severe mental retardation and motor developmental delays as well as poor feeding. His past history is significant for intrauterine growth restriction in pregnancy and cryptorchidism. On examination, he has microcephaly, craniofacial dysmorphisms including hypertelorism with epicanthal folds, short nose with upturned nares, and micrognathia, tachycardia, a sacral dimple, and generalized hypotonia. šš

Most likely diagnosis: Miller-Dieker syndrome (MDS) or lissencephaly type 1

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Next diagnostic step: Magnetic resonance imaging (MRI) of the brain

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Next step in therapy: Symptomatic management of seizures and poor feeding/ swallowing, genetic counseling

ANALYSIS Objectives 1. Know the clinical features and epidemiology of MDS. 2. Understand the differential diagnosis of lissencephaly. 3. Understand the management of lissencephaly patients and their families.

Considerations The 13-month-old child in the case is a typical case of MDS. Severe mental retardation, recurrent seizures, and infantile spasms are typical. Refractory epilepsy presents during the first 6 months of life in 75% of affected children, with infantile spasms beginning shortly after birth in 80%. Overall, more than 90% of these patients will develop seizures. Mental retardation and developmental delay are severe, with most affected children not capable of progressing beyond the 3- to 6-month level of milestones. Distinct craniofacial dysmorphic features as described for our patient, generalized hypotonia that progresses to opisthotonus, and spasticity with age, contractures, clinodactyly, cryptorchidism, omphaloceles (an abdominal wall defect), cardiac and renal abnormalities are all phenotypic. Feeding and swallowing problems often result in poor weight gain and aspiration pneumonia. Past history will often reveal a gestation complicated by polyhydramnios, intrauterine growth restriction, and decreased fetal movements.

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APPROACH TO: Lissencephaly DEFINITIONS LISSENCEPHALY: Genetic malformation of the cerebral cortex in which abnormal neuronal migration during early neural development results in smooth cerebral surfaces with absent (agyria) or decreased (pachygyria) convolutions. MILLER-DIEKER SYNDROME (MDS): A severe lissencephaly phenotype secondary to deletion on chromosome 17p13.3 with agyria and characteristic dysmorphic features. ISOLATED LISSENCEPHALY SEQUENCE: Milder phenotype compared to MDS, with pachygyria and mild or absent dysmorphic features because of autosomal dominant mutations in the LIS1 gene on chromosome 17p13.3 or X-linked mutations in the doublecortin (DCX) gene on chromosome Xq22.3. Pachygyria caused by LIS1 mutations is posterior predominant on neuroimaging, whereas anterior-predominant pachygyria is more typical of DCX mutations. SUBCORTICAL BAND HETEROTROPIA: It refers to a band of heterotopic gray matter located just beneath the cortex and separated from it by a thin zone of normal white matter. INFANTILE SPASMS: Dramatic repetitive bouts of rapid neck flexion, arm extension, hip and knee flexion, and abdominal flexion, often with arousal from sleep. The mother might describe them as unprovoked startle responses or colicky spells as a result of abdominal pain, although there is no crying typical of colic. Typical presentation occurs between 3 and 8 months of age. HYPERTELORISM: Abnormally increased distance between the eyes. EPICANTHAL FOLD: Skin fold of the upper eyelid (from the nose to the medial side of the eyebrow) covering the medial corner (medial canthus) of the eye. CLINODACTYLY: Congenital condition where the little finger is curved toward the ring finger. OPISTHOTONUS: Severe hyperextension of the back caused by spasm of the muscles along the spinal column.

CLINICAL APPROACH Epidemiology and Differential Diagnosis MDS is an inherited form of lissencephaly and has been reported to occur in 11.7 per million live births. This severe form is estimated to be the cause of almost onethird of patients with identified lissencephaly. It is caused by chromosome microdeletions in the chromosome 17p13.3 of the LIS1 gene. In approximately 80% of cases it is due to a de novo deletion, and in 20% of cases it is inherited from a parent who carries a balanced chromosome rearrangement. The main differential

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diagnosis is isolated lissencephaly sequence (ILS), which has a milder phenotype and is caused by a smaller mutation in the LIS1 gene, with an autosomal dominant pattern of inheritance, or a mutation in the DCX gene, with X-linked transmission. Microdeletions in the LIS1 gene will cause the “agyria-pachygyria-band” spectrum of cortical malformation. The phenotypes include MDS, ILS, and subcortical band heterotopia (SBH). These microdeletions will cause central nervous system (CNS) abnormalities of the embryo, due to interruption or disruption of three development stages: cell proliferation, cell migration, and cortical organization. Lissencephaly refers to smooth brain and is due to disruption of abnormal cell migration. The word lissencephaly is derived from the Greek word lissos meaning smooth and encephalos meaning brain. With lissencephaly, the early brain development is normal until month 3 or 4 of development, when the brain fails to progress normally. The human brain normally has a convoluted surface, but in patients with lissencephaly these convolutions are completely or partially absent from the brain, or areas of it, giving the smooth appearance. The convolutions are also called gyri, and their absence is known as agyria (without gyri). In some cases, convolutions are present, but thicker and reduced in number, and the term pachygyria (broad gyri) is used. The neocortex of patients contains four layers instead of six. The diagnosis is usually made by MRI scan of the brain, which can show classical findings of the hourglass configuration, thick cortex, thin subcortical white matter interdigitation, and shallow sylvian fissure (Figure 50–1).

Figure 50–1.  Features of classical lissencephaly showing the four severity grades. All images are T1- or T2-weighted MRI scans. The top row shows axial scans, and the bottom row shows coronal scans. Grade 1 is near complete agyria, grade 2 is posterior agyria and rudimentary shallow gyri anteriorly, grade 3 is posterior agyria and anterior pachygyria, and grade 4 is generalized pachygyria. (Leventer RJ, Guerrini R, Dobyns WB. Malformations of cortical development and epilepsy. Dialogues Clin Neurosci. 2008;10[1]:47-62.)

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Both MDS and ILS are considered classical lissencephalies or lissencephaly type 1. The differential diagnosis also includes other migration defect syndromes that present with seizures, mental retardation, and lissencephaly, including lissencephaly with cerebellar hypoplasia (AR, RELN gene on 7q22) and lissencephaly with abnormal genitalia (X-linked, ARX on Xp22.13). Related syndromes that present with similar clinical presentations but different neuroimaging findings include SBH (LIS1 or DCX), polymicrogyria, bilateral periventricular nodular heterotopia, and schizencephaly.

DIAGNOSIS An accurate diagnosis is important for two reasons. First, if the condition is genetic and has been inherited, it will allow parents to understand the risk for future pregnancies and also whether other children in the same family are also carriers for the faulty gene. Second, it is useful for parents of children with lissencephaly to meet other parents and children with the same condition so they can learn from each other’s experience. A condition of lissencephaly or pachygyria is not a full diagnosis, and the cause cannot be determined without a more detailed evaluation from a neurologist, pediatrician, or geneticist. Neuroimaging is very important in the evaluation and diagnosis. An MRI scan is almost always superior for detailing the brain malformation, especially for conditions such as polymicrogyria where computed tomography (CT) scans do not provide the resolution required.

TREATMENT The management for patients with lissencephaly is mainly supportive, centering around the three major complications: epilepsy, poor feeding, and spasticity. Improved symptomatic therapy has lengthened the life expectancy of these patients from a few years to the early teens. The use of steroids (prednisone) and adrenocorticotropic hormone (ACTH) is an accepted treatment for infantile spasms but may or may not be successful. Seizures will return following treatment with steroids and are often intractable. Multiple anticonvulsants are often required with vigilance for life-threatening status epilepticus. Poor feeding and swallowing predispose to malnutrition and aspiration pneumonia; a feeding tube and gastrostomy in the long term can help reduce these comorbidities. Hypotonia in the early years progresses to spasticity and contractures that, if untreated, can result in severe pain and discomfort, as well as immobility and complications such as falls, atelectasis, and decubitus ulcers. Frequent stretching physical therapies, braces, and muscle relaxants can slow the development of spasticity and contractures, and special wheelchairs and mattresses can reduce problems arising from immobility. Lissencephaly patients can also have congenital cardiac and renal abnormalities that must be closely monitored and managed. As in the case of this patient’s family, genetic counseling plays an important role because of concern for a hereditary syndrome. The recurrence risk for MDS is very low because most cases are caused by a de novo chromosomal deletion. However, recurrence risk can be as high as 33% if a familial reciprocal translocation is determined.

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The workup can begin with a fluorescent in situ hybridization (FISH) analysis for the 17p13.3 deletion, and a genetics specialist can be consulted. Prenatal testing is possible through fetal chromosome analysis by karyotyping, FISH, chorionic villus sampling, or amniocentesis. Imaging for cerebral gyral malformations is more sensitive beyond 28 weeks of gestation.

COMPREHENSION QUESTIONS 50.1 A 14-month-old child is diagnosed as having MDS. Which of the following would be most likely noted on physical examination? A. Macrocephaly B. Motor delay C. Ambiguous genitalia E. Abnormal X-chromosome studies 50.2 Which of the following is one of most common sequela of MDS? A. Epilepsy B. Respiratory failure C. Hypotonia D. Rhabdomyolysis 50.3 A 2-month-old infant is noted to draw up his legs and tighten his abdomen after feeding with formula. There seems to be no abnormal seizure activity. The developmental milestones seem to be normal. Which of the following is the most likely diagnosis? A. Infantile spasms B. Intestinal colic C. Lissencephaly, early onset D. Noonan syndrome

ANSWERS 50.1 B. Motor delay, seizures, and microcephaly are the hallmarks of MDS. Ambiguous genitalia is typically not seen. Chromosome 17 (17p13.3 microdeletion) is typically affected and not the X chromosome. 50.2 A. The management of the Miller-Dieker lissencephaly patient is supportive, centering around the three major complications: epilepsy, poor feeding, and spasticity. The children are affected with profound psychomotor retardation, failure to thrive, and muscle spasms. Typically, rhabdomyolysis is not seen.

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50.3 B. This infant is normal in every way except the drawing up of his legs and tightening of the abdomen after feeding, which is most likely intestinal colic. The keys include measurement of the head circumference, reaching developmental milestones, and absence of seizure activity.

CLINICAL PEARLS »»

Lissencephaly should be considered in the differential diagnosis of a child presenting with mental retardation, motor delay, infantile spasms, and characteristic craniofacial dysmorphic features including microcephaly, short nose with upturned nares, and micrognathia.

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MRI of the brain and consultation with a pediatric neurologist are important steps in the workup of lissencephaly.

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Treatment of lissencephaly patients should focus on symptomatic therapy for complications including epilepsy, poor feeding, and spasticity.

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Genetic counseling is an important part of the care of lissencephaly patients and their families.

REFERENCES Battal B, Ince S, Akgun V, Kocaoglu M, Ozcan E, Tasar M. Malformations of cortical development: 3T magnetic resonance imaging features. World J Radiol. 2015;7(10):329-335. Dobyns WB, Curry CJ, Hoyme HE, et al. Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Hum Genet. 1991;48(3):584-594. Dobyns WB, Das S. LIS1-associated lissencephaly/subcortical band heterotopia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® (Internet). Seattle, WA: University of Washington; 1993-2017. Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res. 2006;173:322-333. Leventer RJ, Guerrini R, Dobyns WB. Malformations of cortical development and epilepsy. Diaglogues Clin Neurosci. 2008;10(1):47-62. Lissencephaly Contact Group. About lissencephaly. http://www.lissencephaly.org.uk/aboutliss/index.htm. Accessed Nov 1, 2016. Pilz D. Miller-Dieker syndrome. Orphanet encyclopedia. http://www.orpha.net/data/patho/GB/uk-MDS. pdf. Accessed September 2003. Radiology.com. CT scan files—lissencephaly type 1. http://www.radiologyworld.com/Ctscan-lissen.htm. Tulane University. Lissencephaly type 2. http://www.mcl.tulane.edu/classware/pathology/medical_ pathology/neuropathology/congenitalq.htm. Accessed Nov 1, 2016.

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CASE 51 A 3-year-old boy is brought to the doctor’s office by his parents because he “isn’t talking like other kids of his same age.” He was the product of an uncomplicated pregnancy and vaginal delivery at term. Although he is not a particularly warm or cuddly child, his parents did not notice anything unusual in the first year of life. At age 2, the child had not yet articulated any words, although he was noted to babble occasionally and showed no affection to his parents or siblings. His parents report that he gets easily upset, particularly by changes from his usual routine, and soothes himself by rocking back and forth or slowly spinning in a circle. Developmental history in the family is normal. The child’s two older siblings are healthy and neurodevelopmentally normal. The child has physically been healthy, has never been hospitalized, and has never had surgery. His immunizations are up to date. On examination, the child has not developed any spoken words, and his temperament remains irritable and isolative. His parents state that he hardly ever makes eye contact, and if forced by others, he becomes upset. He appears to be an active and healthy-appearing toddler who is wandering around the office, ignoring the doctor and his parents, paying attention only to the books, which he rhythmically pulls off the shelf without playfulness. When his mother tries to keep him from the books, he screams, looks up to the ceiling, flaps his arms, and then retreats to the corner and rocks back and forth. He has a normal toddler gait but seems somewhat uncoordinated for his age when reaching for and grasping objects. There are no noted dysmorphic features, and his skin examination is normal. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 51: Autism Spectrum Disorder Summary: This physically healthy 3-year-old boy presents with delayed language development, abnormal social interactions, and unusual behaviors. He is physically healthy, and there is nothing of note in his prenatal, medical, surgical, or family histories. His examination is significant only for demonstrating the language deficits and behaviors reported by the parents. šš šš

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Most likely diagnosis: Autism spectrum disorder (ASD) Next diagnostic step: Audiologic evaluation to ensure that there is no hearing deficit Next step in therapy: Educational intervention and behavioral modification, applied behavior analysis (ABA)

ANALYSIS Objectives 1. Understand the difference between developmental delay and developmental regression. 2. Know the four domains of development and how to assess them clinically. 3. Remember the importance of evaluating hearing in evaluating a language delay. 4. Know the cardinal features of ASD.

CLINICAL CONSIDERATIONS This 3-year-old boy is brought to the office with concerns about his language development and behavior. Clinically, the most important first step is to carefully distinguish between developmental delay and developmental regression. Delay implies that the child is making progress, although at a rate slower than that considered to be normal. This is generally because of a static process and can lead to an eventual diagnosis of mental retardation. Developmental regression, conversely, implies that the child is now losing previously attained skills and raises the possibility of a progressive neurodegenerative process. Distinguishing between delay and regression can be clinically difficult, at times. For example, a child can inconsistently demonstrate a new developmental skill, leading to the impression that it has been lost. True developmental regression is a red flag, which necessitates an expedited search for a progressive disorder of the nervous system. In this patient, however, there is no hint of developmental regression but instead a picture of developmental delay. Evaluation of problems with development is facilitated by assessing four distinct developmental aspects: gross motor skills, fine motor skills, personal-social interactions, and language capabilities. An isolated language deficit, for example, can be caused by hearing impairment alone, while global developmental delay (involving

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all four domains) is more likely to be caused by a significant in utero, perinatal, or genetic disturbance. A delay in gross motor skills arising early on in infancy suggests the diagnosis of cerebral palsy. Assessing which developmental spheres are impacted is facilitated by the use of the Denver Developmental Screening Test (DDST) and confirmed with more sophisticated psychometric measures that are available, either for use in the office or on referral to a pediatric neuropsychologist. Applying such an approach to this patient reveals that although the child is meeting gross motor milestones appropriately, he is slightly behind in fine motor skills (uncoordinated for his age when reaching for and grasping objects) and disproportionately significantly delayed in the language and personal-social domains (the child has not developed any spoken words, and his temperament remains irritable and isolative). With respect to language, children normally begin babbling by approximately 6 months of age, articulate one word by approximately 1 year, and by 2 years are able to combine two words to form rudimentary sentences, as well as follow simple verbal commands. This patient, at age 3, is therefore significantly delayed, given that he is only able to babble and does not seem to follow commands. Although most newborns are screened for hearing problems in the newborn nursery (using a neurophysiologic test called auditory brainstem-evoked responses), clinicians must be sure that hearing is normal when faced with a language delay. This patient, however, has delays in more than just the language domain. By parental report and based on observations, he also has significant problems with social reciprocity. He is not affectionate toward his parents and siblings and does not maintain eye contact. At times, he seems to treat people in the same detached way that he treats other objects around him. Although solitary play is a normal developmental stage, this child has never progressed to including any type of social play, which is certainly abnormal at his age. Furthermore, he has a variety of odd and idiosyncratic behaviors. For example, he is fascinated with removing books from shelves and does so in a mechanical way rather than a playful one. Also, he uses repetitive behaviors such as rocking, slowly spinning, or rapidly flapping his hands in order to soothe himself when upset rather than seeking comfort from his caretakers. These repetitive stereotyped self-stimulating behaviors are referred to as stereotypies and are commonly seen in children with ASD. Taken together, this child’s clinical condition appears to meet criteria for ASD.

