Alastair Wilkins Editor Progressive Multiple Sclerosis Second Edition 123 Progressive Multiple Sclerosis Alastair Wilkins Editor Progressive Multiple Sclerosis Second Edition Editor Alastair Wilkins Southmead Hospital University of Bristol Bristol United Kingdom ISBN 978-3-319-65920-6 ISBN 978-3-319-65921-3 (eBook) https://doi.org/10.1007/978-3-319-65921-3 Library of Congress Control Number: 2017960800 © Springer International Publishing AG 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface Since the first edition of Progressive Multiple Sclerosis, knowledge concerning the disease has advanced significantly. The drive for therapies to address disease pro- gression is active and our understanding of the pathophysiology of the disease grows year on year. This has helped inform development of new treatments, and the hope is that the significant advances in relapsing and remitting disease will be rep- licated in progressive MS over the coming years. Importantly, the first successful clinical trials in progressive MS are being reported and a novel drug therapy approved and licenced. The second edition of Progressive Multiple Sclerosis is intended to update read- ers with an overview of the current state of knowledge concerning this common disease. The field is evolving and new concepts have arisen since the publication of the first edition. New chapters on novel therapies and rehabilitation have been added and existing chapters updated. It is hoped that this book will be of use to neurolo- gists, both those in training and those who have practiced for many years. The book composes chapters covering the expanse of knowledge on progressive multiple scle- rosis from clinical features and epidemiology through to current and future treatments. Bristol, UK Alastair Wilkins v Acknowledgments The editor would like to acknowledge the hard work and determination of all the authors who contributed to this book. vii Contents 1 General Introduction: What Is Progressive Multiple Sclerosis? ......... 1 Alastair Wilkins and Stanley Hawkins 2 Epidemiology of Progressive Multiple Sclerosis .................................... 31 Katharine Harding and Neil Robertson 3 The Neuropathology of Progressive Multiple Sclerosis ........................ 49 Nikos Evangelou, Simon M.L. Paine, and Emma C. Tallantyre 4 Mechanisms of Disease Progression ....................................................... 71 Alastair Wilkins 5 Imaging Disease Progression ................................................................... 93 Declan Chard and Olga Ciccarelli 6 Biomarkers of Disease Progression ........................................................ 123 Axel Petzold 7 Symptomatic Treatment for Progressive Multiple Sclerosis ................ 155 Steven M. Bailey and Claire M. Rice 8 Trials of Licenced RRMS DMTs in Progressive MS ............................ 207 Michael Hutchinson and David P.J. Hunt 9 Trials of Novel Therapies Specifically for Progressive MS ................... 233 R.S. Nicholas, A. Nandoskar, M. Hutchinson, and T. Friede 10 Rehabilitation in People with Progressive MS ...................................... 253 Jennifer Freeman 11 Future Therapies for Progressive Multiple Sclerosis ............................ 275 Neil Scolding Index ................................................................................................................ 301 ix Chapter 1 General Introduction: What Is Progressive Multiple Sclerosis? Alastair Wilkins and Stanley Hawkins 1.1 Introduction Over the past decade major advances in multiple sclerosis (MS) therapies have occurred, as well as significant increases in our understanding of disease aetiology: over a hundred susceptibility genes have been identified, complex immunological pathways have been mapped out and rapid changes in imaging techniques have vastly added to our understanding of temporal changes occurring in the course of the disease. Numerous large scale drug trials have been conducted and increasingly efficacious treatment options are emerging with effects on relapse frequency, allow- ing the clinician an array of therapeutic options. Indeed for patients with relapsing and remitting disease, therapies are offering the real prospect of significant disease modification with reduction in disease burden and disability [1]. Yet despite these advances, treatments for those with progressive MS remain limited and, once estab- lished, current drug therapies have little influence on the disease course of progres- sive MS. Patients with progressive disease are often frustrated by the lack of effective disease modifying therapies and often feel ‘left behind’ when compared to the range of treatments being offered to relapsing patients. This is an understandable frustration and one which is often difficult for patients to comprehend. Having said that, knowledge concerning the disease mechanisms is burgeoning and many research groups are starting to develop strategies to treat disease progression. As time goes on, a clearer understanding of exactly what needs to be treated is A. Wilkins (*) Institute of Clinical Neurosciences, University of Bristol, Southmead Hospital, Bristol, UK e-mail: [email protected] S. Hawkins Department of Neurology, Royal Victoria Hospital, Belfast, UK © Springer International Publishing AG 2018 1 A. Wilkins (ed.), Progressive Multiple Sclerosis, https://doi.org/10.1007/978-3-319-65921-3_1 2 A. Wilkins and S. Hawkins becoming apparent and improved trial protocols are being developed. At the heart of such strategies is an increasing knowledge of the pathophysiology of disease progression. The second edition of Progressive Multiple Sclerosis will review the current state of knowledge concerning disease progression and put it in the context of developing and future therapies for this particular phase of MS. To set the scene, in this chapter some general features of MS will be discussed and definitions and clinical characteristics of progressive MS will be presented. 