Progressive Multiple Sclerosis

309 Pages·2018·5.254 MB·English

by  Alastair Wilkins (eds.)

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
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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: [e-mail]
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