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`MULTIPLE
`SCLEROSIS
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`ALASTAIR COMPSTON
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`Christian Confavreux
`Hans Lassmann
`Ian McDonald
`David Miller
`John Noseworthy
`Kenneth Smith
`Hartmut Wekerle
`
`CHURCHILL
`LIVINGSTONE
`ELSEVIER,
`
`ARGENTUM EX1023
`
`Page 1
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`

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`
`McAlpine's
`MULTIPLE SCLEROSIS
`
`Page 2
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`Portrait by Howard Morgan. Reproduced by permission of Harveian Librarian, Royal College of Physicians of London.
`
`Commissioning Editor: Susan Pioli
`Project Development Manager: Louise Cook
`Project Managers; Cheryl Brant (Elsevier), Gillian Whytock (Prepress Projects)
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`Page 3
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`

`

`I
`
`McAlpine's
`MULTIPLE SCLEROSIS
`
`FOURTH EDITION
`
`Alastair Compston PHD FRCP FMedSci
`Professor of Neurology, University of Cambridge, Cambridge, UK
`
`Christian Confavreux MD
`Professor of Neurology, HSpital Neurologique, Hospices Civils de Lyon and University Claude Bernard,
`Lyon, France
`
`Hans Lassmann MD
`Professor of Neuroimmunoiogy, Center for Brain Research, Medical University of Vienna, Vienna, Austria
`Ian McDonald PhD FRCP FMedSci
`Professor Emeritus of Clinical Neurology, Institute of Neurology, University College London, London, UK
`David Miller MD FRCP FRACP
`Professor of Clinical Neurology, Institute of Neurology, University College London, and Consultant
`Neurologist, National Hospital for Neurology and Neurosurgery, London, UK
`
`John Noseworthy MD FRCPC
`Professor and Chair, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
`Kenneth Smith PHD
`Professor of Neurophysiology and Head of Neuroinflammation Group, King's College London School of
`Medicine at Guy's, London, UK
`
`Hartmut Wekerle MD
`Professor and Director, Max Planck Institute of Neurobiology, Planegg-Martinsried, Germany
`
`CHURCHILL
`LIVINGSTONE
`
`' i
`V^V:
`
`ELSEVIER
`
`Page 4
`
`