APPROACH TO: Autism DEFINITIONS AUTISM SPECTRUM DISORDER (ASM): Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision (DSM-V-TR) revised the definition as a single broad category of ASD. ASD in new criteria has two cardinal features: (1) impaired social communication and social interaction and (2) restricted, repetitive behaviors, interests, or activities. In this new criterion, the well-known labels of Asperger syndrome (AS) and pervasive developmental disorders not otherwise specified (PDD-NOS) are no longer present.

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DEVELOPMENTAL DELAY: Developmental delay occurs when children have not reached milestones by the expected time period for all five areas of development or just one (cognitive, language and speech, social and emotional, fine motor, and gross motor).

CLINICAL APPROACH ASD involves deficits in social interactions and behaviors. The diagnosis is made clinically according to the following criteria detailed in DSM-V-TR: 1. With regard to deficits in social communication and social interaction, to qualify for ASD, the patient must have persistent deficits in all three social communication criteria: A. Lack of social or emotional reciprocity, ranging from, for example abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions. B. Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body posture, and gestures necessary to regulate social interaction. C. Deficits in developing, maintaining, and understanding relationships and/ or adjusting to social contexts. 2. Restricted, repetitive pattern of behavior, interests, or activities. To qualify for ASD, the patient must meet two out of the four criteria: A. Stereotyped or repetitive speech, motor movements, use of objects or speech. B. Excessive adherence to routines or rituals or nonverbal behavior. C. Highly restricted, fixated interests that are abnormal in intensity or focus. D. Hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment. 3. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life). 4. Symptoms should limit and impair everyday functioning. 5. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Severity level of ASD is defined based on the level of impairment in social communication and restricted, repetitive patterns of behavior. ASDs are more common in boys than in girls (4:1) and have an overall prevalence rate of approximately 1 in 68 children in the United States. If findings suggestive of ASD are obtained by history or on a developmental screening examination, then the patient should be referred for more detailed evaluation by a clinician familiar with the formal diagnosis of autism. It is imperative that children are screened for early signs of deficits in social communication and social interaction at their well-child

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examinations and referred to specialists if any red flags arise. The cause of ASD is unknown, but increasing evidence points to an underlying pathophysiologic process that is ongoing long before the developmental delays become evident and is likely present from birth. Although multiple brain regions are likely to be involved in such a complex disorder, it appears as though the frontal lobe and the amygdala are significantly involved. This makes sense given the frontal lobe’s involvement in regulating emotion and behavior, as well as the role of the amygdala in mediating the response to stress. Recently there has been a flurry of research investigating a possible link between routine childhood vaccinations containing the preservative thimerosal and autism. Although large epidemiologic studies have clearly failed to support this linkage, it remains a significant concern in the minds of many parents and might be an important concern that needs to be addressed directly with them.

MANAGEMENT Perhaps the most important aspect of management in patients with ASD is a welldesigned, appropriately structured educational environment. Given that autism is a developmental disorder, it is vital to begin such interventions early to maximize the development of the child’s potential. Additionally, behavioral interventions can be very helpful both for the patient and the family and caretakers. ABA is a notable treatment approach for people with ASD. It encourages positive behaviors and discourages negative behaviors to improve a variety of skills. Pharmacologic interventions are sometimes employed, although there currently are not many large clinical trials to support their use. Smaller studies have suggested that the use of selective serotonin reuptake inhibitors and atypical antipsychotic medication can have some benefit. It should be noted that no medication currently has an indication from the Food and Drug Administration (FDA) for use in treating the symptoms of autism. It is not surprising, therefore, that many complementary and alternative treatments have been promoted for these patients: mercury chelation therapy, intravenous secretin treatments, and a host of supplements. Parents should be asked about the use of such therapies and counseled about their potential dangers.

PROGNOSIS The disease usually is nonprogressive, although occasionally, as an affected child grows, additional deficits can be evident. Although less affected individuals can develop improvement in social relationships, the outlook for those children who are significantly affected is poor. The degree of language impairment and intelligence ability usually predicts outcome of eventual function; a child who has not learned to speak by 5 years usually will not gain communicative ability.

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COMPREHENSION QUESTIONS 51.1 Of the following patients referred for developmental problems, who would be the most clinically concerning? A. A 3-year-old child who has never learned to speak B. A 5-year-old child who has moderate delays in all four developmental domains C. A 2-year-old child with cerebral palsy and epilepsy D. A 30-month-old child who was speaking normally as per age but now has no intelligible words E. A 4-year-old child who has always been clumsy 51.2 The DDST is best described as which of the following? A. Comprehensive evaluation of all developmental spheres B. An unnecessary tool with modern neuroimaging techniques such as magnetic resonance imaging (MRI) C. A quick method for picking up potential developmental problems in an office practice D. A well-standardized tool for diagnosing autism E. A test of expressive and receptive language skills 51.3 Which of the following is most important in the diagnosis of autistic disorder? A. A family history of autism B. Atrophy of the frontal lobe on MRI C. Development of symptoms before 5 years of age D. Normal language function E. Abnormal social reciprocity 51.4 An 8-year-old boy has recently been diagnosed with autism. Which of the following interventions is most important in the management of this child? A. Prescribing a moderate dose of an atypical antipsychotic drug such as risperidone B. Making sure that the child gets no further immunizations C. Enrolling the child in a highly structured educational program D. Getting the child involved in highly social activities such as team sports E. Daily multivitamin therapy

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ANSWERS 51.1 D. In each of the children described other than answer D, there is developmental delay of one type or another. Although developmental delay is concerning, typically, this problem is caused by a “static” insult of some type and not one that is progressing. In these cases the brain is trying to “catch up.” These conditions should not be ignored and must be evaluated. However, the child who spoke normally for age and now is not able to speak intelligently is showing developmental regression, losing ground. This speaks toward a new and ongoing problem, which, if not diagnosed and treated, may lead to progressive permanent issues or even death. Any sign of developmental regression (such as the loss of expressive language skills) is very concerning. 51.2 C. The DDST is useful “quick tool” to pick up potential developmental problems in the office; it assesses four key milestones, including gross motor, language, fine motor, and personal-social. It is not designed as a comprehensive or in-depth assessment device, and some states do not accept it as sufficient for early childhood screening. 51.3 E. Abnormal social reciprocity, along with abnormalities in communication and behavior, is a key feature of ASD. ASD is a clinical diagnosis without useful findings on ancillary tests such as MRI or electroencephalography (EEG). Thus, one of the most important points of evaluation is to have an experienced clinician evaluate any patient with suspected ASD. 51.4 C. Children with autism benefit from a very structured educational environment designed to teach skills in a concrete way. Some of the key behavioral principles include modification of events that precede negative behavior, and positive reinforcement for positive behaviors. Recent research has added a plethora of evidence-based strategies to help these individuals. Although medication can be helpful in some patients, there are no large-scale trials at present to support their usage.

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CLINICAL PEARLS »»

Although developmental regression is a red flag, it is not uncommon to see some language regression as autistic symptoms become evident late in the second year of life.

»»

Often children with autism will develop a vocabulary with a few words at an apparently appropriate age and then lose the use of those words by 2 years. This autistic regression is seen in approximately 25% of patients.

»»

More than 25% of children with ASD develop epilepsy, which is a striking increase from the rate of 1% in the general population. Patients with lower IQs are at higher risk of developing epilepsy.

»»

Although language and communication problems do not show up until the second year of life in patients with classic autism, parents often report that these children seem different from early in the first year of life.

REFERENCES American Psychiatric Association. Neurodevelopmental disorders. Autism spectrum disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. Barbaresi W, Katusic S, Voigt R. Autism—a review of the state or the science for pediatric primary health care clinicians. Arch Pediatr Adolesc Med. 2006;160:1167-1175. Lobar SL. DSM-V changes for autism spectrum disorder (ASD): implications for diagnosis, management, and care coordination for children with ASDs. J Pediatr Health Care. 2016;30(4):359-365. Sugden S, Corbett B. Autism—presentation, diagnosis, and management. Continuum. 2006;12(5): 47-59.

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CASE 52 A 43-year-old right-handed woman presents to the office with hearing loss, facial paralysis, and headache. Her history began 1 month ago with a sudden decrease in hearing from her right ear. One week prior to this visit, she noticed weakness of the right face, which has now progressed to complete paralysis. Over the last 3 months she has had intermittent right occipital headache, and clumsiness and imbalance if she turns quickly. She denies any change in her voice or difficulty with swallowing. Her past medical history is unremarkable. She is not on any medications except birth control pills. Her physical examination shows an obvious right facial paralysis. Her pulse is 62 beats/min; blood pressure is 118/62 mm Hg; and temperature is 36.7°C (98.6°F). The head and face have no lesions. Her voice is normal, but her speech is slightly distorted because of the facial paralysis. Her extraocular movements are normal. Her eye grounds do not show any papilledema. Her ears have normal tympanic membranes. The Weber tuning fork lateralizes to the left ear. Air conduction is louder than bone conduction in both ears. There is no neck lymphadenopathy or other masses. There are no cerebellar signs. The remaining physical examination, including the neurologic examination, is normal. An audiogram shows a mild sensorineural hearing loss in the right ear; the left ear has normal hearing. An auditory brainstem response (ABR) is abnormal for the right ear; it is normal for the left ear. »» »»

What is the most likely neuroanatomic site of disease and diagnosis? What is the next diagnostic step?

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ANSWERS TO CASE 52: Meningioma of the Acoustic Nerve Summary: A 43-year-old woman has a history of headache, right-sided hearing loss, and right-sided facial paralysis of 1-month duration. The physical examination and ABR tests indicate a sensorineural hearing loss of the right side. šš

šš

Most likely neuroanatomic etiology and diagnosis: Cerebellopontine angle (CPA) tumor, with the most common tumors being acoustic neuroma and meningioma Next diagnostic step: Magnetic resonance imaging (MRI) with gadolinium

ANALYSIS Objectives 1. Learn the most common tumors that occur in the CPA. 2. Learn the most common imaging features of these tumors. 3. Learn the available treatment options for these tumors.

Considerations This 43-year-old woman has symptoms of progressive right-sided hearing loss, facial paralysis, and headache. She also has symptoms of imbalance and disequilibrium. The most common cause of facial nerve paralysis is Bell palsy; however, this patient also has hearing loss, balance issues, and headache, which point to a central rather than peripheral disorder. The ABR confirms an abnormal cranial nerve VIII (or cochlear) function. Patients who present with the combination of hearing loss and facial paralysis demand evaluation by diagnostic imaging to assess for a central nervous system lesion. This patient’s symptoms strongly suggest an abnormality in the CPA. Modern imaging techniques have revolutionized the evaluation of this area. MRI with contrast can readily differentiate the various pathologic processes that occur in this area (Table 52–1).

APPROACH TO: Cerebellopontine Angle Tumors DEFINITIONS ACOUSTIC NEUROMA: A benign tumor that is derived from Schwann cells and arise from the vestibular portion of the acoustic nerve. This is the most common tumor found in the CPA. AUDITORY BRAINSTEM RESPONSE (ABR): An electrical-evoked hearing test. In this test, electrodes are placed on each ear lobe and on the forehead. A stimulus

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sound (either a click or tone burst) is delivered into the test ear at a specified loudness; an attached computer captures the electrical brain activity that results from this stimulus and filters out background noise. BELL PALSY: Idiopathic facial weakness. CEREBELLOPONTINE ANGLE (CPA): The anatomic space between the cerebellum, pons, and temporal bone. This space contains cranial nerves V through XI. CONDUCTIVE HEARING LOSS: A form of hearing loss that results from a defect in the sound-collecting mechanism of the ear. These structures include the ear canal, tympanic membrane, middle ear, and ossicles. MENINGIOMA: Common benign extra-axial tumors of the coverings of the brain. The cell of origin is probably from arachnoid villi. Several histologic subtypes are described: syncytial, transitional, fibroblastic, angioblastic, and malignant. SENSORINEURAL HEARING LOSS: A form of hearing loss that results from an abnormality in the cochlea or auditory nerve.

CLINICAL APPROACH Tumors of the Cerebellopontine Angle CPA tumors are the most common neoplasms of the posterior fossa and account for 7% to 10% of intracranial tumors. Most CPA tumors are benign, with the most common being acoustic neuromas and vascular malformations. The most common nonacoustic CPA neoplasms are meningiomas and epidermoid tumors.

Acoustic Neuromas Acoustic neuromas are intracranial tumors arising from the Schwann cell sheath involving either the vestibular or cochlear nerve. These comprise about 80% of the tumors in the CPA. They are diagnosed in about 1 per 100,000 people with a rising incidence, perhaps because of the expanded use of MRI. Autopsy studies show a higher incidence of asymptomatic schwannomas. Although a small fraction of affected individuals has neurofibromatosis, the vast majority have no risk factors. Most acoustic neuromas are slow growing, although a small number will increase in size rapidly. Unilateral hearing loss is the most common presentation, although vertigo, headaches, and facial nerve palsy are also seen.

Meningiomas Meningiomas are usually benign tumors of mesodermal origin and are attached to the dura. These commonly are located along the sagittal sinus, over the cerebral convexities, and in the CPA. Grossly, they are gray, sharply demarcated, and firm. Microscopically, the cells are uniform with round or elongated nuclei and have a characteristic tendency to whorl around each other. Meningiomas tend to affect women more than men in the middle age. Most meningiomas are asymptomatic and are discovered incidentally on neuroimaging. Clinical presentation of meningioma varies due to the location of the tumor. If it is located in optic pathway, visual field

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defects are noted. CPA tumor locations are generally associated with sensorineural hearing loss. Spinal meningiomas can present with extremity weakness. MRI usually reveals a dural-based mass with dense homogeneous contrast enhancement. Differentials for such appearance on MRI can be lymphoma, tuberculoma, metastatic carcinoma, inflammatory lesions such as sarcoidosis and granulomatosis. Surgical therapy is optimal, and complete resection is curative. For lesions not amenable to surgery, local or stereotactic radiotherapy can ameliorate symptoms. Small asymptomatic lesions in older patients can be observed. Rarely, meningiomas can be more aggressive and have malignant potential; these tumors tend to have higher mitosis and cellular and nuclear atypia. Surgical therapy followed by radiotherapy should be used in these instances. Epidermoid tumor: A benign tumor composed of squamous epithelial elements thought to arise from congenital rests. Glomus tumor: The common name for paraganglioma. This highly vascular tumor arises from neuroepithelial cells. These tumors are further named by the structures that they arise from: glomus tympanicum (middle ear), glomus jugulare (jugular vein), glomus vagale (vagus nerve), and carotid body tumor (carotid artery). A rule of 10% is associated with this tumor: approximately 10% of these tumors produce a catecholamine-like substance, approximately 10% of these tumors are bilateral, approximately 10% are familial, and approximately 10% are malignant (ie, potential to metastasize).

APPROACH TO: Facial Paralysis Facial paralysis is a relatively common disorder. In its most common presentation, facial paralysis occurs as a sudden sporadic cranial mononeuropathy. It is not associated with hearing loss; rather, it might be associated with hyperacusis. This form of facial paralysis, also called Bell palsy, is not associated with middle ear disease, parotid tumor, Lyme disease, or any other known cause of facial paralysis. Essentially, Bell palsy is a diagnosis of exclusion. Generally, a pointed history and detailed physical examination will eliminate most of the differential diagnoses. Likewise, the various causes of hearing loss can be eliminated by a careful physical examination. Disease processes, such as otitis media, cholesteatoma, and otosclerosis, can be eliminated by careful history and physical examination with tuning fork tests. However, to know the type and degree of hearing loss, an audiogram is necessary. Although it requires patient’s cooperation, the audiogram will give the clinician a very accurate measure of the patient’s hearing level. The audiogram can distinguish between sensorineural and conductive hearing loss. Occasionally, patients have mixed hearing loss, a combination of conductive and sensorineural losses in a single ear. Furthermore, the audiogram can give a clue regarding the presence of retrocochlear hearing loss or hearing loss caused by diseases proximal to the cochlea.

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Tests that might indicate retrocochlear pathology include speech discrimination, acoustic reflexes, and reflex decay.

DIAGNOSIS Sensorineural hearing loss can be further evaluated by ABR. This test measures the electrical activity within the auditory pathway, and as such, this test helps to evaluate retrocochlear causes of hearing loss. The ABR has five waves that are numbered I through V, and these are correlated to major neural connections in the auditory pathway. These waves have expected morphologies and occur at predictable latencies. Waves that are absent or delayed are indicative of pathology at that point in the auditory pathway. The interwave latencies (such as I-III, III-V, or I-V) can be compared to the opposite side or to standard norms. Abnormalities on ABR need to be further evaluated by imaging studies. MRI provides excellent definition of the structures within the posterior fossa. Gadolinium contrast allows additional differentiation of various pathologies. Additionally, newer technology, such as fat suppression and diffusion-weighted imaging, can help to identify pathology (Figure 52–1). The MRI appearances of the most common tumors in the posterior fossa are indicated in Table 52–1. Although MRI with gadolinium contrast gives excellent resolution for the brain, nerve, and soft tissues, computed tomography (CT) scanning is necessary for bony imaging. Often, both imaging modalities are combined to understand the full extent of the disease process within the skull base.

