`

`McAlpine's
`MULTIPLE SCLEROSIS
`
`2
`
`

`

`For NDC (1918-1986)
`
`Portrait by Howard Morgan. Reproduced by permission of Harveian Librarian, Royal College of Physicians of London.
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`3
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`

`

`

`CHURCHILL
`LIVINGSTONE
`BI.EEVIER
`
`© 2006, Elsevier Inc. All rights reserved.
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`First edition 1985
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`Third edition 1998
`Fourth edition 2005
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`I
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`5
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`

`

`Contents
`
`Preface to the fourth edition
`
`SECTION 1
`THE STORY OF MULTIPLE SCLEROSIS
`
`1 The story of multiple sclerosis
`Alastair Compston, Hans Lassmann and Ian McDonald
`The evolving concept of multiple sclerosis
`Naming and classifying the disease: 1868-1983
`Oinical 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 CAU SE 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 mu ltiple sclerosis
`
`3 The genetics of multiple sclerosis
`Alastair Compston and Hartmut Wekerle
`Genetic analysis of multiple sclerosis
`Methods of genetic analysis
`Racial susceptibility
`
`viii
`
`3
`
`3
`3
`7
`13
`21
`
`24
`39
`45
`54
`62
`
`69
`
`71
`
`71
`71
`75
`76
`77
`81
`83
`85
`86
`87
`92
`93
`94
`95
`100
`105
`
`11 3
`
`11 3
`114
`123
`
`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
`Christian Conf avreux and Alastair Compston
`Methodological considerations
`The outcome landmarks of multi ple sclerosis: dependent
`variables
`The onset of multiple sclerosis
`The overall course of multiple sclerosis
`The prognosis in multiple sclerosis
`Survival in multiple sclerosis
`Disease mechanisms underlying the clinical course
`lntercurrent life events
`Conclusion
`
`5 The origins of multiple sclerosis: a synthesis
`Alastair Compston, Hartmut Wekerle and Ian M cDonald
`Summary of the problem
`The geography and phenotype of multiple sclerosis
`The environmental factor in mu ltiple 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 course of the disease
`Individual symptoms and signs
`Associated diseases
`Multiple sclerosis in childhood
`Conclusion
`
`7 The diagnosis of multiple sclerosis
`David Miller, Ian McDonald and Kenneth Smith
`Diagnostic criteria for multiple sclerosis
`Selection of investigations
`
`126
`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
`298
`300
`341
`343
`346
`
`347
`
`347
`350
`
`6
`
`

`

`Contents
`
`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 differential 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(cid:173)
`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, Ian 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: taki ng 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
`H artmut 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
`
`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
`
`Pathogenesis of demyelination and tissue damage
`351
`Peripheral blood biomarkers for multiple sclerosis
`373
`and disease activity
`380
`383 Markers of multiple scl~rosis 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
`lmmunopathology 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
`
`13 The pathophysiology of multiple sclerosis
`601
`Kenneth Smith, Ian M cDonald, David Miller and Hans Lassmann
`Introduction
`601
`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
`
`602
`610
`
`627
`
`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 multiple sclerosis
`524
`530 David Miller, John Noseworthy and Alastair Compston
`
`669
`
`671
`
`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
`
`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 tr~atment ot 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
`81 O
`
`811
`
`947
`
`8
`
`