`

`CHURCHILL
`LIVINGSTONE
`ELSEVIER
`© 2006, Elsevier Inc. All rights reserved.
`
`First published December 2005
`
`First edition 1985
`Second edition 1992
`Third edition 1998
`
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`ly^j
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`3
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`/#
`11
`
`Contents
`
`Preface to the fourth edition
`
`SECTION 1
`THE STORY OF MULTIPLE SCLEROSIS
`
`1 The story of multiple sclerosis
`Alastair Compston, Hans Lassmann and lan McDonald
`The evolving concept of multiple sclerosis
`Naming and classifying the disease: 1868-1983
`Clinical descriptions of multiple sclerosis: 1838-1915
`Personal accounts of multiple sclerosis: 1822-1998
`The social history of multiple sclerosis
`The pathogenesis and clinical anatomy of multiple
`sclerosis: 1849-1977
`The laboratory science of multiple sclerosis: 1913-1981
`Discovery of glia and remyelination: 1858--1983
`The aetiology of multiple sclerosis: 1883-1976
`Attitudes to the treatment of multiple sclerosis: 1809-1983
`
`SECTION 2
`THE CAUSE AND COURSE OF MULTIPLE SCLEROSIS
`
`2 The distribution of multiple sclerosis
`Alastair Compston and Christian Confavreux
`The rationale for epidemiological studies in multiple
`sclerosis
`Definitions and statistics in epidemiology
`Strategies for epidemiological studies in multiple sclerosis
`The geography of multiple sclerosis
`Multiple sclerosis in Scandinavia
`Multiple sclerosis in the United Kingdom
`Multiple sclerosis in the United States
`Multiple sclerosis in Canada
`Multiple sclerosis in Australia and New Zealand
`Multiple sclerosis in Continental Europe
`Multiple sclerosis in the Middle East
`Multiple sclerosis in Africa
`Multiple sclerosis in Asia and the Far East
`Multiple sclerosis in migrants
`Epidemics and clusters of multiple sclerosis
`The environmental factor in multiple sclerosis
`
`3 The genetics of multiple sclerosis
`Alastair Compston and Hartmut Wekerle
`Genetic analysis of multiple sclerosis
`Methods of genetic analysis
`Racial susceptibility
`
`viii
`
`1
`
`3
`
`Gender differences in susceptibility
`Familial multiple sclerosis
`Candidate genes in multiple sclerosis
`Systematic genome screening
`Lessons from genetic studies of experimental autoimmune
`encephalomyelitis
`Conclusion
`
`4 The natural history of multiple sclerosis
`3
`3 Christian Confavreux and Alastair Compston
`7 Methodological considerations
`13 The outcome landmarks of multiple sclerosis: dependent
`variables
`2 1
`The onset of multiple sclerosis
`24 The overall course of multiple sclerosis
`39 The prognosis in multiple sclerosis
`45
`Sun/ival in multiple sclerosis
`54 Disease mechanisms underlying the clinical course
`62
`Intercurrent life events
`Conclusion
`
`5 The origins of multiple sclerosis: a synthesis
`Alastair Compston, Hartmut Wekerle and lan McDonald
`Summary of the problem
`The geography and phenotype of multiple sclerosis
`The environmental factor in multiple sclerosis
`Genetic susceptibility and multiple sclerosis
`Genetics and the European population
`Multiple sclerosis: an evolutionary hypothesis
`
`SECTION 3
`THE CLINICAL FEATURES AND DIAGNOSIS OF
`MULTIPLE SCLEROSIS
`
`6 The symptoms and signs of multiple sclerosis
`Ian McDonald and Alastair Compston
`Multiple sclerosis as a neurological illness
`Symptoms at onset of the disease
`Symptoms and signs in the cuuise uf ihe disease
`Individual symptoms and signs
`Associated diseases
`Multiple sclerosis in childhood
`Conclusion
`
`7 The diagnosis of multiple sclerosis
`Dai'id Miller, Ian McDonald and Kenneth Smith
`Diagnostic criteria for multiple sclerosis
`Selection of investigations
`
`69
`
`71
`
`71
`71
`75
`76
`77
`81
`83
`85
`86
`87
`92
`93
`94
`95
`100
`105
`
`113
`
`113
`114
`123
`
`1 2 6
`126
`136
`163
`
`175
`180
`
`183
`
`183
`
`193
`197
`202
`209
`221
`228
`243
`269
`
`273
`
`273
`273
`276
`279
`281
`284
`
`285
`
`287
`
`287
`291
`-tno
`
`300
`341
`343
`346
`
`347
`
`347
`350
`
`V
`
`Page 6
`
`