Figure 52–1.  Post-gadolinium T1 MRI with fat suppression. CPA meningioma. (Reproduced, with permission, from Lalwani A. Current Diagnosis and Treatment in Otolaryngology: Head & Neck Surgery. 2nd ed. New York, NY: McGraw-Hill; 2008:154.)

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Table 52–1  •  MRI CHARACTERISTICS OF COMMON PATHOLOGY IN THE CEREBELLOPONTINE ANGLE Tumor Type

Gadolinium T1 Appearancea T2 Appearancea Enhancement Special Features

Schwannoma

Isointense

Intermediate

++++

Can be cystic, inside or centered on the IAC

Meningioma

Isointense or slightly hypointense

Hyperintense to hypointense

+++

Dural tail, eccentric to the IAC, can have calcification

Epidermoid

Hypointense

Isointense

None

Internal stranding

Glomus tumor (paraganglioma)

Hypointense

Isointense

+++

“Salt and pepper appearance”

Arachnoid cyst

Hypointense

Hyperintense

None

Homogenous contents

Lipoma

Hyperintense

Hypointense

None

Intensity disappears with fat suppression

Cholesterol cysts Hyperintense

Hyperintense

None

Located within the petrous apex

Intensity relative to brain. +++, moderate enhancement; ++++, maximal enhancement; IAC, internal auditory canal; MRI, magnetic resonance imaging. Commonly used pneumonic for CPA is AMEN: A: acoustic neuroma (~ 80% of the CPA tumor) M: meningioma (~ 10% of the CPA tumor) E: ependymoma (~ 5% of the CPA tumor) N: neuroepithelial cyst (~ 5% arachnoid/epidermoid) a

TREATMENT A treatment plan must be created once a CPA tumor is diagnosed. Many factors must be considered when approaching these tumors. The patient’s age, overall health status, tumor size and location, degree of hearing loss, and other neurologic signs should be taken into account. The various available treatment options must be discussed with the patient; the final decision of treatment course must be decided between the patient and the physician. At least three options should be considered in managing tumors in the posterior fossa: observation and serial imaging, stereotactic radiosurgery, or conventional surgery. Some of these options might be unavailable or unwise for certain tumor types or tumor size. Clearly, the patient who has a large tumor that produces brainstem compression or obstructive hydrocephalus should not be observed over time and serially imaged. These findings demand immediate attention. Surgery can provide several benefits to the patient. Removal of the tumor allows for final pathologic diagnosis, might correct neurologic deficits, and might prevent further complications caused by continued tumor growth. These benefits can come

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at a price of new neurologic deficits, meningitis, infection, stroke, facial palsy, or even death. The patient’s underlying health status must be considered because these surgical procedures are often lengthy. Patients with a low overall health status might not tolerate such a procedure. A relatively new (although >20 years’ experience) type of therapy involves the use of a directed, focus radiation beam to the tumor; this is called gamma knife radiation. Several different proprietary devices have been developed to destroy or at least prevent growth of these types of tumors. The experience with stereotactic radiotherapy is probably greatest with acoustic neuroma because it is the most common mass found in the CPA. Stereotactic radiotherapy has been found to be very effective at managing small- to medium-sized tumors (up to 3 cm). In these tumors, the complication rate for stereotactic radiotherapy is at least as low as that from conventional surgery; and with this type of therapy, a long hospital stay or recovery period is not required. Using the currently recommended marginal dose of 12 to 13 Gray (Gy), longterm reported outcomes include not only tumor control rates of 92% to 100% but also functional preservation of the trigeminal and facial nerves, with values of 92% to 100% and 94% to 100%, respectively. Nonetheless, hearing preservation remains in the range of 32% to 81%. The disadvantage with stereotactic radiotherapy is the potential for continued growth, and this growth does occur in a significant number of patients. Unfortunately, surgery following stereotactic radiotherapy is technically more difficult, and surgical results are not as successful as from surgery alone. Stereotactic radiotherapy has its limitations. It is not useful for certain tumor types (meningiomas and epidermoids). Stereotactic radiotherapy cannot provide pathologic specimens for study, and it should never be used when the pathologic diagnosis is in doubt.

CASE CORRELATION šš

See also Case 35 (Facial Paralysis)

COMPREHENSION QUESTIONS 52.1 A 45-year-old painter is found to have ataxia. An MRI scan shows a tumor of the CPA. What is the most likely tumor in this location? A. Epidermoid tumor B. Paraganglioma C. Meningioma D. Acoustic neuroma E. Lipoma

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52.2 What is the best test to elucidate the etiology of unilateral sensorineural hearing loss? A. Otoacoustic emissions B. ABR C. MRI of the internal auditory canals with gadolinium D. Electronystagmography E. Detailed physical examination 52.3 What is the most common cause of unilateral facial paralysis? A. Idiopathic B. Otitis media C. Parotid malignancy D. Acoustic neuroma E. Lyme disease

ANSWERS 52.1 D. By far, the most common tumor in the CPA is the acoustic neuroma, comprising about 80% of the CPA neoplasms. This patient has the symptom of ataxia, which is less common than hearing loss; however, his occupation as a painter may cause a higher threshold for seeking medical attention for balance and coordination issues. 52. 2 C. Although ABR is used to evaluate unilateral sensorineural hearing loss, its limitation is a lack of specificity for diagnosis. Otoacoustic emissions can measure the degree of hearing loss, but it cannot shed light on a pathologic cause. Electronystagmography is a test that measures the vestibular ocular reflex. Detailed physical examination is an important prerequisite before any diagnostic tests are ordered. Only MRI with contrast enhancement can elucidate the cause of unilateral sensorineural hearing loss. 52.3 A. The most common form of facial paralysis is idiopathic. It is also called Bell palsy. Recent evidence suggests that the cause of Bell palsy is probably recrudescence of herpes simplex virus. Every patient should have a careful examination to rule out other causes of facial paralysis, such as those diagnoses listed. Where indicated, this examination might require an audiogram or MRI.

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CLINICAL PEARLS »»

Idiopathic facial paralysis (also called Bell palsy) is the most common cause of unilateral facial weakness.

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Bell palsy is a diagnosis of exclusion, and patients with facial paralysis require a careful otologic and cranial nerve examination.

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Patients who present with a complaint related to one cranial nerve require evaluation of all cranial nerves.

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Acoustic neuromas are the most common tumor of the CPA.

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Unilateral sensorineural hearing loss should be further evaluated by MRI with gadolinium contrast.

REFERENCES Fan G, Curtin H. Imaging of the lateral skull base. In: Jackler R, Brackmann D, eds. Neurotology. 2nd ed. Philadelphia, PA: Elsevier; 2004:383-418. Hummel M, Krausgrill C, Perez J, Hagen R, Ernestus RI, Matthies C. Management of vestibular schwannoma: a pilot case series with postoperative ABR monitoring. Clin Neurol Neurosurg. 2016;143:139-143. Lo W, Hovsepian M. Imaging of the cerebellopontine angle. In: Jackler R, Brackmann D, eds. Neurotology. 2nd ed. Philadelphia, PA: Elsevier; 2005:349-382.

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CASE 53 A 59-year-old retired bartender presents to his primary care physician (PCP) complaining of headaches over the past 6 weeks. He has been healthy all of his life and takes no medications. He says the headaches are located primarily over the right frontal and temporal region, and the headaches are described as “dull and aching” in nature. He has experienced occasional nausea but no vomiting with the headaches. The headaches are worse in the morning upon waking. Additionally, he has had difficulty focusing and concentrating on tasks at hand, such as reading the newspaper or playing cards. His wife states that he has been more irritable, moody, and “not himself” for 1 month. There is no history of alcohol abuse or exposure to toxins. He admits to a 30-pack-year smoking history. The review of systems is significant for weight loss and a productive cough. His examination reveals that he is afebrile with a blood pressure of 124/ 72 mm Hg and a heart rate of 78 beats/min. His general examination is normal. He is oriented to person, time, location, and situation, although he becomes upset during the examination. Cranial nerve and sensory examination findings are unremarkable. Motor strength testing is normal except for questionable weakness in the left finger extensors. The deep tendon reflexes are normal except for a Babinski sign present on the left. With ambulation, he has decreased arm swing on the left. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 53: Metastatic Brain Tumor Summary: A 59-year-old previously healthy man presents with a 6-week history of right frontal temporal headaches associated with difficulty concentrating, weight loss, and productive cough. His headaches are often associated with nausea, are dull in nature, and are predominantly present upon waking in the morning. His wife reports he has experienced a mild personality change, and the patient himself recognizes mood disturbances. His examination is notable for decreased arm swing on the left, questionable weakness of the left finger extensors, and a left Babinski sign. šš

šš

šš

Most likely diagnosis: Metastatic brain tumor affecting the right cerebral hemisphere. Next diagnostic step: Magnetic resonance imaging (MRI) of the brain with and without gadolinium and chest x-ray. Next step in therapy: Corticosteroids and anticonvulsants should be started immediately while waiting for surgical evaluation.

ANALYSIS Objectives 1. Know the clinical presentation and diagnostic approach to metastatic brain tumor. 2. Be familiar with the differential diagnosis of metastatic brain tumor. 3. Describe the treatment for metastatic brain tumor.

Considerations This 59-year-old otherwise healthy man with a 30-pack year tobacco history presents with unilateral dull headaches worse upon waking and associated with nausea and personality changes. Additionally, there is a history of difficulty concentrating, weight loss, and cough. His physical examination suggests mild left-sided weakness that is most likely from an upper motor neuron lesion in the right hemisphere, given the left Babinski sign. Based on the history and examination, the most likely diagnosis is a right hemispheric mass lesion. The history of weight loss and cough are concerning for possible primary lung cancer. With this in mind, metastatic lung cancer should be considered. A primary brain tumor is also on the differential. A chest x-ray reveals that he has a large right upper lobe mass lesion highly suggestive of lung cancer. An MRI of the brain shows a right frontal-temporal wellcircumscribed lesion at the gray-white junction with hemorrhage and surrounding edema. Evidence of midline shift or impending herniation should be evaluated. Corticosteroids such as dexamethasone should be initiated, as this reduces cerebral edema and capillary permeability. Anticonvulsant prophylaxis in individuals with

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metastatic tumors who have not experienced a seizure is controversial. Approximately 40% of patients with metastatic brain tumors will experience a seizure. Only 20% of patients with metastatic brain tumors present with seizures as the first symptom. In this particular case, the patient has a hemorrhagic metastatic lesion, which is known to be epileptogenic. Most physicians would begin or at least strongly consider anticonvulsants. Caution should be taken in patients who receive both anticonvulsants and corticosteroids, as the latter can significantly reduce anticonvulsant levels. Neurosurgical consultation should be obtained, as should an oncology consultation.

APPROACH TO: Metastatic Brain Tumors DEFINITIONS METASTATIC BRAIN TUMORS: Tumors that arise from the metastasis of systemic neoplasms to the brain parenchyma. BABINSKI SIGN: Extension of the great toe followed by abduction of the other toes when the lateral sole of the foot is stimulated. Stroking the foot at the heel and moving the stimulus toward the toes elicit this reflex. It is a sensitive and reliable sign of corticospinal tract disease. It is also known as the plantar extensor reflex. The normal plantar reflex is flexor. MIDLINE SHIFT: Movement of a cerebral hemisphere to the contralateral side secondary to intracranial swelling. This can cause compression of the lateral ventricles and contribute to further elevated intracranial pressure. HERNIATION: Downward displacement of the cerebral hemisphere from increased intracranial pressure.

CLINICAL APPROACH Epidemiology Metastatic brain tumors can arise from primary systemic cancers that spread to the leptomeninges, brain parenchyma, calvaria, or dura. Brain metastases are 10 times more common than primary brain tumors. In the United States, roughly 150,000 new cases of metastatic brain tumors are reported each year. Men have a slightly higher incidence than females with a ratio of 1.4:1. Approximately, 66% of metastatic brain tumors involve the parenchyma, with almost 50% of these being a solitary lesion. The most common tumors that metastasize to the brain are listed in Table 53–1, with lung cancer being most common. Tumors metastasize to the brain most commonly by entering the systemic circulation through hematogenous spread. The distribution of tumor parallels arterial blood flow to the brain, with approximately 82% metastasizing supratentorially, 15% spreading to the cerebellum, and 3% affecting the brainstem. Metastatic brain tumors are commonly located at the gray-white junction and arterial

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Table 53–1  •  METASTATIC TUMOR AND FREQUENCY Tumor Type

Cases (%)

Lung cancer

50%

Breast cancer

20%

Melanoma

10%

Unknown primary

10%

Others: thyroid and sarcoma

Unknown

border zones, locations that have narrowed blood vessels that can trap tumor cells. Venous embolization of tumor cells through the vertebral venous plexus of Batson has also been proposed as an alternative route of the spread of pelvic and retroperitoneal tumors.

Clinical Evaluation Clinical features of metastatic brain tumors are varied and depend on their location. Neurologic symptoms occur from direct tumor infiltration, hemorrhage, edema, or even hydrocephalus. Table 53–2 illustrates the most common clinical features of brain metastases. The differential diagnosis for metastatic brain tumors includes brain abscess, demyelinating diseases, radiation necrosis, cerebral vascular accidents, intracranial bleed, and primary brain tumors. Approximately 60% of those without any known primary tumor who present with brain metastasis have a primary lung cancer. Of these, 25% to 30% of non–small cell cancer patients will have brain metastasis. The clinical evaluation in patients with an unknown primary cancer is focused and includes an MRI of the brain with gadolinium. Gadolinium or contrast is critical, as it will show enhancement around the lesions suggestive of vasogenic edema. A chest x-ray followed by a computed tomography (CT) scan of the chest should be Table 53–2  •  CLINICAL FEATURES OF BRAIN TUMORS Clinical Features

Patients Presenting With Features (%)

Headaches are dull and associated with nausea (and often most prominent upon waking) Visual disturbances including blurred vision; unilateral on side of tumor and more commonly associated with posterior fossa metastases

45%-50%

Cognitive impairment including personality changes, mood and memory problems

33%

New-onset seizure is more frequently associated with frontal, temporal, or multiple metastases

10%-20%

Stroke-like syndrome

5%-10%

Papilledema

10% (at time of presentation)

Other nonspecific neurologic findings

20%-40%

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performed since lung cancer is the most common type of cancer to metastasize to the brain. If these studies are unrevealing, an abdominal or pelvic CT scan should be performed. Careful attention should be paid to the prostate, testicles, breasts, and rectum during clinical examination. Stool examination should be performed to evaluate for occult blood as a screening tool to evaluate for gastrointestinal cancers. A positron emission topography (PET) may be helpful in identifying the primary tumor and the degree of metastatic spread. Unfortunately, an MRI of the brain cannot diagnose the type of tumor in patients with an unknown primary malignancy. One exception to this is malignant melanoma, which is typically hyperintense on T1-weighted images and hypointense on T2-weighted images due to either melanin or blood products. A brain biopsy may be necessary if the primary tumor remains elusive. Patients with signs of severe increased intracranial pressure may benefit from surgical decompression.

TREATMENT Treatment with corticosteroids such as dexamethasone is important in reducing intracranial pressure and edema. Commonly, a dose of 10 mg of dexamethasone, either orally or intravenously, followed by 4 mg every 6 hours, is given. As previously discussed, it is controversial as to whether anticonvulsants are necessary in patients who have not experienced seizures. However, individuals who have had a seizure warrant anticonvulsant therapy. The decision to pursue surgical resection is dependent on several variables, such as the number of brain metastases, the location, the size, the likelihood of response to treatment, and the patient’s overall health status. The most important factor when considering surgery is the tumor burden located outside the brain. Improved survival and quality of life have been shown in patients with single lesions when they have been treated with whole brain radiotherapy and surgery. Factors that portend a better response to surgical and radiotherapy include presentation at a younger age, absence of extracranial disease, and later than early development of brain metastasis. Radiation therapy has been shown to decrease the mortality from neurologic dysfunction. The most common regimen is given over a period of 2 weeks using 30 Gy in 10 fractions. Radiation therapy improves neurologic symptoms in 50% to 93% of patients. A Cochrane review of several studies suggests that the combination of radiotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non–small cell lung cancer improved overall survival. Complications from radiotherapy include brain necrosis, brain atrophy, cognitive deterioration, leukoencephalopathy, and neuroendocrine dysfunction. Stereotactic radiation via the gamma knife, linear particle accelerators, or charged particles can also be used. This has been found to decrease toxicity to healthy tissue and minimize side effects. Stereotactic radiation is often used in tumors that are surgically inaccessible; complications from stereotactic radiation include seizures, headaches, nausea, hemorrhage, and radiation necrosis. For the most part, chemotherapy is not used for brain metastasis due to challenges in delivering the agents across the blood-brain barrier.