1.2 Multiple Sclerosis in General 1.2.1 Presentation and Diagnosis of MS The diagnosis of MS rests heavily on clinical assessment. A history of ‘attacks’ (relapses or exacerbations) should be sought and consist of episodes typical of acute inflammatory demyelinating events in the CNS with duration of at least 24 h. Such attacks will typically be characterised by visual disturbance (optic nerve); hemisensory change (cerebral white or grey matter); hemiparesis (cerebral white or grey matter); vertiginous symptoms and diplopia (brainstem); or parapa- resis and urinary dysfunction (spinal cord). A detailed neurological history docu- menting more than one episode of such an attack, coupled with an examination revealing objective clinical evidence for more than one lesion within the central nervous system, is enough to make a diagnosis of MS in the appropriate clinical setting. In general patients presenting in such a manner will, however, have inves- tigations both to confirm clinical suspicions and also to exclude other causes. Magnetic resonance imaging (MRI) is the paraclinical test most commonly employed in MS diagnosis, often combined with spinal fluid analysis and electro- physiological tests. For the ‘typical’ patient, the diagnosis may not prove to be too challenging. However, in a number of scenarios the diagnosis may not be immediately clear and may only transpire after a further clinical episode has occurred or additional paraclinical evidence has been obtained. In order to address some of the issues relating to MS diagnosis and also to allow an ‘earlier’ diagnosis of MS, a number of criteria have been developed. Most notably, in recent times, the McDonald cri- teria for MS have been developed combining clinical and paraclinical markers of disease dissemination in time and space [2, 3]. Thus, if a patient has two attacks suggestive of an inflammatory central nervous system lesion, but only objective evidence of one lesion on examination, then the diagnosis of MS can be supported by MRI dissemination in space (one or more T2 lesions in at least 2 of 4 CNS areas typically affected by MS (periventricular, juxtacortical, infratentorial or spi- nal cord). Similarly, when patients have had only one attack but there is objective 1 General Introduction: What Is Progressive Multiple Sclerosis? 3 evidence on examination of two or more lesions, the diagnosis of MS may be sup- ported by MRI evidence of dissemination in time (either new T2 lesion(s) or new gadolinium-enhancing lesion(s) on follow-up MRI; or the simultaneous presence of both an asymptomatic gadolinium enhancing lesion and non-enhancing lesions on the same scan). Regarding a clinically isolated syndrome (CIS; one clinical attack suggestive of CNS inflammation with objective clinical evidence for one lesion on examination), the McDonald criteria require MRI dissemination in both space and time (one or more T2 lesions in at least 2 of 4 CNS areas typically affected by MS (periventricular, juxtacortical, infratentorial or spinal cord) for dissemination in space; and either new T2 lesion(s) or new gadolinium-enhancing lesion(s) on follow-up MRI or the simultaneous presence of both an asymptomatic gadolinium enhancing lesion and non-enhancing lesions on the same scan for dis- semination in time). In summary, the McDonald criteria ‘allow’ dissemination in space and time to be fulfilled by observing MRI patterns or changes in MRI lesions over time in those patients who would otherwise not meet the clinical criteria for the diagnosis of MS. Whilst earlier diagnosis has been driven by the notion that earlier treatment may lead to a long-term reduction in disability, there is still much to be learnt about the optimal time and type of disease modifying therapies for CIS or ‘McDonald criteria MS’. The diagnosis of primary progressive MS (PPMS) and secondary progressive MS (SPMS) will be discussed later in this chapter. 1.2.2 Aetiological Factors in MS An exact understanding of the precise cause of MS is still lacking. Despite this, important recent advances in MS aetiology have been made. In many parts of the world MS is a common disorder, the incidence of which is dependent on a number of factors including age, gender, family history and geographical location [4]. These factors, particularly familial risks and the variations in incidence depen- dent on geographical latitude have provided clues concerning aetiological factors in the disease. Most now accept that underlying the pathogenesis of the disease are combinations of genetic factors leading to disease susceptibility coupled to environmental influences. Of the genetic influences, certain polymorphisms in the human leucocyte antigen (HLA) region of chromosome 6, notably the DRB1*1501 allele, appear to confer the largest portion of the genetic susceptibil- ity [5, 6], but this is only about 12% of the genetic susceptibility. Perhaps not surprisingly a number of other variations in genes regulating the immune system confer disease susceptibility [7]. The relationship between genetic factors and disease course, that is to say what genetic factors regulate aggressiveness of the