Multiple Sclerosis DIAGNOSIS AND THERAPY EDITED BY Howard L. Weiner and James M. Stankiewicz
Multiple Sclerosis
Multiple Sclerosis Diagnosis and Therapy EDITED BY Howard L. Weiner, MD Robert L. Kroc Professor of Neurology Director, Co-Director, Center for Neurologic Diseases James M. Stankiewicz, MD Assistant Professor of Neurology Director of Education, Neurology Clerkship Director
This edition first published 2012, Ó 2012 by John Wiley & Sons Ltd Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley s global Scientific, Technical and Medical business with Blackwell Publishing. Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/ wiley-blackwe ll The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Multiple sclerosis : diagnosis and therapy / edited by Howard L. Weiner, James M. Stankiewicz. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-0-470-65463-7 (hardcover : alk. paper) ISBN-10: 0-470-65463-5 I. Weiner, Howard L. II. Stankiewicz, James M. [DNLM: 1. Multiple Sclerosis etiology. 2. Multiple Sclerosis therapy. WL 360] LC classification not assigned 616.8 34 dc23 2011031415 A catalogue record for this book is available from the British Library. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Set in 9.5/13pt Meridien by Thomson Digital, Noida, India 1 2012
Contents List of Contributors, vii Preface, ix Part I Pathology and Diagnosis, 1 1 Disease Pathogenesis, 3 Roopali Gandhi and Howard L. Weiner 2 Biomarkers, 26 Manuel Comabella and Samia J. Khoury 3 Epidemiology and Genetics, 56 Philip L. De Jager 4 Diagnosis, 77 James M. Stankiewicz, Varun Chaubal, and Guy J. Buckle 5 Pediatric Multiple Sclerosis and Acute Disseminated Encephalomyelitis, 101 Tanuja Chitnis 6 Magnetic Resonance Imaging in Multiple Sclerosis, 136 Mohit Neema, Antonia Ceccarelli, Jonathan S. Jackson, and Rohit Bakshi 7 Predicting Clinical Course, 163 Brian Healy and Maria Liguori Part II Management, 181 8 Medication Treatment in Multiple Sclerosis, 183 James M. Stankiewicz and Samia J. Khoury 9 Symptom Management, 213 Lynn Stazzone and Brandon Brown 10 Cognitive Dysfunction in Multiple Sclerosis, 239 Bonnie I. Glanz and Maria K. Houtchens v
vi Contents 11 Depression and Other Psychosocial Issues in Multiple Sclerosis, 263 David J. Rintell 12 Future Therapeutic Approaches, 283 Howard L. Weiner and Laura Edwards Index, 301
List of Contributors Rohit Bakshi, MD FAAN Laboratory for Neuroimaging Research, Brandon Brown, PharmD Novartis Pharmaceuticals West Roxbury, MA, USA Guy J. Buckle, MD MPH Antonia Ceccarelli, MD Laboratory for Neuroimaging Research, Varun Chaubal, MD Tanuja Chitnis, MD Assistant Professor of Neurology ; Director, Partners Pediatric Multiple Sclerosis Center Department of Pediatric Neurology Massachusetts General Hospital for Children Manuel Comabella, MD Centre d Esclerosi Multiple de Catalunya, CEM-Cat Unitat de Neuroimmunologia Clinica Hospital Universitari Vall d Hebron (HUVH) Barcelona, Spain Philip L. De Jager, MD, PhD Program in Translational NeuroPsychiatric Genomics Institute for the Neurosciences and, Boston Program in Medical & Population Genetics Broad Institute of Harvard University and Massachusetts Institute of Technology Cambridge, MA, USA Laura Edwards, PhD Roopali Gandhi, PhD Bonnie I. Glanz, PhD vii
viii List of Contributors Brian Healy, PhD Maria K. Houtchens, MD, Msci Director, Women s Health Program Jonathan S. Jackson, PhD Laboratory for Neuroimaging Research, Samia J. Khoury, MD, FAAN Jack, Sadie and David Breakstone Professor of Neurology Co-Director, Maria Liguori, MD, PhD National Research Council Institute of Neurological Sciences Mangone, Italy Laboratory for Neuroimaging Research, and Mohit Neema, MD Laboratory for Neuroimaging Research David J. Rintell, EdD Clinical Instructor in Psychiatry Lynn Stazzone, RN, MSN, NP