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PROGNOSIS Favorable prognostic factors include age less than 60, two or less brain metastases, good baseline function, and successful surgical resection. Individuals with single brain metastasis who receive brain radiation plus surgery have a median survival of 10 to 16 months. Patients who have metastasis to infratentorial regions of the brain carry a worse prognosis than those with supratentorial metastasis.

COMPREHENSION QUESTIONS 53.1 A 56-year-old man presents to the emergency department (ED) with confusion and motor deficits. CT imaging shows multiple lesions to the brain. A metastatic tumor is suspected. Which of the following is the most common primary tumor causing the brain metastases in this patient? A. Breast B. Melanoma C. Renal D. Lung E. Thyroid 53.2 A 50-year-old man is noted to have some symptoms suggestive of a brain tumor. Which of the following is the most common symptom of brain tumors? A. Seizures B. Headaches C. Papilledema D. Personality changes E. Ataxia 53.3 A 45-year-old man with a history of smoking presents after experiencing a generalized tonic-clonic seizure. He has been experiencing dull left-sided headaches over the past 2 months. His examination reveals hyperreflexia on the right with mild weakness of the right iliopsoas and finger extensor muscles. The MRI of the brain shows a large 7- × 10-cm lesion over the left frontal region with associated midline shift. A chest x-ray shows a left lower lobe mass. What is the next step? A. Consult neurosurgery for immediate brain biopsy and debulking. B. Start dexamethasone at a dose of 10 mg followed by 4 mg every 6 hours. Concomitantly begin an anticonvulsant medication. C. Start dexamethasone at a dose of 100 mg followed by 4 mg every 6 hours and hold off on starting anticonvulsant medication. D. Consult the oncology service to assist you in deciding on chemotherapy. E. Start whole brain radiation therapy.

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ANSWERS 53.1 D. This is a 56-year-old man with multiple metastases to the brain. We are not given any other risk factors or information. Lung cancer is the most common tumor metastasizing to the brain, accounting for approximately 50% of all cases. 53.2 B. Headache is the most commonly found symptom associated with brain tumors and is found in approximately half of cases. About a third of affected individuals will have cognitive loss such as memory loss, language disorder, or seizures. Nausea and vomiting and papilledema are late findings only in about 10% to 12% of cases. 53.3 B. Patients with brain metastasis that present with seizures should be started on anticonvulsant therapy in addition to dexamethasone. In this particular case, there is associated midline shift that warrants immediate management.

CLINICAL PEARLS »»

Metastatic tumors account for the majority of brain tumors in adults.

»»

Enhancing brain lesions on MRI located at the gray-white junction are likely to be metastatic brain tumors.

»»

The most common malignancy to metastasize to the brain is lung, followed by breast cancer.

»»

Patients who present with new-onset headaches, personality changes, and mood disorders should be evaluated for an intracranial structural lesion, such as central nervous system (CNS) metastases.

REFERENCES Jiang T, Min W, Li Y, Yue Z, Wu C, Zhou C. Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis. Cancer Med. 2016;5(6):1055-1065. Nathoo N, Toms SA, Barnett GH. Metastases to the brain: current management. Expert Rev Neurother. 2004;4(4):633-640. Sawaya R, Ligon BL, Bindal RK. Management of metastatic brain tumors. Ann Surg Oncol. 1994; 1(2):169-178.

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CASE 54 A 2-day-old full-term infant is seen in the intermediate care nursery for evaluation of generalized hypotonia. He was born to a 25-year-old G2 P2 mother, who received adequate prenatal care during an uncomplicated pregnancy. However, the mother notes that, in retrospect, she felt much less in utero movement with this baby than with her prior pregnancy. His clinical course thus far has been significant for poor feeding with inadequate sucking upon attempts to breastor bottle-feed. On examination, the patient appears bright, alert, and attentive to visual and auditory stimuli. His respiratory effort seems adequate, but his cry is somewhat muted and weak. He is lying supine with his arms extended, hips abducted, and knees somewhat flexed. There is paucity of spontaneous movement and, upon stimulation, he does not seem to have antigravity strength. He has significant axial and appendicular hypotonia as well as diffuse hyporeflexia. Cranial nerve examination is significant for normal horizontal extraocular movements with fibrillations of the tongue. His hips readily dislocate bilaterally. »» »» »»

What is the most likely diagnosis? What is the next diagnostic step? What is the next step in therapy?

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ANSWERS TO CASE 54: Spinal Muscular Atrophy Type 1 Summary: A 2-day-old full-term infant, product of an uncomplicated pregnancy, has profound hypotonia and weakness. His mother noted decreased in utero movements compared to her prior pregnancies. In addition to hypotonia and weakness, the patient’s examination is significant for an alert and attentive sensorium, a weak cry, congenital hip dislocations bilaterally, diffuse hyporeflexia, normal extraocular muscles, and tongue fibrillations. šš šš

šš

Most likely diagnosis: Spinal muscular atrophy (SMA) type 1 Next diagnostic step: Molecular testing for survival motor neuron 1 (SMN1) gene Next step in therapy: Supportive therapy including respiratory support, physical and occupational therapy, a discussion of prognosis, and consideration of genetic counseling for the parents

ANALYSIS Objectives 1. Describe the typical clinical presentation of SMA type 1. 2. State the underlying pathogenesis of SMA type 1. 3. Describe a diagnostic approach to hypotonic infants. 4. Discuss newly approved treatment for SMA I.

Considerations This newborn is profoundly hypotonic and weak yet appears alert and attentive. His examination reveals multiple lower motor neuron findings: hypotonia, weakness, hyporeflexia, and tongue fibrillations. Taken together, this constellation suggests a peripheral etiology rather than a central or combined etiology, as discussed in the following text. Congenital hip dislocations suggest in utero hypotonia, as development of the acetabulum depends on firm application of the femoral head. Similarly, paucity of in utero movement suggests fetal weakness. Poor feeding, tongue fibrillations, and a weak cry suggest involvement of bulbar and respiratory musculature. Given these findings, the most likely diagnosis is SMA type 1. This disorder will be briefly presented, followed by a discussion of the general approach to hypotonic infants—the so-called “floppy baby.”

Spinal Muscular Atrophy Type 1 During in utero development of the spinal cord there is a relative overproduction of motor neurons, which are subsequently winnowed down through a process of programmed cell death. In SMA type 1, this process goes awry and too many cells are pruned, resulting in an insufficient number of these motor neuron cells. SMA is

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therefore a pure motor neuron disorder characterized by lower motor neuron signs such as hypotonia, weakness, hyporeflexia, and fibrillations. Since this process does not affect the cerebral cortex or subcortical structures, patients appear alert and attentive. Interestingly, although bulbar and respiratory muscles are affected, extraocular muscles are largely spared. While the infantile form of SMA (type 1) is most common and severe, there are also less severe forms that present later in infancy or early childhood (types 2 and 3), as well as an adult-onset form (SMA 4). Mutation or deletion of the SMN1 gene causes the vast majority of cases of SMA. The most common mutations are readily detected with commercially available molecular genetic testing with targeted mutation analysis. However, point mutations require gene sequencing; a reasonable second step in diagnosis should target mutation analysis and does not reveal the underlying genetic cause in an otherwise typical case. Ancillary testing such as electromyography (EMG) and, particularly, muscle biopsy are much less commonly used given the availability of genetic testing. The prognosis for SMA type 1 has been generally quite poor, with most patients dying in the first year of life, though there are reports of longer-term survivors. The presence of a virtually identical gene—SMN2—contributes to the clinical variability in patients with SMA. Management focuses principally on respiratory and nutritional support as well as avoidance of contractures. However, with the landmark approval of the targeted gene therapy, nusinersen, the natural history of the most severe infantile form is now characterized by increased survival and children achieving motor milestones, which would have never been possible.

APPROACH TO: Infantile Hypotonia When supine, hypotonic neonates generally lack the normal flexed posture of the arms and legs and instead will have their arms extended at their sides with their legs abducted at the hip (Figure 54–1). There is often a history during pregnancy of decreased fetal movements and polyhydramnios due to decreased fetal swallowing of amniotic fluid. Delivery may be prolonged and difficult due to abnormal fetal positioning as well as decreased fetal movement. Because of perinatal difficulties, many patients may manifest initial neonatal depression, regardless of the cause of their hypotonia. As discussed in the following text, the patient’s level of alertness is an important clue to localization, but it must be interpreted in light of this caveat. Severe hypotonia may be associated with congenital contractures (arthrogryposis) or excessive joint flexibility. If weakness is prominent, poor feeding and respiratory difficulties may also be seen. Involvement or sparing of bulbar musculature is an important clue to the underlying localization. For example, normal facial strength with profound appendicular weakness suggests a possible spinal cord process. However, as in the case of SMA, bulbar involvement may be incomplete. Dysmorphic features and involvement of other organ systems suggest a chromosomal abnormality and are therefore important to look for on examination. Developmental reflexes are important to assess as they may help distinguish between cerebral and peripheral causes. The Moro reflex is elicited by rapid extension of the neck relative to the

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Hypotonia (decreased muscle tone)

Figure 54–1.  An infant demonstrating hypotonia with draping over the examiner’s hand when held in ventral suspension. Normally the head will be kept in the same plane as the trunk and the limbs will be flexed. Head control may be poor or absent, with the head falling backward or to the side with elevation of infant’s body.

trunk and is characterized by initial abduction and extension of the arms with subsequent adduction and flexion. The asymmetric tonic neck reflex is elicited by turning the head to the side, which results in extension of the arm and leg on the side to which the head is turned with flexion of the arm and leg on the opposite side. Initial categorization into a cerebral, spinal, peripheral, or combined localization helps to narrow down the protean causes of infantile hypotonia, thereby focusing the differential diagnosis and evaluation. Cerebral hypotonia is generally seen in association with other cortical and subcortical findings such as alteration of awareness and attentiveness and epileptic seizures or subcortical myoclonus. On examination, the patient’s tone is likely to be disproportionately reduced as compared to the patient’s strength. The Moro and tonic neck reflexes will likely be present and—in the latter case—may be obligate (ie, the patient’s extended arm remains extended in an obligate fashion until the head is returned to the neutral position). Cerebral causes of infantile hypotonia include chromosomal disorders such as Prader-Willi syndrome, inborn errors of metabolism such as Zellweger syndrome, cerebral dysgenesis such as the various forms of lissencephaly, and cerebral injury as in hypoxic-ischemic encephalopathy. Common peripheral causes of hypotonia include motor neuron disorders (such as SMA), congenital neuropathies or myopathies, muscular dystrophies, neuromuscular junction disorders, and neurometabolic conditions such as mitochondrial disease. In contrast to cerebral causes, peripheral etiologies tend to produce proportionate weakness and hypotonia as well as lower motor neuron findings as described above.

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Also, as in this case, the patient’s sensorium tends to be unaffected unless there is a superimposed secondary encephalopathy caused by, for example, initial respiratory depression and hypoxia. Given the significant weakness, postural reflexes such as the Moro and tonic neck reflex are difficult to elicit (proportionate to the degree of weakness) and, if present, are not obligate in nature. Involvement of other organ systems may be seen (such as cardiac muscle in some congenital myopathies). Ancillary testing may be helpful to further localize a peripheral process to the motor neuron, nerve, neuromuscular junction, or muscle. As with SMA1, a typical clinical presentation may lead to confirmatory genetic testing. If the history and examination do not suggest a particular diagnosis, EMG and nerve conduction velocity (NCV) testing may be useful. Serum creatine kinase may be significantly elevated in some congenital myopathies or muscular dystrophies. The use of muscle biopsy and nerve biopsy has become much less common given the availability of genetic tests for many conditions. However, these tests are still useful when the diagnosis remains unclear. Isolated myelopathies are relatively uncommon causes of infantile hypotonia— although the spinal cord may often be affected in conjunction with cortical and subcortical structures. As mentioned previously, significant preservation of bulbar function in a patient with hypotonia of the arms and/or legs and trunk strongly suggests a spinal cord localization. The most common cause of a spinal cord lesion resulting in hypotonia would be an injury to the cord during the process of delivery. Finally, some processes may involve both central and peripheral structures, resulting in a combined phenotype. This may be seen in both genetic syndromes such as mitochondrial disorders, as well as in acquired conditions such as profound hypoxic-ischemic encephalopathy.

COMPREHENSION QUESTIONS 54.1 Which of the following clinical findings would be typically seen in SMA type 1? A. Encephalopathy B. Obligate tonic neck reflex C. Ophthalmoplegia D. Preserved deep tendon reflexes E. Tongue fibrillations 54.2 Which of the following pathogenic processes is responsible for SMA type 1? A. Abnormality of nicotinic acetylcholine receptor function at the neuromuscular junction B. Absence of a protein connecting the muscle cell membrane with the sliding filaments C. Accumulation of abnormal protein products in skeletal muscle cells D. Excessive programmed cell death of spinal motor neurons E. Failure of spinal motor neuron axons to extend out of the spinal cord

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54.3 Which of the following findings would most specifically suggest a cerebral cause of a patient’s hypotonia? A. Areflexia B. Epileptic seizures C. Preservation of bulbar function D. Visual attentiveness E. Weakness

ANSWERS 54.1 E. Tongue fibrillations are commonly seen in SMA type 1. These patients also have preserved eye movements, normal sensorium, hyporeflexia, and absence of postural reflexes—all consistent with a peripheral cause of hypotonia. 54.2 D. SMA is caused by excessive programmed cell death of spinal motor neurons, resulting in a pure lower motor neuron disorder. 54.3 B. Epileptic seizures, being a cortical finding, strongly suggest a cerebral cause of hypotonia. Areflexia suggests a peripheral cause. Weakness may be seen in association with any cause of hypotonia but is generally more profound with peripheral causes. Visual attentiveness would suggest that the cortex is intact, while preservation of bulbar function would suggest a spinal cord process.

CLINICAL PEARLS »»

An awake, attentive infant with significant weakness and hypotonia likely has a peripheral process.

»»

Seizures, myoclonus, and altered sensorium strongly suggest cerebral involvement.

»»

Always evaluate respiratory function, ability to protect the airway, and feeding in hypotonic infants.

REFERENCES Bodensteiner JB. The evaluation of the hypotonic infant. Semin Pediatr Neurol. 2008;15(1):10-20. Fenichel G. The hypotonic infant. In: Clinical Pediatric Neurology: A Signs and Symptoms Approach. Philadelphia, PA: Saunders Elsevier; 2009:153-176. Prasad AN, Prasad C. Genetic evaluation of the floppy infant. Semin Fetal Neonatal Med. 2011;16(2): 99-108. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017. Tulinius M, Oldfors A. Neonatal muscular manifestations in mitochondrial disorders. Semin Fetal Neonatal Med. 2011;16(4):229-235. Wee CD, Kong L, Sumner CJ. The genetics of spinal muscular atrophies. Curr Opin Neurol. 2010;23(5):450-458.

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SECTION III

Review Questions

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Review Question Notes: The following are strategically designed review questions to assess whether the student is able to integrate the information presented in the cases. The explanations to the answer choices describe the rationale, including which cases are relevant.

REVIEW QUESTIONS   R-1. A 62-year-old man is noted to have weight loss, cough, and night sweats of 1-month duration. He also complains of weakness of the legs, especially difficulty climbing stairs, and some double vision. On examination, the lower extremity strength is 3/5 bilaterally. Which of the following is the most likely mechanism for his neurologic condition? A. Acetylcholine receptor antibodies B. Decreased levels of serum calcium C. Inhibition acetylcholine degradation D. Voltage-gated calcium channel antibodies   R-2. A 56-year-old woman is noted by her daughter to be moving slowly, walking with a shuffling gait, and having a noticeable tremor. On examination, the patient shows little facial expression, and her extremities have some rigidity to passive movement. Which of the following medications should be considered as initial therapy in this case? A. Coenzyme Q10 B. Dopamine agonists C. Levodopa D. Monoamine oxidase B inhibitors E. Catechol-o-methyl transferase inhibitor   R-3. A 31-year-old woman is being evaluated for abnormal uterine bleeding. She had a T4 spinal cord transection 4 years previously due to a motor vehicle accident and is paraplegic. During the insertion of the vaginal speculum, the patient developed the acute onset of a severe headache and flushing of her face. Her blood pressure is noted to be 180/110 mm Hg and heart rate (HR) is 140 beats/min. Which of the following is the most likely diagnosis? A. Autonomic dysreflexia B. Allergic reaction to lubricant C. Preeclampsia D. Panic attack

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  R-4. A 58-year-old man is noted to have the acute onset of aphasia, and right arm and leg weakness. On examination, he is found to have swelling and redness of the right lower extremity. If the neurologic problems occur due to the condition in his leg, which of the following is most likely present in this patient? A. Atrial fibrillation B. Berry aneurysm of the brain C. Carotid bruit D. Atrial septal defect   R-5. A 43-year-old man is being evaluated by his physician for multiple syncopal episodes. He notes that he passes out when he is shaving, and also when he turns his head while wearing a tight collared shirt. He has no past medical problems. His vital signs are normal. Which of the following is the most likely pathophysiology of his syncope? A. Baroreceptor hypersensitivity B. Sinus node dysfunction C. Atrioventricular (AV) nodal heart block D. AV nodal reentry E. Ventricular arrhythmia   R-6. A 62-year-old woman is being evaluated by her physician for problems with concentration and memory, and problems losing urine. On examination, she is found to have a shuffling gait. Computed tomography (CT) imaging shows dilated cerebral ventricles and no mass effect. Which of the following is the most likely diagnosis? A. Alzheimer dementia B. Creutzfeldt-Jakob disease C. Lewy body dementia D. Normal pressure hydrocephalus   R-7. A 24-year-old man complains of photophobia, headache, and neck stiffness. On examination, his temperature is 100.8°F. He appears lethargic and has nuchal rigidity. There is a normal neurologic examination otherwise. If the patient has herpes simplex virus (HSV) meningoencephalitis, which of the following cerebrospinal fluid (CSF) findings would be expected?  