`

`

`

`3 CHAPTER SEVEN The diagnosis of multiple sclerosis
`
`Table 7.1 Poser criteria for t he diagnosis of multiple sclerosis
`
`Table 7.2 McDonald criteria for multiple sclerosis: categories
`of multiple sclerosis
`
`Category
`
`Attacks
`
`Clinical
`evidence
`
`Paraclinical
`evidence
`
`CSF
`OB/lgG
`
`Clinical presentation
`
`Additional data needed for
`diagnosis of multiple sclerosis
`
`A. Clinically definite mult iple sclerosis
`2
`2
`CDMS A1
`
`CDMS A2
`
`2
`
`1
`
`and 1
`
`8. Laboratory-supported definite multiple sclerosis
`1
`or 1
`2
`LSDMS B1
`
`LSDMS B2
`
`LSDMS B3
`
`1
`
`1
`
`2
`
`1
`
`C. Clinically probable multiple sclerosis
`CPMS C1
`2
`1
`
`CPMS C2
`
`CPMS C3
`
`1
`
`1
`
`2
`
`1
`
`and 1
`
`and 1
`
`D. Laboratory-supported probable multiple sclerosis
`LSPMS D1
`2
`
`+
`
`+
`
`+
`
`+
`
`CSF, cerebrospinal fluid; OB, oligoclonal band; lgG, immunoglobulin G.
`From CM. Poser et al (1983) with permission.
`
`Table 7.3 McDonald criteria for multiple sclerosis: MRI
`evidence for d issem ination in space
`
`Three of the following:
`• one or more gadolinium enhancing lesions or nine or more
`T2 hyperintense lesions if there is no gadolinium enhancing
`lesion
`• one or more infratentorial lesions
`• one or more juxtacortical lesions
`•
`three or more periventricular lesions
`Notes: (i) one spinal cord lesion can substitute for one brain lesion; (ii) two
`T2 lesions plus cerebrospinal fluid oligoclonal bands also constitute
`evidence for dissemination in space.
`From 111/.I. McDonald et al (2001) with permission.
`
`Table 7.4 M cDonald criteria for multiple sclerosi s: M RI
`evidence for dissemination in t ime.
`
`1. If a first scan is >3 months after the onset of the clinical event,
`the presence of a gadolinium enhancing lesion is sufficient to
`demonstrate dissemination in time, provided that it is not at the
`site implicated in the original clinical event. If there is no
`enhancing lesion at this time, a follow-up scan is required. The
`timing of this follow-up scan is not crucial, but 3 months is
`recommended. A new T2 or gadolinium enhancing scan at this
`time then fulfils the criterion for dissemination in time.
`
`2. If the first scan is performed <3 months after the onset of the
`clinical event, a second scan done 3 months or more after the
`clinical event showing a new gadolinium enhancing lesion
`provides sufficient evidence for dissemination in time. However,
`if no enhancing lesion is seen at this second scan, a furth er scan
`:2:3 months after the first scan that shows a new T2 or gadolinium
`enhancing lesion will suffice.
`
`From 111/.I. McDonald et al (2001) with permission.
`
`348
`
`Two or more attacks;
`objective clinical evidence
`of two or more lesions
`
`Two or mare attacks;
`objective clinical evidence
`of one lesion
`
`One attack;
`objective clinical evidence
`of two or more lesions
`
`One attack;
`objective clinical evidence
`of one lesion
`(monosymptomatic
`presentation; clinically
`isolated syndrome)
`
`Insidious neurological
`progression suggestive of
`multiple sclerosis
`
`None"
`
`Dissemination in space
`demonstrated by MRlb
`or
`Up to two MRI detected lesions
`consistent with multiple sclerosis
`plus positive cerebrospinal fluidc
`or
`Await further clinical attack
`implicating a different site
`
`Dissemination in time
`demonstrated by MRld
`or
`Second clinical attack
`
`Dissemination in space
`demonstrated by MRlb
`or
`Up to two MRI detected lesions
`consistent with multiple sclerosis
`plus positive cerebrospinal fluid'
`and
`Dissemination in time
`demonstrated by MRld
`or
`Second clinical attack
`
`Positive cerebrospinal fluid'
`and
`Dissemination in space
`demonstrated by:
`(i)
`nine or more T2 lesions in the
`brain or
`two or more lesions in the
`spinal cord or
`four to eight brain lesions
`plus one spinal cord lesion
`
`(iii)
`
`(ii)
`
`or
`Abnormal visual evoked potential•
`associated with four to eight brain
`lesions, or with fewer than four
`brain lesions plus one spinal cord
`lesion demonstrated by MRI
`and
`Dissemination in time
`demonstrated by MRld
`or
`Continued progression for 1 year
`
`a No additional tests are required (however, if MRI and cerebrospinal fluid
`are undertaken and are negative extreme caution should be taken before
`making a diagnosis of multiple sclerosis. Alternative diagnoses must be
`considered and there must be no better explanation for the clinical
`picture).
`b Must fulfil the Barkhof/Tintore criteria (Table 7.3).
`c Positive cerebrospinal fluid established by oligoclonal bands detected by
`established methods (preferably isoelectric focusing) different from any
`such bands in serum or by a raised immunoglobulin G index.
`d Must fulfil the criteria in Table 7.4.
`e Abnormal visual evoked potential of the type seen in multiple sclerosis
`(delay with well-preserved wave form).
`From 111/.I. McDonald et al (2001) with permission.
`
`10
`
`