Preface Until it was shown that immunosuppressive therapy could affect the course of multiple sclerosis (MS) in the early 1980s, the disease was considered to be untreatable. Today a patient receiving a diagnosis of MS has reason to hope. Great strides have been made in our understandings of MS in the last three decades and several drugs have now been approved by the FDA for the treatment of this disease. Because we now have treatments to offer, a diagnosis of MS can be made more frequently and often at earlier stages of the disease. A number of genetic loci involved in susceptibility to the disease have been identified. Immunologic discoveries continue, sometimes driven by treatments that are shown to confer protection from the disease. Although the T cell remains at center stage, the B cell now shares some of the limelight with other components of the immune system, such as dendritic cells and microglia. We are now able to profile the immune system for signatures that are characteristic of different stages of the disease. This ability will ultimately help us to administer a more individualized treatment, and increase our chances of success. We now have the first orally approved medication with others on the way. Despite these advances, many challenges remain. MS is still the most common non-traumatic cause of disability in the young. More sophisticated imaging techniques have revealed that injury occurs early in the disease and that even tissue with a normal appearance can be damaged. MS can affect not only white matter, but gray matter. We now better appreciate how MS affects children, often causing cognitive and psychiatric challenges. Sometimes, notwithstanding our best efforts, the symptoms of MS remain and we have no medicine that can halt the progressive phase of the disease. This book endeavors to define our current understanding of MS in terms of diagnosis and treatment, as well as its underlying pathophysiology. We continue to be deluged with clinical and research findings that expand our conception of the disease, and have done our best to provide an up-todate, informative, and as engaging as possible view of MS in the current era. We hope it will also serve as a practical guide that can be used to help clinicians to provide the best possible care to patients. ix
PART I Pathology and Diagnosis
CHAPTER 1 Disease Pathogenesis Roopali Gandhi and Howard L. Weiner, Center for Neurologic Diseases, and,, Introduction Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that primarily affects young adults [1]. The role of immune system in MS is indisputable. The primary function of the immune system is to protect the body against myriad ever-evolving pathogens and it broadly falls into two categories the innate immune system and adaptive immune system. The important difference in the innate and adaptive arms of immunity is that the adaptive immune system is highly specific toward an antigen. The immune-mediated inflammation of MS was initially recognized in 1948 by Elvin Kabat who observed the presence of oligoclonal immunoglobulins in the cerebrospinal fluid from MS patients. In following years, great strides have been made in understanding the role of both adaptive and innate immune system in Experimental Autoimmune Encephalomyelitis (EAE, an animal model of MS) MS but it is not known the degree to which the adaptive and innate immune systems interact in MS. In most instances, MS begins as a relapsing remitting disease that in many patients becomes secondary progressive. Approximately 10% of patients begin with a primary progressive form of the disease. Although primary progressive MS differs clinically and in treatment response from relapsing MS [2], it is somehow related as there are families in which one member has relapsing MS and another the primary progressive form. Not all patients enter the secondary progressive stage and, in addition to these, there are benign and malignant forms of MS. This heterogeneity of the clinical course may relate to changes that occur in the adaptive and innate immune system over the course of the illness (Figure 1.1). The progressive forms of the disease are the most disabling and are likely similar in terms of pathogenic mechanisms. Epidemiologic studies have raised the question Multiple Sclerosis: Diagnosis and Therapy, First Edition. Edited by Howard L. Weiner and James M. Stankiewicz. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley and Sons, Ltd. 3