A

WBC/mL

Type of Cells

CSF Glucose

CSF Protein (mg/dL)

Erythrocytes/mm3

2000

Neutrophils

Low

300

5

B

50

Lymphocytes

Normal

50

2

C

260

Lymphocytes

Normal

80

120

D

500

Lymphocytes

Low

140

0

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See also Case 25 (Acute Disseminated Encephalomyelitis) and Case 26 (Viral Meningitis)

  R-8. A 45-year-old woman complains of right hand pain. She states that she is dropping items such as mugs and her phone. She complains of numbness of the thumb and index finger. On examination, she has weakness of opposition of the right thumb. Which of the following is the most likely mechanism of her condition? A. Cerebral white matter disease B. Plexopathy C. Spinal cord anterior horn degeneration D. Peripheral nerve entrapment   R-9. A 4-year-old boy is brought into the pediatrician’s office due to not speaking much over the past 2 months. The child had met most developmental milestones until recently and has stopped interacting with other children or even family members. On examination, the child is sitting in the middle of the room and does not respond to his name or questions. He is playing with a toy car. When his mother attempts to touch him, he shrugs away and does not look at her. Which of the following is the most likely diagnosis? A. Autism spectrum disorder B. Down syndrome C. Impaired hearing D. Fetal alcohol syndrome R-10. A 9-month-old male infant is brought into the emergency department due to fever and seizures. The seizure was described as thrashing arms and legs and lasting for 2 minutes. The infant is noted to have a temperature of 101.8°F rectally. There is no nuchal rigidity and no neurologic abnormalities. Which of the following is the best therapy for this patient? A. Antipyretics B. CT imaging C. Lumbar puncture (LP) D. Magnetic resonance imaging (MRI)

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ANSWERS  R-1. D. This patient likely has lung cancer and weakness due to Lambert-Eaton syndrome (LES), which is caused by antibodies to presynaptic voltage-gated calcium channels resulting in a decrease release of acetylcholine. In this case, it is a paraneoplastic syndrome, similar to myasthenia gravis (MG). However, as opposed to MG, LES is associated with more lower extremity weakness. Answer A would be the mechanism of MG, in which upper extremity and eye weakness is prominent. Low levels of calcium can induce weakness, but it is usually generalized with muscle twitching. Answer C would be the mechanism by which pyridostigmine delays degradation of acetylcholine and improves weakness in MG and LEMS patients.

See also Case 3 (NMDA Encephalitis), Case 27 (Infantile Botulism), and Case 36 (Ptosis [Myasthenia Gravis]).

 R-2. D. This patient likely has Parkinson disease (PD). Currently, there are no known medications that impact clinical disease process. Thus, medications are prescribed as symptomatic therapy. Thus, the medications are considered to be symptomatic. Levodopa slows down the onset of symptoms, although with long-term use, motor fluctuation and dyskinesias often develop. Monoamine oxidase (MAO) B inhibitors have better side-effect profiles and are useful early in the disease and in younger patients with milder disease, since they have only a modest effect on the motor symptoms of PD. COMT inhibitors extend the benefit of levodopa by reducing “off ” symptoms between doses. Thus, COMT inhibitors as a monotherapy, have no effect on Parkinson’s symptoms.

See also Case 4 (Parkinson Disease), Case 1 (Essential Tremor), and Case 2 (Huntington Disease).

 R-3. A. In a patient who has a spinal cord lesion above T6, stimulation below the level (such as pelvic examination, rectal examination, full bladder) can lead to an uninhibited sympathetic discharge, so-called autonomic dysreflexia. Because of the spinal cord discontinuity, parasympathetic stimulation (inhibiting the sympathetic discharge) cannot occur. The presentation is the acute onset of headache, nasal congestion, flushing or goose bumps above the level of the lesion, profuse sweating, and dangerously elevated blood pressure and HR. This complication can be life-threatening. An allergic reaction to lubricant would lead to hives, itching, and hypotension. There is no indication of pregnancy or retention of fetal tissue and would not present acutely in association with pelvic examination. A panic attack would typically present as hyperventilation, anxiety, and sweating, but the BP would not be so elevated.

See also Case 7 (Spinal Cord Injury, Traumatic).

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 R-4. D. This is a patient with a probable cerebrovascular accident (or transient ischemic attack [TIA]). These are typically ischemic events, although they can be hemorrhagic, or more rarely embolic. Embolic strokes can be caused by arterial atherosclerotic plaques such as those involving the carotid artery, or thrombi within the left atrium (atrial fibrillation). This patient has what appears to be a deep vein thrombosis (DVT) (venous system). Embolization of the thrombus would cause pulmonary emboli unless the patient has a right-to-left shunt, such as an atrial septal defect. Such an intracardiac defect can allow a venous thrombus to enter the systemic circulation and cause a stroke.

See also Case 11 (Acute Cerebral Infarct), Case 12 (Subarachnoid Hemorrhage), and Case 13 (Stroke in a Young Patient [Acute Ischemic]).

 R-5. A. This patient likely has carotid hypersensitivity. The history of syncope with shaving and turning one’s head especially with a tight-fitting collar is very suggestive of this condition. To confirm the condition, a carotid massage may be performed prior to auscultation of the carotid arteries to ensure that no bruits are present. The patient has normal vital signs, which rules out a sinus node dysfunction or AV nodal heart block. The patient has no symptoms of palpitations, which makes AV nodal reentry or ventricular arrhythmia unlikely.

See also Case 16 (Cardiogenic Syncope).

 R-6. D. This patient has the classic triad of dementia, gait abnormality, and urinary incontinence. Additionally, the CT scan shows dilated cerebral ventricles. The dementia can be characterized with memory or concentration. The difficulty with gait can be a shuffling or wide-based gait, or balance issues related to apraxia (loss of previously learned motor function). The urinary complaints can be urinary frequency or frank incontinence. Normal pressure hydrocephalus (NPH) is demonstrated by dilated ventricles with a normal opening pressure on lumbar puncture (LP). Treatment such as with ventriculoperitoneal (VP) shunt can reverse the symptoms.

See also Case 20 (Alzheimer Dementia) and Case 21 (Lewy Body Dementia).

 R-7. C. The CSF characteristics associated with HSV meningoencephalitis usually show a moderately increased number of white blood cells (10-1000/ mm3), normal CSF glucose, elevated CSF protein, and numerous erythrocytes (10-500/mm3). A bloody CSF is distinctive. Answer A is more typical of a bacterial meningitis with a large number of PMN cells, low-to-normal glucose, high protein (>100 mg/dL), and few erythrocytes. Viral meningitis is associated with less than 100 cells/mm3, usually with lymphocyte predominance, normal glucose and protein, and no erythrocytes. Tuberculous (TB) meningitis is associated with a moderate number of cells (10-1000), usually of lymphocyte predominance, low glucose, elevated protein, but no RBCs.

See also Case 12 (Subarachnoid Hemorrhage), Case 25 (Acute Disseminated Encephalomyelitis), and Case 26 (Viral Meningitis).

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 R-8. D. This patient has median nerve entrapment, also known as carpal tunnel syndrome. The carpal tunnel at the wrist impinges on the median nerve, leading to motor weakness of the opposition of the thumb, and sensory dysfunction of the palmar surface of the thumb, index finger, and middle finger. An example of spinal cord anterior horn degeneration is amyotrophic lateral sclerosis (ALS). A brachial plexopathy could involve the same nerve roots, but there nerve roots contribute to other nerves and would involve other dermatomes and muscles, not specifically innervated by the median nerve.

See also Case 41 (Amyotrophic Lateral Sclerosis), Case 42 (Median Nerve Mononeuropathy), and Case 43 (Foot Drop).

 R-9. A. This child most likely has autism spectrum disorder. The history is typical with regression of developmental milestones, especially lack of social interaction. Often there is also lack of verbal ability and stereotypical nonpurposeful behavior. Down syndrome would lead to developmental delay from birth. Hearing loss must be ruled out in this case but would not fully explain the lack of social interaction, stereotypical non-purposeful behavior, or lack of eye contact. Fetal alcohol syndrome has a classic facies and mental retardation from birth.

See also Case 51 (Autism Spectrum Disorder).

R-10. A. This is a very classic example of a simple febrile seizure, in which a child has a single tonic-clonic seizure less than 15 minutes in duration, is aged 6 months to 6 years, is without neurologic findings, and is associated with a fever that is not due to meningitis. In these cases, further imaging of the brain or LP are not necessary. The use of prophylactic antiseizure medication is controversial.

See also Case 45 (Febrile Seizures).

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INDEX

Page numbers followed by t or f indicate that the entry is included in a table or figure.

A ABA. See applied behavior analysis abdominal examination, 6 abducens palsy. See sixth nerve palsy abnormal heart rate or rhythm, 137–138 abnormal peripheral vascular tone or flow, 138 abnormal social reciprocity, 438, 439 ABR. See auditory brainstem response absence seizures (petit mal), 126, 384, 385 atypical, 127, 127f clinical approach etiology and pathogenesis, 130 evaluation and treatment, 130–131, 130t features and epidemiology, 128–129, 129t lifestyle and activity, 132 treatment and management, 131–132 complex motor automatisms vs., 129t acetaminophen (Tylenol), 159, 163, 164, 400 acetazolamide, 157, 291 acetylcholine (ACh), 181, 314, 470 acetylcholinesterase inhibitors, 179, 182, 316 acetylsalicylic, 158 ACh. See acetylcholine ACh receptor antibodies, 314 acoustic nerve meningioma, 442 acoustic neuromas, 306, 442, 443, 447, 448, 449 acquired CJD, 251 acquired epileptic aphasia, 120 ACTH. See adrenocorticotropic hormone action tremor, 19 acute angle-closure glaucoma, 157–158 acute ascending weakness, 335 acute cerebral infarct, 96 clinical approach, 97–99 clinical presentation, 99–100 definitions for, 97 acute communicating hydrocephalus, defining, 105 acute disseminated encephalomyelitis (ADEM), 220–224 acute inflammatory demyelinating polyneuropathy (AIDP), 334, 336, 338, 339 acute ischemic stroke, 112 acute motor-sensory axonal neuropathy (AMSAN), 336 acute motor-sensory neuropathy (AMAN), 336 acute necrotizing hemorrhagic encephalomyelitis (ANHE), 220

acute panautonomic neuropathy, 336 acute post-infectious demyelinating syndrome, 217 acute serous labyrinthitis, 324t, 326 acute suppurative labyrinthitis, 324t, 326 acute weakness, 335–338 acyclovir, 222 AD. See Alzheimer disease ADCAs. See autosomal dominant cerebellar ataxias ADEM. See acute disseminated encephalomyelitis ADHD. See attention deficit hyperactivity disorder Adie pupil, 279 adrenocorticotropic hormone (ACTH), 429 adult-onset seizures, 118–119 clinical approach clinical presentation, 120–121 etiologies, 119–120 treatment, 121, 121t definitions, 119 AFO. See ankle-foot orthosis agnosia, 99 AIDP. See acute inflammatory demyelinating polyneuropathy AIDS dementia complex, 246f akinetic mutism, 246 alcohol, tremor and, 20 alcohol abuse, 80 alcoholism, dementia in, 178 alemtuzumab, 216 allergies, 5 almotriptan, 158, 400 alpha methyl-p-tyrosine, 60 alpha synclein, 185 alpha-2 agonists, 416 alprazolam (Xanax), 21 ALS. See amyotrophic lateral sclerosis Alzheimer, Alois, 178 Alzheimer dementia, 174 definitions for, 175–176 Alzheimer disease (AD), 176f, 177, 178–182, 185 defining, 176 AMAN. See acute motor-sensory neuropathy amantadine, 45, 46, 216 aminoglycosides, 231 amitriptyline, 159, 399 amlodipine, 95 473

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474

INDEX

ampicillin, 230 AMSAN. See acute motor-sensory axonal neuropathy amyloid plaques, 178, 179f, 182 amyloid precursor protein, 181 amyotrophic lateral sclerosis (ALS), 352–353, 358–359, 376, 472 clinical features and epidemiology, 354 diagnosis, 355–356 etiology and pathogenesis, 354–355 treatment, 356–357 analgesic overuse, 169, 170 anemia macrocytic, 193, 197 megaloblastic, 196 aneurysms, 104–106, 108, 274 angiogram, 107f angiography, 108 cerebral, 104 CT, 113 MRA, 113, 168, 312, 313, 316 ANHE. See acute necrotizing hemorrhagic encephalomyelitis anisocoria, 281–282 clinical approach differential diagnosis, 277–279 imaging, 280 physical examination, 276–277 physiology, 275 definitions for, 275 pharmacologic, 278, 280, 281 physiologic, 279, 280, 281 ankle-foot orthosis (AFO), 374, 375 anterior cord syndrome, 65 anterograde memory loss, 188, 189 anticholinergic medications, 157, 182 anticholinesterase medications, 188 anticoagulation therapy, 100, 101 anticonvulsant medication, 118 anticonvulsant therapy, 131–132 anticonvulsants, 159, 391, 429, 452, 455 antiepileptic drugs, 159, 167, 168, 382, 383, 385 antihistamines, 159 anti-Jo-1 antibody, 343 anti-Lrp4 antibodies, 311 anti-MuSK antibodies, 311 anti-NMDA receptor encephalitis, 34, 36, 38 antiplatelet therapy, 101 antipsychotics, 180, 437 LBD and, 189 antipyretics, 391 antiseizure medications, 21 antithrombotic drugs, 114 aphasia, 99, 177 apixaban, 100 applied behavior analysis (ABA), 434, 437 apraclonidine, 278 apraxia, 99, 185, 246 arachnoid cyst, 446t

57_Toy-Neuro_Index_p473-488.indd 474

ARAS. See ascending reticular-activating system areflexia, 464 Argyll Robertson pupils, 257, 259, 261, 262, 263, 279 aripiprazole, 415 arrhythmia, 136, 138 arteriovenous malformations (AVMs), defining, 112, 113–114 AS. See Asperger syndrome ascending reticular-activating system (ARAS), 89 ASDs. See autism spectrum disorders Asperger syndrome (AS), 435 aspirin, 100, 163 asterixis, 81 ataxia, 191, 192, 223 ADCAs, 51–55 definitions for, 51, 245 SCAs, 50–55 spinocerebellar, 50–51 atenolol, 95 athetosis, 27 atonic seizures, 120, 120t atrial fibrillation, 98, 100, 101 atrial septal defect, 468, 471 atropine, 278 attention, 81 attention deficit hyperactivity disorder (ADHD), 411, 413, 414, 415–417 atypical absence seizures, 127, 127f atypical antipsychotics, 415, 437 atypical neuroleptics, 30 atypical parkinsonian syndromes, 184, 185t audiogram, 302 auditory brainstem response (ABR), 442–443, 445, 448 auditory brainstem-evoked response, 435 auras, 126–127, 129, 134, 153, 161, 384 brainstem, 322 visual, 154, 398 autism spectrum disorders (ASDs), 413, 434–440, 469 defining, 435 autistic regression, 440 automatisms, 128–129 autonomic dysfunction, 138 autonomic dysreflexia, 68, 467, 470 autosomal dominant cerebellar ataxias (ADCAs), 52t, 55 clinical approach, 51–54 treatment, 54 AVMs. See arteriovenous malformations axon, 329 azathioprine, 315, 347, 349 B Babinski signs, 181, 192, 453 back and spine examination, 6 baclofen, 60, 216

