Table Of Content

F Fast Facts “I find the revised edition of Fast Facts MS a good reference for the a s understanding of MS as well as the intricate process of diagnosing MS.” t F Fast Facts: Non Smit, Director, Multiple Sclerosis South Africa Western Cape a c t s Multiple M u l t i p Fast Facts: l Sclerosis e Multiple Sclerosis S c l e r o 7 Epidemiology and genetics s i s Mary Rensel and Orla Gray 15 Pathology Fourth edition 25 The clinical picture 59 Treatment of relapses and symptoms 79 Disease-modifying treatment 105 Emerging therapies 113 Special MS populations 125 Lifestyle considerations and the multidisciplinary team 134 Advanced multiple sclerosis F o u r t h ISBN 978-1-910797-23-5 e d it io n the best offers are on fastfacts.com 9 781910 797235 © 2016 Health Press Ltd. www.fastfacts.com Fast Facts Fast Facts: Multiple Sclerosis Fourth edition Mary Rensel MD Staff Neurologist in Neuroimmunology Mellen Center for Multiple Sclerosis Treatment and Research Cleveland Clinic Cleveland, OH, USA Orla Gray MD FRCP Neurologist with specialist interest in Multiple Sclerosis Ulster Hospital Upper Newtownards Road Belfast, UK Declaration of Independence This book is as balanced and as practical as we can make it. Ideas for improvement are always welcome: [email protected] © 2016 Health Press Ltd. www.fastfacts.com Fast Facts: Multiple Sclerosis First published 2000; second edition 2006; third edition 2014 Fourth edition September 2016 Text © 2016 Mary Rensel, Orla Gray © 2016 in this edition Health Press Limited Health Press Limited, Elizabeth House, Queen Street, Abingdon, Oxford OX14 3LN, UK Tel: +44 (0)1235 523233 Book orders can be placed by telephone or via the website. For regional distributors or to order via the website, please go to: fastfacts.com For telephone orders, please call +44 (0)1752 202301. Fast Facts is a trademark of Health Press Limited. 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, without the express permission of the publisher. The rights of Mary Rensel and Orla Gray to be identified as the authors of this work have been asserted in accordance with the Copyright, Designs & Patents Act 1988 Sections 77 and 78. The publisher and the authors have made every effort to ensure the accuracy of this book, but cannot accept responsibility for any errors or omissions. For all drugs, please consult the product labeling approved in your country for prescribing information. Registered names, trademarks, etc. used in this book, even when not marked as such, are not to be considered unprotected by law. A CIP record for this title is available from the British Library. ISBN 978-1-910797-23-5 Rensel (Mary) Fast Facts: Multiple Sclerosis/ Mary Rensel, Orla Gray Cover image: Colored sagittal fluid-attenuated inversion recovery MRI scan showing globular and pericallosal lesions in a patient with MS. Medical illustrations by Annamaria Dutto, Withernsea, UK. Typesetting by Thomas Bohm, User Design, Illustration and Typesetting, UK. Printed in the UK w ith Xpedient Print. © 2016 Health Press Ltd. www.fastfacts.com List of abbreviations 4 Introduction 5 Epidemiology and genetics 7 Pathology 15 The clinical picture 25 Treatment of relapses and symptoms 59 Disease-modifying treatment 79 Emerging therapies 105 Special MS populations 113 Lifestyle considerations and the multidisciplinary team 125 Advanced multiple sclerosis 134 Useful resources 140 Index 142 © 2016 Health Press Ltd. www.fastfacts.com List of abbreviations ACE: angiotensin-converting enzyme IFNb: interferon-beta (inhibitor) Ig: immunoglobulin ACTH: adrenocorticotropic hormone INO: internuclear ophthalmoplegia ADEM: acute disseminated HLA: human leukocyte antigen encephalomyelitis LETM: longitudinally extensive AHSCT: autologous hematopoietic transverse myelitis stem cell transplantation LFT: liver function test APC: advanced practice clinician MHC: major histocompatibility AQP-4: aquaporin-4 complex ASA: acetylsalicylic acid (aspirin) MRI: magnetic resonance imaging CBC: complete blood count MS: multiple sclerosis CIS: clinically isolated syndrome MSFC: Multiple Sclerosis Functional CNS: central nervous system Composite CSF: cerebrospinal fluid NMO: neuromyelitis optica DIS: dissemination in space NSAID: non-steroidal anti- inflammatory drug DIT: dissemination in time PLEX: plasma exchange DMT: disease-modifying treatment PML: progressive multifocal EBV: Epstein–Barr virus leukoencephalopathy EDSS: Expanded Disability Status Scale RAPD: relative afferent pupillary defect EMG: electromyography SLE: systemic lupus erythematosus ENA: extractable nuclear antigen STIR: short time inversion recovery FBC: full blood count (imaging) FDG-PET: fludeoxyglucose positron UV: ultraviolet emission tomography FLAIR: fluid attenuated inversion recovery (imaging) 4 © 2016 Health Press Ltd. www.fastfacts.com Introduction Multiple sclerosis (MS) affects people in the most productive period of their lives, affecting quality of life, family and career. MS produces both physical and neuropsychiatric effects, and carries considerable individual and societal economic burden. Since the last edition of this book, ‘no evidence of disease activity’ (NEDA), or ‘freedom from disease activity’ has been proposed as a new treatment target in MS. NEDA is defined as no relapses, no increase in disability or no new or active (enhancing) lesions on MRI. The first pharmaceutical products for progressive MS and the first remyelination trial have shown positive effects on nerve repair, and for the youngest patients with MS, some of the risk factors have been elucidated. These developments may herald a new era for MS management. Coupled with recent developments in imaging, they are helping clinicians to diagnose and potentially treat MS in the earliest phases of the disease. . In this new edition of Fast Facts: Multiple Sclerosis we hope to emphasize the sense of optimism embodied by these advances. Here, we present the latest evidence on disease pathomechanisms, clinical aspects and modern diagnostic criteria, and review novel therapies that have been recently incorporated into an expanding MS treatment armamentarium. We also emphasize the importance of multidisciplinary management in patients with MS, and with this in mind have written this handbook for the benefit of all healthcare professionals involved in the care of patients with this complex disease. Acknowledgments. The authors wish to thank the authors of the third edition of Fast Facts: Multiple Sclerosis, Drs Michael Barnett, Omar Malik and Ann Donnelly, for the strong foundation on which this new edition is based. 