`

`i onU'nt.i
`
`Magnetic resonance imaging
`Evoked potentials
`Examination of the cerebrospinal fluid
`A strategy for the investigation of demyelinating disease
`Updating the McDonald diagnostic criteria and the prospect
`of future revisions
`
`8 The differentia! diagnosis of multiple sclerosis
`David Miller and Alastair Compston
`The spectrum of disorders mimicking multiple sclerosis
`Diseases that may cause multiple lesions of the central
`nervous system and also often follow a relapsing-
`remitting course
`Systematized central nervous system diseases
`Isolated or monosymptomatic central nervous system
`syndromes
`Non-organic symptoms
`How accurate is the diagnosis of multiple sclerosis?
`
`9 Multiple sclerosis in the individual and in groups;
`a conspectus
`David Miller, lan McDonald and Alastair Compston
`The typical case
`Isolated syndromes and their outcome: judicious use of
`investigations and critique of the new diagnostic criteria
`Comorbidity and associated diseases
`Situations in which alternative diagnoses should be
`considered
`When to ignore 'inconvenient' laboratory results or clinical
`findings: taking the best position
`'Pathognomonic' versus 'unheard of features of multiple
`sclerosis
`
`SECTION 4
`THE PATHOGENESIS OF MULTIPLE SCLEROSIS
`
`10 The neurobiology of multiple sclerosis
`Alastair Compston, Hans Lassmann and Kenneth Smith
`Organization in the central nervous system
`Cell biology of the central nervous system
`Macroglial lineages in the rodent and human nervous
`system
`Interactions between glia and axons
`Demyelination
`Axon degeneration and recovery of function
`Remyelination
`
`11 The Immunology of inflammatory demyelinating
`disease
`Hartmut Wekerle and Hans Lassmann
`Multiple sclerosis as an autoimmune disease
`Immune responses: innate and adaptive
`T lymphocytes
`B lymphocytes
`Autoimmunity and self-tolerance in the central
`nervous system
`Regulation of central nervous system autoimmune
`responses
`Immune reactivity in the central nervous system
`
`vi
`
`351
`373
`380
`383
`
`386
`
`389
`
`389
`
`390
`413
`
`422
`435
`436
`
`439
`
`439
`
`441
`445
`
`445
`
`446
`
`446
`
`447
`
`449
`
`449
`450
`
`455
`463
`469
`477
`483
`
`491
`
`491
`492
`494
`504
`
`505
`
`524
`530
`
`Pathogenesis of demyelination and tissue damage
`Peripheral blood biomarkers for multiple sclerosis
`and disease activity
`Markers of multiple sclerosis and disease activity in
`cerebrospinal fluid
`
`12 The pathology of multiple sclerosis
`Hans Lassmann and Hartmut Wekerle
`Introduction
`Pathological classification of demyelinating diseases
`The demyelinated plaque
`Immunopathology of inflammation
`Demyelination and oligodendroglial damage
`Remyelination
`Axonal pathology
`Grey matter pathology and cortical plaques
`Astroglial reaction
`Abnormalities in the 'normal' white matter of patients
`with multiple sclerosis
`Distribution of lesions in the nervous system
`Is there evidence for an infectious agent in the lesions of
`multiple sclerosis?
`Dynamic evolution of multiple sclerosis pathology
`Differences between acute, relapsing and progressive
`multiple sclerosis
`Molecular approaches to the study of the multiple sclerosis
`lesion: profiling of transcriptome and proteome
`Association of multiple sclerosis with other diseases
`Conclusion
`
`536
`
`540
`
`547
`
`557
`
`557
`557
`559
`564
`572
`582
`584
`587
`589
`
`589
`590
`
`592
`593
`
`594
`
`596
`598
`599
`
`602
`610
`
`627
`
`601
`13 The pathophysiology of multiple sclerosis
`Kenneth Smith, Ian McDonald, David Miller and Hans Lassmann
`601
`Introduction
`Methods for exploring the pathophysiology of
`multiple sclerosis
`Relapsing-remitting multiple sclerosis: loss of function
`Relapsing-remitting multiple sclerosis: recovery of function
`and remission
`Physiological explanations for clinical symptoms in multiple
`sclerosis
`Permanent loss of function in the context of disease
`progression
`Conclusion
`
`634
`
`649
`658
`
`14 The pathogenesis of multiple sclerosis; a pandect
`661
`Hans Lassmann, Kenneth Smith, Hartmut Wekerle and Alastair
`Compston
`Core features in the neuropathology of multiple sclerosis
`The pathophysiology of functional deficits and recovery
`The relation between inflammation and neurodegeneration in
`multiple sclerosis
`The role of autoimmunity in multiple sclerosis
`Complexity and heterogeneity in multiple sclerosis
`
`665
`666
`667
`
`661
`663
`
`SECTION 5
`THE TREATMENT OF MULTIPLE SCLEROSIS
`
`15 Care of the person with rnuittple sclerosis
`David Miller, John Noseworthy and Alastair Compston
`
`669
`
`67 i
`
`Page 7
`
`