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475

INDEX bacterial encephalitis, 34 bacterial meningitis, 34, 228, 229t, 232, 233, 471 Balance Error Scoring System, 90 barbiturates, medication overuse headache and, 167 baroreceptor hypersensitivity, 468, 471 basilar-type migraine. See migraine with brainstem aura Becker muscular dystrophy (BMD), 376, 405–409 BECTS. See benign epilepsy with centrotemporal spikes behavioral arrest, 134 behavioral interventions, 437 Bell palsy, 302, 304, 305, 443, 444–445, 448, 449 benign epilepsy with centrotemporal spikes (BECTS), 420–424 benign paroxysmal positional vertigo (BPPV), 320, 321, 322, 323t, 325, 326 benign rolandic epilepsy, 381, 383, 385, 420 benzathine penicillin G, 261 benzodiazepines, 60, 382, 385 in delirium management, 83 medication overuse headache and, 167 berry aneurysms, 105 beta-blockers, 21, 159, 160, 168 bilateral seizure, without confusion or unconsciousness, 146 binocular diplopia, 299, 300 clinical approach, 295–296, 298 definitions for, 294 treatment, 298 biofeedback, 168 bizarre automatisms, 128 bladder dysfunction, in MS, 212 bladder incontinence, 139 BMD. See Becker muscular dystrophy Botox. See botulinum toxin type A botulinum immunoglobulin, 239 botulinum toxin type A (Botox), 21, 60, 160, 168, 415 botulism, 336 food-borne, 238, 240 infantile, 236–241 bovine spongiform encephalopathy (BSE), 251 bowel incontinence, 139 BPPV. See benign paroxysmal positional vertigo brachial plexopathy, 363, 364, 368, 472 bradycardia paradoxical, hypotension with, 138 symptomatic, 137 bradykinesia, 19, 28, 30, 31, 41, 43 brain biopsy, 255, 271 brain tumors dementia and, 178 headache in, 158, 452, 456, 457 metastatic, 452–457 brainstem auras, 322

57_Toy-Neuro_Index_p473-488.indd 475

Brandt-Daroff exercise, 325 breast cancer, 456, 457 breast examination, 6 Brown-Séquard syndrome, 65, 69 Brudzinski sign, 225, 227, 233 BSE. See bovine spongiform encephalopathy bulbar weakness, 311 C C6 radiculopathy, 366, 367 caffeine, 163 calcinosis cutis, 345 calcium, 408 Campylobacter jejuni, 334–335, 336, 339 captopril, 159 carbamazepine, 383, 385 carbidopa, 40, 44 cardiac examination, 6 cardioembolic conditions, 100 cardiogenic syncope, 136 abnormal heart rate or rhythm, 137–138 abnormal peripheral vascular tone or flow, 138 clinical approach, 137 definitions, 137 neurocardiogenic/vasovagal syncope, 138 orthostatic syncope, 138 risk factors for poor outcomes after, 139, 139t seizures, 139–140 carotid artery dissections, 113 carotid dissection, 156, 160, 161 defining, 112 carotid hypersensitivity, 468, 471 carpal tunnel syndrome (CTS), 362, 363, 368, 373, 472 definitions for, 363 diagnosis, 364–366 epidemiology and clinical features, 363–364 treatment, 366–367 CBC. See complete blood count CBD. See corticobasal degeneration CBT. See cognitive behavioral therapy cefotaxime, 230 ceftriaxone, 230, 261 central cord syndrome, 65 central herniation, 317 central scotoma, 203 centrotemporal spikes, 420–424 cephalosporins, 230–231 cerebellopontine angle (CPA), 443 cerebellopontine angle tumors, 442–444, 446–449, 446t cerebral angiography, 104 cerebral arteriogram, 114f cerebral concussion complications, 92 definitions for, 88 diagnosis, 89–90 epidemiology, 89, 89t initial management, 90–91

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476

INDEX

cerebral concussion (Cont.): pathophysiology, 89 return-to-play guidelines, 91, 92t signs and symptoms, 90t cerebral hypotonia, 462 cerebral infarct, 102 acute, 96–100 cerebral ischemia, 113 cerebral vasospasm, 156 cerebrospinal fluid (CSF), 35, 36–37 in meningitis evaluation, 229 in MS evaluation, 214 in neurosyphilis, 259 cerebrovascular accident (CVA), 97, 471 cervical myelopathy, 359 cervical radiculopathy, 363, 364 Charcot, Jean-Martin, 42 CHF. See congestive heart failure chicken pox, 301 childhood absence epilepsy, 381, 384, 385 cholesteatoma, 303, 322 cholesterol cysts, 446t chorea, 27, 28, 30 chronic daily headache, 165 chronic headache, 164, 169, 170 chronic/transformed migraine, 165–166 clinical approach, 165–167 definitions for, 165 evaluation, 167–168 tension-type, 166 treatment, 168 chronic inflammatory demyelinating polyneuropathy (CIDP), 328–332 chronic migraine clinical approach, 165–166 defining, 165 chronic sinusitis, 400, 401 chronic tension-type headache, 166 chronic traumatic encephalopathy, 92 CIDP. See chronic inflammatory demyelinating polyneuropathy CIS. See clinically isolated syndrome MS CJD. See Creutzfeldt-Jakob disease CK. See creatine kinase classic migraine, 153 classical clinical problem-solving, 8–10 Classification of Epileptic Seizures (1981), 119 clinical problem-solving, approach to, 8–10 clinically isolated syndrome MS (CIS), 215 clinodactyly, 427 clipping, 108 clonazepam, 188, 216 clonic tics, 413 clonidine, 159, 415 clopidogrel, 100 Clostridium botulinum, 236–238, 336 cluster headaches, 166, 397 CNS stimulants, 415

57_Toy-Neuro_Index_p473-488.indd 476

cobalamin, 193 cocaine, 278 coenzyme Q10, 402 cognitive behavioral therapy (CBT), 147, 168 cognitive impairment, in MS, 212 cognitive screening tests, 175 cogwheel rigidity, 19 common migraine, 153 compartment syndrome, 373 Compazine (prochlorperazine), 46 complete blood count (CBC), 7, 232 complete spinal cord injuries, 65 complex febrile seizure, 389, 392, 393 complex motor automatisms, 128 absence seizures vs., 129t complex partial seizure (CPS), 126, 134, 381, 421 clinical approach etiology and pathogenesis, 130 evaluation and treatment, 130–131, 130t features and epidemiology, 128–129, 129t lifestyle and activity, 132 treatment and management, 131–132 complex partial status epilepticus, 129 complex tics, 414 complications, 12–13 compressive neuropathy, 373, 375 computed tomography (CT), 34, 37, 52, 106, 126 in cerebral infarct evaluation, 99f, 101 in concussion evaluation, 93 in CPA tumor evaluation, 445 in EDH, 75–76, 75f, 77, 78 in migraine evaluation, 155, 399, 400, 401 in myasthenia gravis evaluation, 315 noncontrast, 104, 106f computed tomography angiography (CTA), 113 COMT inhibitors, 470 concussion. See cerebral concussion conductive hearing loss, 443 confusion, bilateral seizure without, 146 congenital contractures, 461 congestive heart failure (CHF), 139 continuous seizures, 120t conversion disorder, defining, 145 convulsive activity, 139 copper deficiency, 197 coprolalia, 414 cortical dementias, 176–177, 176t, 182 cortical spreading depression, 154 corticobasal degeneration (CBD), 42, 177f, 185t corticobulbar pathways, 303, 305, 306 corticosteroids, 38 in ADEM management, 222–223 in brain tumor management, 452 in CIDP management, 331, 332

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INDEX in CTS management, 366, 368 in MD management, 408, 409 in migraine management, 159 in MS management, 217, 218 in myasthenia gravis management, 315 in spinal cord injury management, 67 in toxoplasmosis management, 269 in ON treatment, 205–206 CPA. See cerebellopontine angle CPA meningioma, 445f CPS. See complex partial seizure cranial nerves, 277, 277t, 332 assessment, 6–7 Dozen Ds of progression in, 336–337 creatine kinase (CK), 343, 346, 347, 405, 409, 463 Creutzfeldt-Jakob disease (CJD), 177f, 250, 255–256 categories of, 251 clinical features and epidemiology, 251–252 diagnosis, 253 etiology and pathogenesis, 252 treatment and prevention, 253–254 cryptococcal meningitis, 247, 248 cryptogenic seizure, 383, 384 CSF. See cerebrospinal fluid CT. See computed tomography CTA. See computed tomography angiography CTS. See carpal tunnel syndrome Cushing response, 74 CVA. See cerebrovascular accident cyanocobalamin, 193 cyclosporine, 315 Cylert (pemoline), 415 cyproheptadine, 399 cysticercosis, 129 D dabigatran, 100 dalfampridine, 216, 218 DaTscan, 20, 22, 23, 44 DBP. See diastolic blood pressure DBS. See deep brain stimulation DDST. See Denver Developmental Screening Test de novo automatisms, 128 death, epilepsy and, 129, 134 deep brain stimulation (DBS), 21, 45, 415 deep tendon reflexes (DTRs), 191 deep vein thrombosis (DVT), 471 déjà vu, 127 delirium, 80 clinical approach, 81–83 definitions for, 81, 175 dementia and, 81, 84, 85 diagnosis, 81–83 etiologies, 82t, 85 patient history and, 84 risk factors, 82t

57_Toy-Neuro_Index_p473-488.indd 477

477

treatment, 83 from UTI, 174 dementia, 471. See also Alzheimer dementia; Lewy body dementia in alcoholism, 178 approach to, 176–177 brain tumors and, 178 CJD and, 252, 256 common syndromes, 175 cortical, 176–177, 176t, 182 defining, 176, 245 delirium and, 81, 84, 85 differential diagnosis, 178 frontotemporal, 175, 176f, 354 HIV-associated, 177f, 178, 244–248, 246f multi-infarct, 176, 177, 177f subcortical, 177, 177t vascular, 175, 176 demyelinating, defining, 335 demyelinating ON, 205, 207 denervation, 373 Denver Developmental Screening Test (DDST), 435, 438, 439 Department of Public Safety, 119 depression cortical spreading, 154 in HD, 30 in MS, 212 pseudodementia in, 176, 178, 182 dermatomyositis (DM), 342–350, 347t cutaneous features, 344–345, 344f diagnosis, 345–347 epidemiology and clinical features, 343–344 myocardial involvement, 344 treatment and management, 347–348 developmental assessment, 7 developmental delay, 436, 438, 439, 472 developmental regression, 434, 438, 439, 440, 472 dexamethasone (Decadron), 269, 452, 455, 456, 457 dextroamphetamine (Dexedrine), 415 DHE. See dihydroergotamine diabetic peripheral neuropathy, 138 diagnosis in clinical problem-solving, 9 confirming, 11 establishing most likely, 10–11 next steps after, 11–12 diagnostic adjuncts, 8 Diagnostic and Statistical Manual of Mental Disorders (DSM-V), 413, 435 Diastat. See diazepam diastolic blood pressure (DBP), 138 diazepam (Valium/Diastat), 21, 391–393 dichloralphenazone, 159 diclofenac, 158 diffuse cerebral atrophy, 246 diffuse Lewy body disease (DLB), 42

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478

INDEX

dihydroergotamine (DHE), 158–159 dimethyl fumarate, 216 diphenhydramine, 61, 159 diplopia, 211, 332 binocular, 294–300 defining, 294 evaluation of, 295–296, 298 dipyridamole, 100 disease-modifying therapies, 215, 218 divalproex, 159 Dix-Hallpike maneuver, 320, 321, 322, 325, 326 dizziness, 320 DLB. See diffuse Lewy body disease DM. See dermatomyositis DMD. See Duchenne muscular dystrophy donepezil, 181, 188 dopamine agonists, 44, 416, 417 dopamine receptor blockers, 61 dopaminergic agents, 44 Down syndrome, 472 doxycycline, 261 Dozen Ds of cranial nerve progression, 336–337 droperidol, 159 drug-induced parkinsonism, 41, 46 DSM-V. See Diagnostic and Statistical Manual of Mental Disorders DTRs. See deep tendon reflexes Duchenne muscular dystrophy (DMD), 376, 404–409 duloxetine, 159 DVT. See deep vein thrombosis dysautonomia, 237 dyskinetic disorders, 59t dystonia, 27, 28, 31 dystonic tics, 413 dystonic tremor, 19 dystrophin protein, 405, 406, 407 E echolalia, 414 edavarone (Radicava), 356, 359 EDH. See epidural hematoma edoxaban, 100 edrophonium bromide, 314–315 EEG. See electroencephalography EGFR. See epidermal growth factor receptor EGFR tyrosine kinase inhibitors, 455 El Escorial diagnostic criteria, 355 electrodiagnostic studies, 315, 353, 365 electroencephalography (EEG), 34, 37, 118–119, 126, 127f, 131, 134, 313, 382 in BECTS evaluation, 422 for cardiogenic syncope, 136 defining, 137 febrile seizure evaluation and, 393 headache evaluation and, 399 electromyography (EMG), 237, 259, 310, 315, 346, 355, 358, 403, 461, 463 in CTS evaluation, 365, 366 in foot drop evaluation, 372, 374, 376

57_Toy-Neuro_Index_p473-488.indd 478

electromyography with repetitive nerve stimulation studies, 237 electronystagmogram (ENG), 321, 448 eletriptan, 158 embolic strokes, 471 EMG. See electromyography encephalitis anti-NMDA receptor, 34, 36, 38 bacterial, 34 limbic, 35 NMDA, 34–38 viral, 35, 37, 38 encephaloduroarteriosynangiosis, 115 endovascular coiling, 108 ENG. See electronystagmogram entacapone, 44 enteroviral reverse transcriptase polymerase chain reaction (EV RT-PCR), 228 entrapment neuropathy, 364, 368 epicanthal fold, 427 epidermal growth factor receptor (EGFR), 455 epidermoid tumor, 444, 446t epidural blood patch, 157 epidural hematoma (EDH), 72, 77, 78 defining, 73 diagnostic studies, 74–76 evaluation, 73–74 outcomes, 76 treatment, 76 epilepsy, 123, 127 in ASD, 440 benign, with centrotemporal spikes, 420–424 benign rolandic, 381, 382, 385, 420 childhood absence, 381, 384, 385 classification of, 421 defining, 119, 137 febrile seizures and risk of, 392, 393 frontal lobe, 120 in hypotonia, 464 juvenile myoclonic, 381–382, 385 localization-related (focal), 381, 383, 384 during menstruation, 134 posttraumatic, 120 primary generalized, 383–385 sudden unexpected death in, 129, 134 temporal lobe, 120, 390 vestibular, 323t epileptic encephalopathy, 127 epileptic seizures, PNES and, 145, 149 epileptogenic focus, 118, 123, 126 Epley maneuver, 322, 325 ergotamines, 158 essential tremor (ET), 18–19, 19t, 22–23 clinical approach, 20–21 diagnosis, 20–21 management, 21 pathogenesis, 20 ethosuximide, 131–132, 383, 384 euvolemia, 108

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INDEX EV RT-PCR. See enteroviral reverse transcriptase polymerase chain reaction Excedrin Migraine, 163 executive dysfunction, 189 executive function, 185 exon-skipping, 408 exposure keratoconjunctivitis, 304 extraocular motion, 277 extraocular muscle innervation, 277t extratemporal lobe seizures, 129 extremities/skin examination, 6 eye. See also anisocoria extraocular muscle innervation, 277t nerve pathway, 276f physical examination, 276–277 physiology, 275 structural lesions, 279, 281, 282 sympathetic lesions, 281, 282 F facial nerve paralysis, 302–306 facial neuromas, 304 facial paralysis, 442, 444–445, 448, 449 false localizing sign, 295 familial ALS, 358 family history, 5 in ET, 22, 23 famotidine (Pepcid), 257 fasciculation, 372 fatal familial insomnia (FFI), 251 febrile seizures, 381, 385, 388–393, 472 feeding tubes, 357 fetal alcohol syndrome, 472 fever, seizures with, 388–393 FFI. See fatal familial insomnia fibromuscular dysplasia, 105 fingolimod, 216, 218 flaccid, defining, 335 fluid-attenuated inversion recovery (FLAIR), 120, 155, 214, 253 fluoxetine (Prozac), 416 fluphenazine, 61 focal epilepsy. See localization-related epilepsy focal seizures, 120, 120t, 421, 423, 424 folic acid, 269 folinic acid, 267 food-borne botulism, 238, 240 foot drop, 372–376 fortification spectra, 154 frameshift mutations, 408 frontal lobe epilepsy, 120 frontotemporal dementia (FTD), 175, 176f, 354 frovatriptan, 158 FTD. See frontotemporal dementia functional electrical stimulation devices, 375 functional neurologic symptom disorder, 145 G gabapentin, 159 gadolinium contrast, 445

