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F Fill the gap in your knowledge, fast! A S T FAST FACTS F A with Fast Facts – the ultimate medical handbook series C T S Multiple Sclerosis M u FAST FACTS l t i Multiple Sclerosis p l e S c 9 Epidemiology and genetics le r o s 18 Pathology i s Stella E Hughes and Gabrielle Macaron 28 The clinical picture 63 Treatment of relapses and symptoms 85 Disease-modifying treatment 120 Emerging therapies 128 Special MS populations 145 Lifestyle considerations and the multidisciplinary team 154 Advanced MS ISBN 978-3-318-06797-2 M P FKAARGSETR .CFOAMCTS 9 783318 067972 A new era of disease modificat ion and treatment Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 © S. Karger Publishers Ltd 2021 5 FAST FACTS FIFTH EDITION Multiple Sclerosis Stella E Hughes MB BCh BAO MD FRCP Consultant Neurologist Department of Neurology Royal Victoria Hospital Belfast Health and Social Care Trust Belfast, UK Gabrielle Macaron MD Neurologist Neurology Department, Hotel-Dieu de France Hospital Université Saint Joseph de Beyrouth Beirut, Lebanon Adjunct staff, Mellen Center for Multiple Sclerosis Cleveland Clinic, Cleveland, Ohio, USA Declaration of Independence This book is as balanced and practical as we can make it. Ideas for improvement are always welcome: [email protected] M P © S. Karger Pub lishers Ltd 2021 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 Fast Facts: Multiple Sclerosis First published 2000; second edition 2006; third edition 2014; fourth edition 2016 Fifth edition 2021 Text © 2021 Stella E Hughes, Gabrielle Macaron © 2021 in this edition S. Karger Publishers Ltd S. Karger Publishers Ltd, Elizabeth House, Queen Street, Abingdon, Oxford OX14 3LN, UK Tel: +44 (0)1235 523233 Book orders can be placed by telephone or email, or via the website. Please telephone +41 61 306 1440 or email [email protected] To order via the website, please go to karger.com Fast Facts is a trademark of S. Karger Publishers Ltd. 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 Stella E Hughes and Gabrielle Macaron 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 978-3-318-06797-2 Hughes SE (Stella) Fast Facts: Multiple Sclerosis/ Stella E Hughes, Gabrielle Macaron M MTPyriepndetisecedatl t iiinnll guth sbteyr aU AtKimo nwnsie tbth,y CX Ahpneenn©dain emSan.ia t,K r IPinaar rdiDngiaetu..rt tPou, bW lisithheerrsn sLetda, 2U0K2.1 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 P List of abbreviations 5 Introduction 7 Epidemiology and genetics 9 Pathology 18 The clinical picture 28 Treatment of relapses and symptoms 63 Disease-modifying treatment 85 Emerging therapies 120 Special MS populations 128 Lifestyle considerations and the multidisciplinary team 145 Advanced MS 154 Useful resources 160 Index 161 M P © S. Karger Pub lishers Ltd 2021 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 M P © S. Karger Pub lishers Ltd 2021 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 List of abbreviations 9-HPT: 9-hole peg test FDA: (US) Food and Drug Administration AAN: American Academy of Neurology FLAIR: fluid-attenuated inversion recovery ACTH: adrenocorticotropic hormone HLA: human leukocyte antigen ADEM: acute disseminated encephalomyelitis IFN-β: interferon-beta ADL: activities of daily living IgG: immunoglobulin G AHSCT: autologous hematopoietic IL: interleukin stem cell transplantation INO: internuclear ophthalmoplegia AQP-4: aquaporin 4 IPMSSG: International Pediatric bd: twice daily Multiple Sclerosis Study Group CIS: clinically isolated syndrome i.v.: intravenous CNS: central nervous system JC: John Cunningham (virus) CSF: cerebrospinal fluid MHC: major histocompatibility complex CT: computed tomography MOG: myelin oligodendrocyte DHODH: dihydroorotate glycoprotein dehydrogenase MRI: magnetic resonance imaging DIS: dissemination in space MS: multiple sclerosis DIT: dissemination in time MSFC: Multiple Sclerosis Functional DMT: disease-modifying therapy Composite EAN: European Academy of MSN: multiple sclerosis specialist Neurology nurse EBV: Epstein–Barr virus NEDA: no evidence of disease activity ECTRIMS: European Committee of NMO: neuromyelitis optica Treatment and Research in Multiple Sclerosis NMOSD: neuromyelitis optica spectrum disorder EDSS: Expanded Disability Status Scale Nrf2: nuclear factor (erythroid- M EMA: European Medicin©e Ss .A