`

`General approach to the care of people with
`multiple sclerosis
`The early stages of disease: minimal disability
`The middle stages of disease, moderate disability
`The later stages of disease: severe disability
`Guidelines for the management and investigation of
`multiple sclerosis
`Conclusion
`
`671
`673
`677
`679
`
`680
`681
`
`16 Treatment of the acute relapse
`683
`John Noseworthy, Christian Confavreux and Alastair Compston
`The features of active multiple sclerosis
`683
`The treatment of relapses
`686
`Other approaches to the treatment of acute relapse
`690
`Treatment of acute optic neuritis
`692
`Management of other isolated syndromes and acute
`disseminated encephalomyelitis
`Adverse effects
`Mode of action of corticosteroids
`Practice guidelines
`
`694
`695
`696
`699
`
`17. The treatment of symptoms in multiple sclerosis
`and the role of rehabilitation
`John Noseworthy, David Miller and Alastair Compston
`The general principles of symptomatic treatment in
`multiple sclerosis
`Disturbances of autonomic function
`Mobility and gait disturbance
`Fatigue
`Disturbances of brainstem function
`Perturbations of nerve conduction
`Cognitive function
`Visual loss
`
`701
`
`701
`701
`712
`717
`718
`721
`724
`725
`
`I I' l l t l T l t ' .
`
`Rehabilitation in multiple sclerosis
`Conclusion
`
`18 Disease-modifying treatments in multiple sclerosis
`John Noseworthy, David Miller and Alastair Compston
`The aims of disease-modifying treatment
`The principles of evidence-based prescribing in
`multiple sclerosis
`The role of magnetic resonance imaging in clinical trials
`Drugs that stimulate the immune response
`Drugs that nonspecifically suppress the immune response
`The beta interferons
`Molecules that inhibit T-cell-peptide binding
`Treatments that target T cells
`Agents inhibiting macrophages and their mediators
`Recent miscellaneous treatments
`Postscript
`
`19 The person with multiple sclerosis: a prospectus
`Alastair Compston, David Miller and John Noseworthy
`A perspective on the recent history of therapeutic endeavour in
`multiple sclerosis
`Setting an agenda: the window of therapeutic opportunity
`Prospects for the treatment of progressive multiple sclerosis
`Remyelination and axon regeneration
`Tailoring treatment to defined groups
`Postscript
`
`References
`
`Index
`
`726
`728
`
`729
`
`729
`
`733
`734
`738
`742
`755
`784
`791
`800
`801
`802
`
`803
`
`803
`803
`805
`806
`810
`810
`
`811
`
`947
`
`vii
`
`Page 8
`
`