5 © 2016 Health Press Ltd. www.fastfacts.com © 2016 Health Press Ltd. www.fastfacts.com 1 Epidemiology and genetics Multiple sclerosis (MS) is a neurological condition resulting from inflammation and degeneration within the central nervous system (CNS). This inflammation can affect different sites at different times, producing a variety of symptoms and signs. In the early stages there are periods of relapse and remission, and in most patients a slowly progressive course ensues within one to two decades of disease onset. The cause of MS is unknown, but dysregulation of the immune system is central to the pathogenesis of the disease. Epidemiology MS is the leading cause of neurological disability in the young and middle-aged populations of the developed world. Survey figures from 2013 suggest that it affects around 100 000 people in the UK, 21 000 in Australia and 400 000 in the USA, and an estimated 2.3 million people worldwide. This is likely to be a significant underestimate as there is little published information on populations in many countries. Prevalence. The number of people with MS in a given population at any one time is usually expressed as cases per 100 000 population. MS is most prevalent in northern European Caucasian populations, especially individuals of Nordic descent, and is notably more prevalent in temperate than equatorial regions. The worldwide prevalence of MS appears to be increasing: this is related to many factors, including earlier diagnosis, an aging population and a true increase in disease incidence, especially in females. Prevalence varies worldwide and in some countries exceeds 250 per 100 000. Globally, the median estimated prevalence of MS is 33 per 100 000. Regionally, the median estimated prevalence of MS is greatest in North America and Europe (140 and 108 per 100 000, respectively). The estimated prevalence is 164 per 100 000 people in the UK, 95.6 per 100 000 in Australia and 135 per 100 000 in the USA. Prevalence varies significantly both within regions and within countries. 7 © 2016 Health Press Ltd. www.fastfacts.com Fast Facts: Multiple Sclerosis Incidence. The number of new cases per 100 000 population per year can indicate changes in the risk of a disease within a population, and can signify whether the disease frequency is increasing in a population. It is not affected by changes in survival. The incidence of MS, which peaks at age 30, appears to be rising in both the northern and southern hemispheres, particularly in women. The median estimated global incidence of MS is 2.5 per 100 000 per year, but in some countries the incidence may exceed 10 per 100 000 per year. Geo-epidemiology of MS. The prevalence of MS is significantly associated with latitude, particularly in populations of European descent (Figure 1.1). The ‘latitudinal gradient’ in MS has been confirmed by independent studies in Australia, New Zealand and the USA, with exceptions in Sardinia and northern Scandinavia. In Australia, the prevalence in Tasmania is six times greater than that in northern Queensland. Genetic variation between geographically People per 100 000 with MS 240–300 60–120 180–240 0–60 120–180 Data not provided Figure 1.1 Geographic distribution of MS, showing a greater prevalence at high latitudes. Source: Atlas of MS Database. Multiple Sclerosis International Federation, 2013. www.atlasofms.org, last accessed 8 18 May 2016. © 2016 Health Press Ltd. www.fastfacts.com Epidemiology and genetics discrete populations has been invoked as one explanation for this observation, particularly within the human leukocyte antigen (HLA). However, a statistically significant relationship between MS prevalence and latitude persists in some European populations even after adjustment for HLA-DRB1 allele frequency, supporting a role for environmental factors that vary with latitude (e.g. ultraviolet [UV] light exposure, viral infections and vitamin D levels). Sex. MS is more common in women than men, at a ratio of 2–3:1. In Denmark, where an MS registry has been ongoing since 1948, there appears to be an increase in the incidence of MS in women, with a stable rate in the male population. An increasing incidence in females only has also been observed in Canada, Finland, Japan and southern hemisphere populations such as Australia. The pediatric MS population has a prepubertal sex ratio of 1:1, pointing to a likely association between sex hormones and disease onset. Environmental risk factors include: • UV radiation and season of birth • levels of dietary vitamin D • Epstein–Barr virus (EBV) infection • smoking • migration. Ultraviolet radiation and season of birth. The latitudinal prevalence gradient for MS may be explained in part by a relationship to exposure to UV radiation from sunlight, as there is an association between low levels of UVB exposure and development of MS. This may explain the ‘season of birth effect’ whereby those born in spring (April) in countries in the Northern hemisphere have a significantly higher relative risk of developing MS than those born in winter months (October). This may be related to maternal exposure to UV light. Dietary vitamin D. There is an association between low levels of vitamin D and a number of diseases, including MS. Diet, dietary supplements and ambient UV exposure are all sources of vitamin D. Populations exposed to limited sunlight but who consume diets rich in fatty fish, a good source of vitamin D, have lower MS 9 © 2016 Health Press Ltd. www.fastfacts.com