57_Toy-Neuro_Index_p473-488.indd 479

479

gait training, 374–375 galantamine, 181, 188 gamma knife radiation, 447, 455 GBS. See Guillain-Barré syndrome GCS. See Glasgow Coma Scale GEFS+ syndromes. See generalized epilepsy with febrile seizures plus syndromes general appearance, 5 generalized epilepsy, 381, 383, 384, 385 generalized epilepsy with febrile seizures plus syndromes (GEFS+ syndromes), 390 generalized seizures, 120, 120t generalized tonic-clonic seizure (GTC), 71, 265, 267 genetic counseling, 30, 429, 431 genetic seizures, 120, 120t genetic testing, 52–53, 461 genetically transmitted diseases, 5 genital examination, 6 geotropic nystagmus, 321 geotropic rotatory nystagmus, 322, 326 Gerstmann-Straussler-Scheinker disease (GSS), 251 giant cell arteritis, 206, 207 Glasgow Coma Scale (GCS), 71, 90 intracranial pressure monitoring and, 100 glatiramer acetate, 216 glaucoma, 157–158 glomus tumor, 444, 446t glucocorticoids, 347, 349 glucocorticoid-sparing agents, 347 glutamine, 181 Gottron nodules, 343, 345, 345f Gowers sign, 405 Graded Symptom Checklist, 90 GSS. See Gerstmann-Straussler-Scheinker disease GTC. See generalized tonic-clonic seizure guanfacine, 415 Guillain-Barré syndrome (GBS), 236, 304, 334–339 H H reflex, 259 HAART. See highly active antiretroviral therapy HAD. See HIV-associated dementia Haldol (haloperidol), 31, 60, 61, 83, 415 hallucinations, in LBD, 187 hallucinogens, 84 haloperidol (Haldol), 31, 60, 61, 83, 188, 189, 415–417 hatband distribution, 166 HD. See Huntington disease head and neck examination, 5 head injury, PNES and, 149 headache, 113, 163. See also migraine brain tumors and, 158, 452, 456, 457 chronic, 164–170 clinical history, 152 cluster, 166, 397

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480

INDEX

headache (Cont.): in concussion, 90, 90t definitions for, 165 evaluation, 152, 167–168 medication overuse, 167, 168, 169 new daily persistent, 166–167, 170 pediatric, 396–402 post-LP, 157, 160, 161 postspinal, 157 secondary causes, 156–158, 161 tension type, 156, 166, 170 treatment, 168 vascular, 153 headache pain, 154 hearing loss, 442 heel-knee-shin maneuver, 191, 192 heliotrope rash, 342, 344, 344f hemicrania continua, 166, 170 hemiparesis, 99, 270 hemorrhage intracerebral, 97 intraparenchymal, 97 subarachnoid, 77, 78, 104, 155, 156 death from, 107 definitions, 105 diagnosis and prognosis, 106–107 etiologies, 105–106 treatment, 108 hemorrhagic stroke, 99 treatment, 100 hepatic encephalopathy, 80 hereditary CJD, 251 herniation, 453 herpes simplex virus (HSV), 35, 305 encephalitis from, 222, 231 meningitis from, 231 meningoencephalitis from, 468 herpes simplex virus polymerase chain reaction (HSV PCR), 228 herpes zoster oticus. See Ramsay Hunt syndrome heterochromia iridis, 278 HHV-6. See human herpesvirus 6 highly active antiretroviral therapy (HAART), 245, 247, 268 highly structured educational environments, 438, 439 HIV. See human immunodeficiency virus HIV-associated dementia (HAD), 177f, 178, 244–248, 246f homonymous hemianopia, 97 Horner syndrome, 112, 113, 116, 156, 278, 280, 281 HSV. See herpes simplex virus HSV meningitis, 231 HSV meningoencephalitis, 468 HSV PCR. See herpes simplex virus polymerase chain reaction human herpesvirus 6 (HHV-6), 390 human immunodeficiency virus (HIV), 262, 263

57_Toy-Neuro_Index_p473-488.indd 480

Huntington disease (HD), 26, 177f, 178 approach to, 31 clinical approach, 27–28, 30 definitions for, 27 differential diagnosis, 28, 29t hydrocephalus, 287 acute communicating, 105 normal pressure, 177t, 178, 185, 468, 471 hyperammonemia, 81 hyperemia, 203, 204f hyperlipidemia, 100 hyperreflexia, 181 hypertelorism, 427 hypertension, 39 idiopathic intracranial, 286, 289–290, 291 hyponatremia, 104–105 hyporeflexia, 260 hypotension orthostatic, 138, 141 with paradoxical bradycardia, 138 hypothyroidism, 178 hypotonia, 429 cerebral, 462 epilepsy in, 464 infantile, 461–464, 462f I IBM. See inclusion body myositis ibuprofen, 158, 163, 366, 400, 401 ICA. See internal carotid artery ICHD. See International Classification of Headache Disorders ICP. See intracranial pressure idiopathic facial paralysis, 448, 449 idiopathic inflammatory myopathies, 347t idiopathic intracranial hypertension, 286, 289–290, 291 idiopathic noninflammatory cerebral vasculopathy, 114 idiopathic Parkinson disease. See Parkinson disease idiopathic seizures, 120, 384 ILAE. See International League Against Epilepsy ILS. See isolated lissencephaly sequence image distortion, 154 Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), 90 immune suppression, 38, 222, 315–316, 331, 347 immunization, patient history, 5 immunocompromised hosts, infections in, 267–269 immunomodulating agents, 215–216 ImPACT. See Immediate Post-Concussion Assessment and Cognitive Testing inclusion body myositis (IBM), 342, 345, 346, 347t, 349, 350 incontinence, 139 indomethacin, 158, 166, 169, 170 infantile botulism, 236–241

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INDEX infantile hypotonia, 461–464, 462f infantile spasms, 427 inflammatory, defining, 335 inflammatory myopathy, 346 interferon medications, 216, 218 internal carotid artery (ICA), 114f International Classification of Headache Disorders (ICHD), 167 International Headache Society, 397 International League Against Epilepsy (ILAE), 119, 381, 421 classification scheme, 120t internuclear ophthalmoplegia, 211, 212 interstitial pneumonitis, 344 intestinal colic, 430, 431 intracerebral hemorrhage, 97 intracranial pressure (ICP), 104 intraparenchymal hemorrhage, 97, 98 intravenous immunoglobulin (IVIg), 331, 332, 338, 339, 347 intrinsic factor, 193 ipsilateral neck pain, 113 irritative myopathy, 346 ischemia cerebral, 113 retinal, 113 spinal cord, 69 ischemic heart disease, 102 ischemic mononeuropathy, 294 ischemic optic neuropathy, 201t ischemic stroke, 102 acute, 112 clinical approach, 97–99 etiologies, 98–99 risk factor management, 100 secondary prevention, 100 treatment, 99–100 isolated lissencephaly sequence (ILS), 427, 428, 429 isolated myelopathies, 463 isometheptene mucate, 159 IV drug abuse, 262, 263 IVIg. See intravenous immunoglobulin

481

K keratoconjunctivitis, 304 Kernig sign, 225, 227, 233 ketoprofen, 158 kinetic tremor, 19 kuru, 251

lancinating pain, 259 language regression, 440 latex particle agglutination, 227 LBD. See Lewy body disease LE. See limbic encephalitis lead-pipe rigidity, 19 Lennox-Gastaut syndrome, 127 Lennox-Kleffner syndrome, 120 LES. See Lambert-Eaton syndrome levodopa, 40, 44, 45, 55, 188, 470 Lewy, Frederick, 187 Lewy bodies, 43, 43f Lewy body dementia, 175, 184 clinical approach, 186 clinical history and features, 187 definitions for, 185–186 diagnostic features, 186t diagnostic studies, 187–188 pathology, 187 treatment, 188 Lewy body disease (LBD), 176f, 177, 185t, 188, 189 diffuse, 42 Lhermitte sign, 212 lidocaine, 366 lifestyle changes in headache interventions, 168 in pediatric migraine management, 399 light-near dissociation, 279 limbic encephalitis (LE), 35 lipoma, 446t lissencephaly, 426–431, 428f lithium carbonate, 159 LOC. See loss of consciousness localization-related (focal) epilepsy, 381, 383, 384 loss of consciousness (LOC), 136 defining, 119 Lou Gehrig disease. See amyotrophic lateral sclerosis lower motor neuron disease, 353 lower motor neuron signs, 355 LP. See lumbar puncture lucid interval, 72, 78 lumbar puncture (LP), 34, 106, 288 in ALS evaluation, 355 in chronic headache evaluation, 168 febrile seizure evaluation and, 392, 393 in GBS diagnosis, 337 headache after, 157, 160, 161 in migraine evaluation, 155 in SAH evaluation, 156 lung cancer, 452, 456, 457, 467, 470 Lyme disease, 304, 306

L L5 radiculopathy, 376 laboratory assessments, 7–8 for migraine, 155 lacunar strokes, 98 Lambert-Eaton syndrome (LES), 470

M Machado-Joseph disease (MJD), 53 macrocytic anemia, 193, 197 macular star, 203 mad cow disease. See bovine spongiform encephalopathy

J jamais vu, 127 juvenile myoclonic epilepsy, 381–382, 385

57_Toy-Neuro_Index_p473-488.indd 481

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482

INDEX

magnetic resonance angiography (MRA), 113, 313, 316 in chronic headache evaluation, 168 in ptosis evaluation, 312 magnetic resonance imaging (MRI), 34, 36–38, 52, 53f, 106, 113, 118–119, 126, 134, 139 in ALS evaluation, 355 in BECTS evaluation, 421, 422 of brain, 130, 131f in brain tumor evaluation, 452, 456, 457 in chronic headache evaluation, 168 in CPA tumor evaluation, 445, 445f, 446t, 448 in ON evaluation, 204–205, 205f in foot drop evaluation, 374 in HAD evaluation, 247, 248 in migraine evaluation, 155, 399 in MS evaluation, 212–214, 213f in myasthenia gravis evaluation, 315, 316, 317 magnetic resonance neurography (MRN), 374 malignancy, dermatomyositis and polymyositis and, 348, 349 malignant melanoma, 455 malignant rolandic epilepsy, 424 malingering, defining, 145 MAO-B inhibitors. See monoamine oxidase type B inhibitors MBA. See migraine with brainstem aura McDonald criteria, 211 MD. See muscular dystrophies MDS. See Miller-Dieker syndrome medial longitudinal fasciculus (MLF), 211 median mononeuropathy, 366, 367 median nerve compression, 363–364 median nerve entrapment, 373 median nerve mononeuropathy, 362 medication overuse headache, 167, 168, 169 medications, patient history, 5 megaloblastic anemia, 196 melatonin, 188 memantine, 175 memory, 173 Ménière disease, 322, 323t, 325, 326 meningioma, 443–444, 446t meningioma of acoustic nerve, 442 meningitis, 393 bacterial, 34, 228, 229t, 232, 233, 471 clinical presentation and evaluation, 228–230 cryptococcal, 247, 248 definitions for, 227–228 etiology, 228 meningococcal, 232, 233 treatment, 230–231, 230f, 232–233 tuberculous, 471 viral, 226, 228, 229t, 232, 233, 471 meningococcal meningitis, 232, 233 meningoencephalitis, HSV, 468 menstruation, epilepsy during, 134

57_Toy-Neuro_Index_p473-488.indd 482

mental status examination, 7 mesial temporal sclerosis, 130 metabolic myopathy, 347 metabolic panel, 7 metastatic brain tumor, 452–457 clinical features, 454–455, 454t epidemiology, 453–454, 454t treatment, 455 methotrexate, 347, 349 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 41 methylphenidate (Ritalin), 415 methylprednisolone, 349 methysergide maleate, 159 metoclopramide, 41, 46, 60, 158 metoprolol, 168 MG. See myasthenia gravis microdeletions, 427–428 midazolam, 382 midline shift, 453 midrin, 159 migraine, 152, 163, 402 with aura, 153–154, 160, 161 without aura, 153, 396 chronic, 165–166 clinical approach, 153–154 common triggers, 154t evaluation, 154–156 headache pain in, 154 pediatric defining, 397 evaluation, 398–399 mean age of onset, 398 treatment, 399–400 prodrome, 153 therapy and management abortive treatment, 158–159, 400 prophylactic treatment, 159–160 transformed, 165–166, 169, 170 vestibular, 323t migraine with brainstem aura (MBA), 322 mild TBI, 88, 92 Miller-Dieker syndrome (MDS), 426, 427, 429, 430 Miller-Fisher variant, 336, 337, 339 Mini-Mental State Examination (MMSE), 7, 175, 225, 245, 249, 257 mink encephalopathy, 251 mitoxantrone, 216 MJD. See Machado-Joseph disease MLF. See medial longitudinal fasciculus MMSE. See Mini-Mental State Examination MoCA. See Montreal Cognitive Assessment modafinil, 216 monoamine oxidase type B inhibitors (MAO-B inhibitors), 40, 44, 467, 470 monoclonal antibodies, 216 mononeuropathy, 365 Montreal Cognitive Assessment (MoCA), 7, 175, 243 motor delay, 430

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INDEX motor tics, 413 Moyamoya disease, 114 MPTP. See 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine MRA. See magnetic resonance angiography MRI. See magnetic resonance imaging MRN. See magnetic resonance neurography MS. See multiple sclerosis MSA. See multiple system atrophy multi-infarct dementia, 176, 177, 177f multiple sclerosis (MS), 175, 178, 196, 205, 217–218 clinical approach, 211 clinical course, 214–215 clinical features, 211–212 definitions for, 210–211 diagnosis, 211–214 diagnostic studies, 212–214, 213f differential diagnosis, 214 epidemiology, 211 pathophysiology, 211 ON and risk of, 206, 207 treatment, 215–216 multiple system atrophy (MSA), 42, 138, 185t muscle biopsy, 346, 355, 461 muscle-specific receptor tyrosine kinase (MuSK), 311 muscular dystrophies (MD), 376, 404–409 MuSK. See muscle-specific receptor tyrosine kinase myasthenia gravis (MG), 239–240, 310, 313–317, 315f, 338–339, 470 mycophenolate mofetil, 315 mycotic aneurysms, 106 mydriasis, 278 myelin, 329, 335 myelopathy, 267, 353, 359, 463 myocardial infarction, 84 myoclonic seizures, 132 myoclonus, 28, 31, 252 negative, 81 myoclonus seizures, 120, 120t myopathic, 311 myopathy, 312, 355, 403, 405 myotonic dystrophy, 376 Mysoline (primidone), 21 N naproxen sodium, 158, 163 naratriptan, 158 natalizumab, 216 National Institute of Neurological Disorders and Stroke (NINDS), 253 NCS. See nerve conduction studies neonatal myasthenia gravis, 239, 240 nerve conduction studies (NCS), 196, 197, 259, 310, 313, 315, 346, 355, 358, 403 in CTS evaluation, 365, 366 in foot drop evaluation, 372, 374, 376 nerve conduction velocity (NCV), 463 nerve entrapment disorders, 368, 472

57_Toy-Neuro_Index_p473-488.indd 483

483

nerve fiber, 329 nerve grafting, 375 nerve root compressive neuropathy, 375 neuroanatomic defects, 12 neurocardiogenic/vasovagal syncope, 138 neurofibrillary tangles, 178, 179f, 182 neuroleptics, 83, 415 LBD and, 189 neurologic examination, 6–7 in spinal cord injuries, 65 neuromyelitis optica, 207 neuropathic, 311 neuropsychological testing, 245, 246 neuroretinitis, 203 neurosyphilis, 178, 258–263, 260t, 279 new daily persistent headache, 166–167, 170 new-onset childhood seizure, 380–385 new-onset seizure, adult. See adult-onset seizures nimodipine, 108 NINDS. See National Institute of Neurological Disorders and Stroke NMDA encephalitis, 34 clinical history and features, 36–37, 38 definitions for, 35–36 nonatherosclerotic etiology, 113 noncontrast computed tomography, 104, 106f nonconvulsive status epilepticus, 382 nonorganic syndromes, PNES and, 149 nonsteroidal anti-inflammatory drugs (NSAIDs) in CTS management, 366 in migraine management, 158, 159, 400 overuse headache and, 167, 168 nontraumatic subarachnoid hemorrhage, 105 normal pressure hydrocephalus (NPH), 177f, 178, 185, 468, 471 nortriptyline, 159 NPH. See normal pressure hydrocephalus NSAIDs. See nonsteroidal anti-inflammatory drugs nucleus basalis of Meynert, 176 Nuedexta, 357, 359 NVC. See nerve conduction velocity nystagmus, 211, 228, 321, 325 O obsessive-compulsive behavior (OCB), 412, 416, 417 obsessive-compulsive disorder (OCD), 412, 413, 414 OCB. See obsessive-compulsive behavior occipital lobe hypometabolism, 189 occipital nerve block, 160, 167 occipital neuralgia, 167 occipitocervical pain, 113 OCD. See obsessive-compulsive disorder ocrelizumab, 216 OCT. See optical coherence tomography olanzapine, 30, 415 oligoclonal bands, 207, 214, 217