`

`I he outcome landmarks of multiple sclerosis: dependent variables
`
`2
`
`In general, these phases follow an orderly sequence; but the
`relationship between episodes and progression is far from
`straightforward, and a detailed understanding of their interplay
`is required in order to understand the evolution and dynamics of
`disability and other outcomes,
`
`THE OUTCOME LANDMARKS OF MULTIPLE
`SCLEROSIS: DEPENDENT VARIABLES
`
`The London, Ontario, cohort was established through the
`multiple sclerosis clinic at the University Hospital in 1972 to
`provide comprehensive care for patients in the referral area of
`Southern Ontario [Weinshenker et al 1989a; 1989b; 1991a;
`1991b). This cohort retains the characteristics of both a tertiary
`referral centre for the province of Ontario, and a geographically
`based clinic serving Middlesex County, where an epidemiolog- Relapses and progression
`ical study on 1st January 1984 showed a prevalence of 93/ 105
`with near complete ascertainment: 91 % of patients were known Relapses - exacerbations, attacks, bouts or episodes - are defined
`to be attending the clinic (Hader ef a/l 988). Those patients not
`as the first occurrence, recurrence or worsening of symptoms
`registered were mainly the chronic institutionalized individuals,
`representing neurological dysfunction and marked by subacute
`most of whom were already severely disabled when the clinic onset and a period of stability followed by partial or complete
`was established. Patients are followed annually or biennially by
`recovery - the whole process lasting >24 hours [see Chapter
`neurologists with a special interest in multiple sclerosis. Follow- 16). On a small semantic point, it is not strictly correct to refer
`up is maintained even after patients become institutionalized in
`to the initial episode as a 'relapse'; although this is common-
`nursing homes; and every attempt is made to determine the place, we designate the first experience as the inaugural episode
`reason why an individual might have become 'lost to follow-up',
`and everything that comes later as a relapse[s). Distinction is
`No specific therapies for multiple sclerosis were administered, made between symptoms attributable only to fatigue, and those
`other than corticosteroids for acute exacerbations, although the associated with fever. Events occurring within a 1-month period
`clinic has contributed to many therapeutic trials and adopted are considered part of the same episode (Confavreux et at 1992;
`the prescribing culture now characteristic of centres in North WI. McDonald et al 2001; C.M. Poser et al 1983; G.A.
`America and Canada. Between 1979 and 1984, the authors Schumacher et al 1965). The experienced neurologist will
`reviewed data collected on 1099 consecutive patients evaluated
`recognize that, despite these unambiguous definitions, it is not
`between 1972 and 1984. Information on demographics, clinical
`always easy to decide whether particular neurological symptoms
`course and the progress of disability as a function of time was sys- do genuinely constitute a relapse. Every specialist is familiar
`tematically collected. Data were recorded on standardized forms with the difficult issue of resolving the status of worsening
`and entered onto a mainframe computer. They were analysed as a paraesthesia, a change in walking, or blurred vision - to name
`total population but also in two subgroups: the Middlesex County but a few of the very many challenging examples encountered
`cohort, representing a population-based group for which ascertain-
`in daily practice. Efforts have been made to rank the level of
`ment was near complete; and the 'seen from onset' subgroup com- certainty appropriate for a putative relapse - ranging from highly
`prising 197 patients seen by a neurologist <1 year from onset. Data
`suggestive symptoms with and without objective features on
`on this cohort have been updated to the end of 1996 and the mean
`examination noted by the neurologist, to distinctly atypical or
`duration of the disease at that time reached 24 years (D.A. minimal complaints. Ranking can be based on the severity of the
`relapse with respect to its consequences for daily activities;
`Cottrell et al 1999a; 1999b; Kremenchutzky et al 1999).
`the impact on objective neurological scores; the decision to
`administer corticosteroids and hospitalize the patient; and the
`distinction between new symptoms, those previously experienced
`and worsening of current manifestations of multiple sclerosis.
`It has long been recognized that the course of multiple sclerosis Paroxysmal neurological symptoms present particular difficulties.
`can be described in terms of relapses, remissions and chronic Because very many may occur over a short Period' confiasion can
`progression either from onset or after a period of remissions arise as t0 their status " individually or collectively. Our view is
`(Charcot 1868b: 1868c; Marie 1884; McAlpine and Compston
`that the onset of these manifestations of multiple sclerosis in
`isolation may constitute a new episode indicating a focal area of
`1952). Two major outcome measures usefully describe the clinical
`inflammatory demyelination resulting in ephaptic transmission.
`course and prognosis: the qualitative description, an expression
`In the absence of an agreed classification for relapse assessment,
`of the interplay between relapses and progression; and the quan­
`it is necessary to take a pragmatic approach and adopt common
`titative description, which refers to the accumulation of neuro­
`definitions, both in therapeutic trials and prospective studies
`logical deficits and is characterized as disability, impairment or
`for which the study period lasts < 2-3 years, using standardized
`loss of social functions. Both can be used in therapeutic trials.
`clinical assessments performed at regular and close intervals by
`Here, we confine our discussion to the role of clinical variables:
`an assessor who is blinded to the therapeutic intervention and
`surrogate markers are covered in Chapter 18.
`focus of interest in the study. However, this is not realistic for
`natural history studies where lifelong follow-up is required. In
`this setting, relapse ascertainment and assessment are generally
`less reliable, and differ for a given patient over time, and
`between individuals studied contemporaneously.
`Perhaps no term in the lexicon of multiple sclerosis has
`become so confused as 'progression'. The reason is that, in
`modern therapeutic trials, the word is used merely to describe a
`worsening of neurological disability with reference to the base­
`line. Progression is said to be sustained if confirmed at clinic
`
`Course-related dependent variables
`Physicians and people with multiple sclerosis know that the
`cardinal features that characterize the clinical experience of this
`disease are:
`
`• episodes with full recovery
`• episodes with incomplete recovery
`• chronic progression.
`
`193
`
`Page 9
`
`