Kgaerngceyr Pub lishdPeeCrsrRi vL:e tpdd o 22l0y)2-ml1ikerea 2se chain reaction 5 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 P Fast Facts: Multiple Sclerosis PEG: percutaneous enteral SDMT: Symbol Digit Modalities Test gastrostomy SLE: systemic lupus erythematosus PLEX: plasma exchange SNRI: serotonin–norepinephrine PML: progressive multifocal reuptake inhibitor leukoencephalopathy SPMS: secondary progressive multiple POMS: pediatric-onset multiple sclerosis sclerosis STIR: short time inversion recovery PPMS: primary progressive multiple T25FW: timed 25-foot walk sclerosis TKI: tyrosine kinase inhibitor PRMS: progressive relapsing multiple sclerosis TNF: tumor necrosis factor RCT: randomized controlled trial UTI: urinary tract infection RIS: radiologically isolated syndrome UV: ultraviolet (light) RRMS: relapsing remitting multiple VCAM1: vascular cell adhesion sclerosis molecule-1 S1P: sphingosine 1-phosphate WHO: World Health Organization M P 6 © S. Karger Pub lishers Ltd 2021 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 Introduction Multiple sclerosis (MS) is a leading cause of disability in young adults, and it has a significant effect on patients’ quality of life, family plans and careers. By causing varying degrees of physical and cognitive disability, MS carries a considerable individual and societal economic burden. Fortunately, we are entering a new era in the management of MS. Several recent studies support initiating treatment early in the disease course with higher-efficacy disease-modifying therapies in patients with relapsing-remitting MS. This approach has been associated with better long-term outcomes, specifically a lower risk of conversion to secondary progressive MS. Moreover, new molecules with the potential to induce myelin repair or halt the neurodegenerative process are in the pipeline for the treatment of progressive MS. Coupled with a recent update to the diagnostic criteria, clinicians can now diagnose and treat patients in the earliest phases of their disease. In this new edition of Fast Facts: Multiple Sclerosis, we present the latest evidence on disease pathogenesis and all clinical aspects of the condition, as well as the latest on disease-modifying therapies and other potential treatments. Given the need for multidisciplinary management of MS, we have written this resource for the benefit of all health professionals involved in the care of patients with this complex disease. Acknowledgments. The authors wish to thank the authors of the third and fourth editions of this resource, Drs Michael Barnett, Omar Malik, Ann Donnelly, Mary Rensel and Orla Gray, for the strong foundation on which this new edition is based. M P © S. Karger Pub lishers Ltd 2021 7 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 M P © S. Karger Pub lishers Ltd 2021 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36 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. Periods of relapse and remission occur in the early stages of the disease, 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 2020 suggest that it affects 2.8 million people worldwide.1 Given the lack of complete surveillance data in some countries, this is likely to be an underestimate. Prevalence. The worldwide prevalence of MS appears to be increasing. This is related to many factors, including improved counting methods, better diagnosis, global population growth, people with MS living longer (through improved treatment and support) and a true increase in disease incidence, especially in females. The number of people with MS in a given population at any one time is usually expressed as cases per 100 000 population. Prevalence varies worldwide, but MS is most prevalent in northern European populations, especially in individuals of Nordic descent, and is notably more prevalent in temperate than equatorial regions. While, globally, the median estimated prevalence of MS is 36 per 100 000,1 in some countries, prevalence exceeds 300 per 100 000. Regionally, the median estimated prevalence of MS is greatest in Europe and the Americas (133 and 112 per 100 000, respectively).1 However, prevalence varies significantly both within regions and PM within countries. For© e xSa. mKaprglee,r iPnu bE liushroerpse L, tSda 2n0 2M1arino and Germany 9 Downloaded by: Consortium Luxembourg185.106.24.55 - 1/19/2023 1:57:36