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484

INDEX

oligonucleotides, 408 olivopontocerebellar atrophy. See multiple system atrophy ON. See optic neuritis OnabotulinumtoxinA, 160, 168, 400 opioids, medication overuse headache and, 167 opisthotonus, 427 optic atrophy, 207 optic nerve trauma, 290, 291 optic neuritis (ON), 200, 201t clinical approach clinical presentation, 203–204 diagnosis, 204–205 treatment, 205–206 definitions for, 201 epidemiology, 202–203 in MS, 211–212 pathophysiology, 203 optic neuropathy, causes of, 201t optical coherence tomography (OCT), 205, 214 oral automatisms, 128 oral MS therapies, 216 Orap (pimozide), 415 organophosphates, 278 orthostatic hypotension, 138, 141 orthostatic syncope, 138 defining, 137 otoacoustic emissions, 448 otolith, 321 P pachygyria, 428 palilalia, 414 papilledema, 157, 286, 287f, 290–292, 332 clinical approach, 288 definitions for, 287–288 papillitis, 203, 204f paraganglioma, 444, 446t parakinesias, 414 paralysis facial, 442, 444–445, 448, 449 facial nerve, 302–306 tick, 336, 338, 339 Todd, 97 paraneoplastic cerebellar degenerations (PCDs), 50–51 paraneoplastic syndromes, 35, 38 paraphasic errors, 173, 176 parasympathetic stimulation, 470 Parkinson, James, 42 Parkinson disease (PD), 18, 19t, 40, 41, 470 dementia in, 175, 177, 177f Parkinson disease dementia (PDD), 184 Parkinson plus syndromes, 184, 185t parkinsonism, 31, 177, 178, 188 clinical approach, 42–44 differential diagnosis, 41–42 drug-induced, 41, 46 treatment options, 44–45 tremor in, 41, 43, 45, 46 vascular, 41 Parks-Bielschowsky test, 296, 297f

57_Toy-Neuro_Index_p473-488.indd 484

parotid gland tumors, 304 paroxysmal staring spells, 134 partial seizures. See complex partial seizure; simple partial seizure past medical history, 4 past surgical history, 4–5 patent foramen ovale (PFO), 113, 116, 155–156 defining, 112 patient history, approach to, 3–5 PCDs. See paraneoplastic cerebellar degenerations PD. See Parkinson disease PDD. See Parkinson disease dementia PDD-NOS. See pervasive developmental disorders not otherwise specified pediatric headache, 396–402 pediatric migraine, 401 defining, 397 evaluation, 398–399 mean age of onset, 398 treatment, 399–400 pediatric patients, physical examination and, 7 pemoline (Cylert), 415 penicillamine, 347 penicillin G, 230–231, 261, 262, 263 Pepcid (famotidine), 257 peripheral compressive neuropathy, 375 peripheral nerve conduction studies, 196 peripheral nerve entrapment, 469, 472 pernicious anemia, 178, 193, 195 peroneal nerve palsy, 372, 375, 376 peroneal neuropathy, 373 pervasive developmental disorders not otherwise specified (PDD-NOS), 435 petit mal seizures. See absence seizures PFO. See patent foramen ovale Phalen sign, 363, 365 pharmacologic anisocoria, 278, 280, 281 phenobarbital, 132, 382, 391, 392, 393 phenylephrine, 278 phenytoin, 382, 383, 385 phonophobia, 153, 154 photophobia, 153, 154, 169, 170, 468 photopsias, 154 physical examination, approach to, 5–8 physical rehabilitation, 375 physical therapy, 348 physiologic anisocoria, 279, 280, 281 physiologic tremor, 19 pilocarpine, 278 pimozide (Orap), 415 plasma exchange, 338, 339 plasmapheresis, 315 PM. See polymyositis PNES. See psychogenic nonepileptic seizures polymyositis (PM), 342, 344, 347t, 348, 350 polyneuropathy, 328–332, 334. See also acute inflammatory demyelinating polyneuropathy; chronic inflammatory demyelinating polyneuropathy defining, 335

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INDEX Post-Concussion Symptom Scale, 90 postconcussion syndrome, 92–94 postconcussion-rehabilitation programs, 91, 92t, 93 posterior circulation lesion, 99 posterior communicating artery aneurysm, 274 postherpetic neuralgia, 303 postictal confusion, 139 post-LP headaches, 157, 160, 161 postspinal headaches, 157 posttraumatic epilepsy, 120 posttraumatic stress disorder (PTSD), 145 postural tremor, 19 postvaccination diseases, 336 pramipexole, 44 preclinical MS, 215 prednisone, 347, 349, 366, 429 present illness history, 4 primary generalized epilepsy, 383, 384, 385 primary progressive aphasia, 177 primary progressive MS, 215 primidone (Mysoline), 21 prions, 252, 256 procaine penicillin, 261 prochlorperazine (Compazine), 46, 158, 159 prodrome, of migraine, 153 progressive multifocal leukoencephalopathy, 216 progressive supranuclear palsy (PSP), 42, 177f, 185t progressive-relapsing MS, 215 propranolol, 21, 159, 160, 168, 399 Prozac (fluoxetine), 416 pseudobulbar affect, 357, 359 pseudodementia, 176, 178, 182 pseudohypertrophy, 406 pseudoneurologic syndromes, PNES and, 149 pseudotumor cerebri, 157, 160–161, 286, 287f, 289–291, 332 PSP. See progressive supranuclear palsy psychogenic nonepileptic seizures (PNES), 144, 149 clinical approach etiologies and clinical presentation, 145–147 treatment, 147 definitions, 145 psychomotor seizures. See temporal lobe CPS ptosis, 259, 294, 309, 310, 316, 317 clinical approach, 311–313 definitions for, 311 etiologies, 312t PTSD. See posttraumatic stress disorder puff of smoke, 114 pulmonary examination, 6 pulmonary function, in ALS, 356 pure motor weakness, 353–359 pyridostigmine, 316, 470 pyrimethamine, 269 Q QT syndrome, 399 quetiapine (Seroquel), 83, 180, 188, 415

57_Toy-Neuro_Index_p473-488.indd 485

485

R radiation therapy, 446, 447, 455 Radicava (edavarone), 356, 359 radiculomyelopathy, 267 radiculopathy, 353–354, 363, 364–365 radiologically isolated syndrome MS, 215 Ramsay Hunt syndrome, 304, 305, 306, 324t rapid eye movement sleep (REM sleep), 184 Raynaud phenomenon, 343 RBD. See REM sleep behavior disorder rectal diazepam gel (Diastat), 391–393 reflexes, 191, 192 relapsing-remitting MS, 214 relative afferent pupillary defect, 201 relaxation therapy, 168 REM sleep. See rapid eye movement sleep REM sleep behavior disorder (RBD), 184, 186, 188, 189 reserpine, 46, 60 resting tremor, 41, 43, 45, 46 retinal ischemia, 113 retinal nerve fiber layer (RNFL), 214 retrobulbar neuritis, 203 return-to-play guidelines, 91, 92t, 94 riboflavin (vitamin B2), 399 rigidity, 28, 30, 31, 41, 43 Rilutek (riluzole), 356, 359 riluzole (Rilutek), 356, 359 ring-enhancing lesion, 267, 268, 269f, 270 Rinne test, 325 risk factors, 12 risperidone (Risperdal), 30, 83, 415 Ritalin (methylphenidate), 415 rivaroxaban, 100 rivastigmine, 181, 188 rizatriptan, 158, 400 RNFL. See retinal nerve fiber layer Romberg sign, 257, 258, 259 ropinirole, 44 rotigotine, 44 ruptured saccular, 105 S SAH. See subarachnoid hemorrhage sarcoidosis, 304 SBH. See subcortical band heterotropia SBP. See systolic blood pressure SCAs. See spinocerebellar ataxias SCAT3. See Sport Concussion Assessment Tool 3 Schwann cells, 329 Schwannoma, 446t scintillating scotomas, 152, 154 SCIWORA. See spinal cord injury without radiographic abnormality scopolamine, 278 scotoma, 154, 201, 203 scrapie, 251 secondary progressive MS, 214–215 second-impact syndrome, 92, 94 sedative-hypnotic agents, 21

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486

INDEX

segmental demyelination of nerve axons, 331, 332 seizures, 123, 141. See also specific types cardiogenic syncope, 139–140 defining, 119, 137, 380 with fever, 388–393 first aid for, 130t in HD, 28, 31 in metastatic brain tumors, 453 new-onset childhood, 380–385 sixth nerve palsy and, 299 selective serotonin reuptake inhibitors (SSRIs), 30, 44, 416, 437 in AD management, 180 in MS symptom management, 216 Semont maneuver, 322 sensorineural hearing loss, 443, 445 Sensory Organization Test, 90 sentinel bleed, 104 defining, 105 Seroquel (quetiapine), 83 serotonin syndrome, 44 sertraline (Zoloft), 416 sexual abuse, PNES and, 145, 149 shawl sign, 344 short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), 166 sick sinus syndrome, defining, 137 simple febrile seizure, 389, 472 simple focal seizures, 421 simple partial seizure, 126, 381, 383, 384 simple tics, 413 single-photon emission CT (SPECT), 130 sinusitis, 156 sixth nerve palsy, 294, 295 skull base tumors, 304 SMA. See spinal muscular atrophy type 1 small-vessel strokes, 98 social history, 5 spasticity, 429 SPECT. See single-photon emission CT speech therapy, 348, 357 spinal cord, 470 subacute combined degeneration of, 192 spinal cord injury complete, 65 epidemiology, 65 initial management, 66–67 long-term care and rehabilitation, 68 medical complications, 67–68 surgery and steroids in management of, 67 traumatic, 64 types of, 65–66 spinal cord injury without radiographic abnormality (SCIWORA), 67 spinal cord ischemia, 69 spinal motor neurons, 463, 464 spinal muscular atrophy (SMA) type 1, 460–461, 463, 464 spinocerebellar ataxias (SCAs), 50, 52t, 53f

57_Toy-Neuro_Index_p473-488.indd 486

clinical approach, 51–54 treatment, 54 sporadic CJD, 250, 251 Sport Concussion Assessment Tool 3 (SCAT3), 90 sports concussion incidence in, 90, 90t return-to-play guidelines, 91, 92t, 94 SSRIs. See selective serotonin reuptake inhibitors STA-MCA. See superficial temporal arterymiddle cerebral artery Standardized Assessment of Concussion, 90 STAT chemistries, 382 statins, 100 status epilepticus, 381, 382, 385, 429 stereotactic radiosurgery, 446, 447, 455 stress management, 168 stroke, 111, 174, 305, 306, 338, 339 embolic, 471 hemorrhagic, 99, 100 ischemic, 97, 102 acute, 112 clinical approach, 97–99 etiologies, 98–99 risk factor management, 100 secondary prevention, 100 treatment, 99–100 lacunar, 98 risk factor management, 100 secondary prevention, 100 small-vessel, 98 in a young patient clinical approach, 113 definitions, 112 etiologies and clinical presentations, 113–115 treatment, 114–115 structural-metabolic seizures, 120 subacute combined degeneration of spinal cord, 192 subarachnoid hemorrhage (SAH), 77, 78, 104, 155, 156 clinical approach diagnosis and prognosis, 106–107 etiologies, 105–106 treatment, 108 death from, 107 definitions, 105 subarachnoid space, defining, 105 subcortical band heterotropia (SBH), 427, 428 subcortical dementia, 177, 177t subdural hematoma, 72, 73 sudden unexpected death in epilepsy (SUDEP), 129, 134 suicide, in HD, 27 sulfadiazine, 269 sulfamethoxazole, 269 sumatriptan, 158, 400 SUNCT. See short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing

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INDEX superficial temporal artery-middle cerebral artery (STA-MCA), 115 swinging flashlight test, 202f Sydenham chorea, 28 sympathetic lesions, 281, 282 symptomatic bradycardia, 137 symptomatic febrile seizure, 389 syncope, 141, 468, 471 defining, 137 synthetic opioids, 41 syphilis, 257, 258 systolic blood pressure (SBP), 138 T tabes dorsalis, 258–263 tardive dyskinesia (TD), 27, 30, 31, 58–61 tardive syndrome (TS), 59 TBI. See traumatic brain injury TBZ. See tetrabenazine TCAs. See tricyclic antidepressants TD. See tardive dyskinesia teichopsias, 154 temporal arteritis, 157 temporal lobe CPS, 129 temporal lobe epilepsy (TLE), 120, 390 Tensilon test, 314, 317 tension-type headache, 156, 170 chronic, 166 teriflunomide, 216 tetrabenazine (TBZ), 30, 46, 60, 415 thiamine (vitamin B1), 178 third nerve palsy, 277–278, 280, 281, 282 thrombolytic therapy, 96, 101 thrombophilia conditions, 113 thymoma, 315 TIA. See transient ischemic attack tick paralysis, 336, 338, 339 tics, 412–413, 414, 416, 417 tilt-table testing, defining, 137 Tinel sign, 363, 365 tinnitus, 321, 322, 325, 326 tissue plasminogen activator (tPA), 96–97, 99–100 tizanidine, 216 TLE. See temporal lobe epilepsy Todd paralysis, 97 tolcapone, 44 tongue biting, 139 tongue fibrillations, 463, 464 tonic pupil, 279 tonic seizures, 120, 120t tonic-clonic seizures, 120, 120t, 132 top shelf syndrome, 322 topiramate (Topamax), 21, 159, 399 Tourette syndrome, 412–417 toxoplasmosis, 262, 263, 266–271, 268t, 269f Toxoplasmosis gondii, 266, 267, 268, 270 tPA. See tissue plasminogen activator transformed migraine, 169, 170 clinical approach, 165–166 defining, 165 transient ischemic attack (TIA), 96, 97, 471

57_Toy-Neuro_Index_p473-488.indd 487

487

transmissible spongiform encephalopathies (TSEs), 251 transverse myelitis, 212 traumatic brain injury (TBI), 64, 69 concussion as, 88, 94 traumatic spinal cord injury, 64 epidemiology, 65 tremor. See also essential tremor approach to, 19–21 clinical approach, 20–21 definitions for, 19 in parkinsonism, 41, 43, 45, 46 in SCA, 54, 55 Treponema pallidum, 259, 260 tricyclic antidepressants (TCAs), 167, 416 trigeminal autonomic cephalalgias, 166, 397 trigeminal neuralgia, 212 trimethoprim, 269 trinucleotide repeat expansion disease, 51 triptans, 158, 400 tropicamide, 278 TS. See tardive syndrome TSEs. See transmissible spongiform encephalopathies tuberculous meningitis, 471 Tylenol (acetaminophen), 163 Tzanck smear, 303 U Uhthoff phenomenon, 212, 218 unconsciousness, bilateral seizure without, 146 unilateral diplopia, 298, 299 unilateral manual automatisms, 128 upper motor neuron disease, 353 upper motor neuron signs, 192, 355 urinalysis, 7 urinary tract infection (UTI), delirium from, 174 V vaccination, 5 ADEM and, 220–223 Valium (diazepam), 21 valproate, 168, 383, 385 valproic acid, 132, 159, 216, 391, 392, 393 vancomycin, 230–231 variant CJD, 251 vascular dementia, 175, 176 vascular headache, 153 vascular parkinsonism, 41 vasospasm, 105 ventilation support, 356 verapamil, 159 verbal automatisms, 128 vertebral artery dissections, 113 vertebrobasilar insufficiency, 323t vertigo, 325–326 clinical approach, 321–322 definitions for, 320–321 differential diagnosis, 323t–324t treatment, 322 vesicles, 303

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488

INDEX

vestibular epilepsy, 323t vestibular migraine, 323t viral encephalitis, 35, 37, 38 viral meningitis, 226, 228, 229t, 232, 233, 471 viral vestibular neuronitis, 324t, 326 visual attentiveness, 464 visual auras, 154, 398 visual hallucinations, 187 visuospatial impairment, 189 vital signs, 5 vitamin B1, 178 vitamin B2 (riboflavin), 399 vitamin B6, 366 vitamin B12 deficiency, 178, 192, 196, 197 causes, 193–194 clinical manifestations, 194t clinical presentation, 193 differential diagnosis, 194–195 laboratory confirmation, 195 treatment, 195 vitamin D, 408 vitamin E, 60 voltage-gated calcium channels, 470

57_Toy-Neuro_Index_p473-488.indd 488

W warfarin, 100 watchful waiting, 423, 424 Weber test, 325 Wernicke encephalopathy, 178 West syndrome, 120 Westphal variant HD, 28, 31 whiplash injuries, 156 World Federation of Neurology Research Group on Motor Neuron Diseases, 355–356 World Health Organization, 253 X Xanax (alprazolam), 21 xanthochromia, 106 X-linked inheritance, 405, 406, 409 Z zidovudine, 347 Zika virus, 336 zolmitriptan, 158, 400 Zoloft (sertraline), 416

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