`

`2 CHAPTER FOUR Tin natural history ot multiplo sclt'iosis
`
`visits, 3-6 months apart. However, disability worsening, even
`when sustained at 6 months, does not necessarily equate to
`an irreversible increase in disability (see below; C. Liu and
`Blumhardt 2000]. Originally, the term was used to define steady
`worsening of symptoms and signs over >6 months (Confavreux
`et al 1992; C.M. Poser et al 1983; G.A. Schumacher et al 1965),
`or >12 months according to more recent criteria [W.I.
`McDonald et al 2001; A.J. Thompson et al 1997). By that
`definition, once started, progression continues throughout the
`disease although occasional plateaus and minor temporary
`improvements may be observed [Lublin and Reingold 1996).
`The date at which progression starts is invariably assigned in
`retrospect, once the required 6- or 12-month duration of con­
`tinuous neurological worsening is confirmed. Herein lies the
`uncertainty. Relapses can be superimposed on progression,
`whenever that first manifests [primary and secondary progres­
`sive multiple sclerosis). Therefore, it is not helpful to use the
`word 'progression' both to characterize the worsening of neuro­
`logical disability attributable to step changes in disability that
`follow a nasty relapse, and situations in which disability
`increases systematically over time, even when interspersed with
`periods of relative stability. For us, this latter is the correct and
`preferred usage of the term.
`
`The phases of multiple sclerosis
`
`The usual course of multiple sclerosis is characterized by
`repeated relapses associated, for the majority of patients, with
`the eventual onset of disease progression. The initial pattern is
`so characteristic that diagnostic criteria are dependent on the
`demonstration of dissemination in time. Consequently, it has
`become commonplace to speak of 'conversion to multiple scle­
`rosis' once the inaugural neurological episode has been followed
`by a first relapse. By definition, >2, distinct neurological episodes
`must be documented in the course of that patient's illness, the
`events separated by >30 days [McAlpine 1961; WI. McDonald
`et al 2001; C.M. Poser et al 1983). Taken with the phase of
`secondary progression, this establishes three distinct clinical
`situations qualifying for the dissemination in time criterion
`[Figure 4.6). In the relapsing-remitting phase, relapses alternate
`with periods of clinical inactivity and may or may not be marked
`by sequelae depending on the presence of neurological deficits
`between episodes. By definition, periods between relapses during
`the relapsing-remitting phase are clinically stable. The pro­
`gressive phase of multiple sclerosis is characterized by a steady
`increase in deficits, as defined above and either from onset or
`after a period of episodes, but this designation does not preclude
`the further occurrence of new relapses. Thus, a full under­
`standing of the natural history requires more than just the two
`basic contexts of clinical activity to be considered.
`
`The several forms of the clinical course
`
`Patients do not necessarily convert from the relapsing-remitting
`to the progressive phase; but if they do, the migration is
`irreversible even though the transition can initially be hard to
`recognize, especially when the early secondary progressive phase
`is characterized by continuing relapses. From the first clinical
`descriptions of multiple sclerosis, it was recognized that the
`disease may also follow a progressive course from clinical onset.
`
`194
`
`30 days at least
`
`A
`
`i
`
`>
`
`Inaugural
`neurological
`event
`
`Second
`neurological
`event
`
`Figure 4.6 Three major patterns of dissemination in time during
`the course of multiple sclerosis. Top; two consecutive distinct
`relapses. Middle: inaugural relapse followed by the onset of the
`progressive phase. Bottom: onset of the progressive phase followed
`by a superimposed relapse. In these three instances, the time
`interval required between any two neurological events is
`> 30 days.
`
`Given this matrix, for many years classification of the clinical
`course in patients with multiple sclerosis distinguished three
`categories; relapsing-remitting; relapsing progressive, describing
`the situation of a relapsing-remitting phase followed by progres­
`sion; and progressive multiple sclerosis, to cover the eventuality
`of a progressive course from onset with or without superimposed
`relapses [Broman et al 1981; Confavreux 1977; Confavreux
`et al 1980; Fog and Linnemann 1970; Leibowitz and Alter 1970;
`1973; Leibowitz et al 1964a; 1964b; McAlpine and Compston
`1952; D.H. Miller et al 1992a; Phadke 1987; 1990; S. Poser
`1978; S. Poser et al 1982a; Runmarker and Andersen 1993;
`Trojano et al 1995; Weinshenker et al 1989a). At that time, a
`specific terminology was used by some authors to make the dis­
`tinction between primary progressive forms with superimposed
`relapses [the so-called 'relapsing progressive' or 'progressive
`relapsing' forms, depending on preference) and primary pro­
`gressive multiple sclerosis without superimposed relapses [the
`so-called 'chronic progressive' forms). To standardize the termi­
`nology used in the description of the pattern and course of
`multiple sclerosis, and to avoid confusion in communication, an
`international survey of clinicians involved in multiple sclerosis
`was performed under the auspices of the National Multiple
`Sclerosis Society of the USA [Lublin and Reingold 1996). The
`consensus intended to classify the disease course in four dif­
`ferent categories (we regret the use of abbreviations but retain
`these for clarity of identification);
`
`• Relapsing-remitting MS (RR-MS): 'clearly defined relapses
`with full recovery or with sequelae and residual deficit upon
`recovery; periods between disease relapses characterized by
`a lack of disease progression'.
`
`Page 10
`
`

`

`• Secondary progressive MS [SP-MS]: 'initial relapsing-
`remitting disease course followed by progression with or
`without occasional relapses, minor remissions, and
`plateaus',
`• Primary progressive MS (PP-MS): 'disease progression from
`onset with occasional plateaus and temporary minor
`improvements allowed'.
`• Progressive relapsing MS (PR-MS): 'progressive disease
`from onset, with clear acute relapses, with or without full
`recovery; periods between relapses characterized by con­
`tinuing progression'.
`
`It must be noted that in this classification the presence of
`superimposed relapses is allowed in cases of secondary progres­
`sive multiple sclerosis, whereas primary progressive cases with
`superimposed episodes are segregated from primary progressive
`cases without relapses (PR-MS vs. PP-MS). Furthermore, the
`term 'relapsing progressive multiple sclerosis' is abandoned
`because the participating clinicians did not agree on its definition
`and the proposed definitions overlap with other categories. This
`classification is illustrated in Figure 4.7. Some authors add 'tran­
`sitional progressive multiple sclerosis' (TP-MS) to this list, in
`order to identify the few patients with a course that is progres­
`sive except for a single relapse at some time (Filippi et al 1995b;
`Gayou et al 1997; Stevenson el al 1999; 2000). Some authors
`reserve this term only for cases with a progressive course devoid
`of superimposed relapses beginning many years after an isolated
`episode (Gayou et al 1997), whereas others allow the single
`attack before or after the onset of disease progression
`(Stevenson et al 1999; 2000). Because there is no consensus
`amongst these authors, and the efforts of the National Multiple
`Sclerosis Society international survey towards standardization
`and rationalization are sound and deserving of support, our posi­
`tion is that the few cases of transitional progressive multiple
`
`Initial course
`
`Overall course
`
`1 i
`
`Relapsing-
`remitting
`onset
`
`1
`
`Progressive
`onset
`
`Relapsing
`remitting
`
`^ Secondary
`progressive
`
`Primary
`progressive
`
`Progressive
`relapsing
`
`Figure 4,7 Classification of the course of multiple sclerosis.
`Adapted from Lublin and Reingold (1996). © 1996, reprinted with
`permission of Lipplncott Williams & Wilkins (lww.com).
`
`The outcome Itmihtuirhs oj iniiltiplc sclerosia: defvndml vuriahlcs
`
`sclerosis can easily be accommodated within the recommended
`classification, assignment to the categories of primary or secondary
`progressive multiple sclerosis being determined by when the
`single episode occurs (Lublin and Reingold 1996). But we
`recognize that this can prove confusing to patients seeking not
`to be classified as having progressive multiple sclerosis when
`negotiating guidelines for the use of disease modifying therapies
`that are only prescribed and reimbursed for individuals with
`relapsing-remitting multiple sclerosis.
`
`Prognosis-related dependent variables
`The second dimension in the history of multiple sclerosis is the
`appearance of disability. This is quantitative and may prove to be
`transient, partially reversible, or definitely irreversible. A way of
`describing the natural outcome of multiple sclerosis is therefore
`to assess the time course to accumulation of disability. We dis­
`cuss schemes that directly address the rate of progression in
`Chapter 6; these depend on two closely related scales used in
`the vast majority of studies that describe the natural history of
`multiple sclerosis - the DSS (Kurtzke 1961; 1965a) and its
`more detailed version, the EDSS [Kurtzke 1983a). Until the
`mid-20th century, standards used to assess the degree of dis­
`ablement in multiple sclerosis were usually based either upon
`the capacity to work, or mobility. However, the former criterion
`is unreliable because it depends on individual fortitude, eco­
`nomic needs, and the nature of employment. The degree of
`mobility soon emerged as a better standard although it also is
`subject to potential confounds (McAlpine and Compston 1952).
`Classifications based mainly on degree of mobility have short­
`comings because they do not take account of upper limb
`function, sensory symptoms, involvement of the bladder and
`bowel, defective vision, cranial nerve abnormalities, cognitive
`deficits, mood disorders or fatigue (McAlpine and Compston
`1952; Rudick et al 1996a). Furthermore, the normal aging
`process may confound results based on these classifications, in
`older individuals where comorbidity with musculoskeletal, car­
`diovascular and respiratory disturbances may introduce com­
`plexities. That said, such classifications do reflect the global
`impairment caused by multiple sclerosis, first manifest as a dis­
`turbance in walking. This undoubtedly explains the popularity
`gained by Kurtzke's scales amongst the community of clinicians
`with a special interest in multiple sclerosis. Rather few other
`systems proposed for use in multiple sclerosis have gained
`acceptance; an