`

`

`

`3 CHAPTER SEVEN The diagnosis of multiple sclerosis
`
`a high predictive value for conversion when four features were
`present:
`
`•
`•
`•
`•
`
`one or more gadolinium enhancing lesions
`three or more periventricular lesions
`one or more juxtacortical lesions
`one or more infratentorial lesions.
`
`Tinton~ et al (2000) proposed a modification of these Barkhof
`criteria, limiting the requirement to any three of the four fea(cid:173)
`tures, and substituting the need for one gadolinium enhancing
`lesion with the alternative of at least nine T 2 lesions. The com(cid:173)
`bined criteria of Barkhof modified by Tintore were adopted by
`the International Panel as evidence for dissemination in space
`(WI. McDonald et al 2001; Table 7.3). The Panel included two
`additional items in its dissemination in space criteria. First, one
`spinal cord lesion can substitute for one brain lesion. Second,
`the criteria are satisfied by the combination of two T 2 lesions
`together with the presence of oligoclonal bands in the cere(cid:173)
`brospinal fluid.
`The key feature for MRI dissemination in time using these
`revised criteria is that a new lesion should appear at least
`3 months after the clinical onset. This could be a gadolinium
`enhancing lesion on any scan obtained 3 or more months after
`clinical onset or, if such a scan does not show any enhancing
`lesions, the presence of a new T 2 lesion on a subsequent scan
`will suffice.
`The new criteria recommend that they are best applied to
`individuals aged between 10 and 59 years. They also no longer
`include the categories of clinically definite or probable multiple
`sclerosis. Rather, the diagnostic categories are:
`
`• multiple sclerosis - when the criteria are met
`•
`possible multiple sclerosis - for those at risk of multiple
`sclerosis but for whom diagnostic evaluation is equivocal
`not multiple sclerosis.
`
`•
`
`Preliminary studi~s have attempted to validate the new cri(cid:173)
`teria in terms of specificity and predictive value for develop(cid:173)
`ment of clinically definite multiple sclerosis ( discussed below).
`The criteria have both strengths and weaknesses and these are
`discussed further in Chapter 9. They are likely to be revised and
`fine tuned as more experience is gained of their application and
`indeed modifications to the criteria are expected following the
`meeting on a reconstituted International Panel in March 2005.
`Here, we consider the contribution that special or paraclinical
`investigations can make to the diagnostic process, but start by
`reiterating that, as in all branches of clinical neurology, labora(cid:173)
`tory investigations should never replace a full evaluation of the
`history and clinical examination when seeking to establish the
`diagnosis.
`
`SELECTION OF INVESTIGATIONS
`
`Three types of investigation may be needed in patients sus(cid:173)
`pected of having demyelinating disease: MRI, evoked potentials
`and cerebrospinal fluid examination. Their purpose is to docu(cid:173)
`ment the dissemination of lesions in space and time; to confirm
`the presence of intrathecal inflammation; and to exclude condi(cid:173)
`tions that mimic demyelination. The starting point for diagnosis
`
`350
`
`in the individual patient is the clinical picture. More than any
`other feature, this determines the nature and number of inves(cid:173)
`tigations required to reach the appropriate level of diagnostic
`certainty. In essence, the neurologist must ask the questions:
`which parts of the nervous system should I investigate; and how
`best can this be achieved?
`The diagnosis of multiple sclerosis cannot by definition be
`made on clinical grounds alone, if there has been only a single
`episode (for example, optic neuritis). However, the risk of dis(cid:173)
`seminated disease developing later may be estimated from MRI,
`evoked potentials and cerebrospinal fluid data (see below).
`Making use of their predictive values may have therapeutic
`implications, especially as treatments that safely delay the
`progression of disability are increasingly made available. By
`applying the most recently published authoritative criteria, such
`paraclinical investigations can be used to make a diagnosis of
`multiple sclerosis 3 months after symptom onset (WI.
`McDonald et al ZOO 1).
`A commonly encountered problem is the patient who has had
`several episodes of neurological symptoms suggestive of
`multiple sclerosis, but who, on examination, has abnormal signs
`relating only to the most recent event. In these circumstances,
`MRI, or occasionally evoked potentials, reveals whether the
`nervous system has been involved at other sites even though
`these have not given rise to clinical manifestations. In selecting
`the parts of the nervous system that should be examined to
`demonstrate dissemination in space, the neurologist is guided by
`the history, deliberately choosing those sites that the current
`clinical assessment indicates not to be involved. For example, for
`patients with recent onset of symptoms attributable to a spinal
`cord lesion, we scan the brain and in some instances select visual
`or auditory evoked potentials. In the context of recent visual
`loss, brain and possibly spinal MRI - on occasions supplemented
`by somatosensory and auditory evoked potentials - are appro(cid:173)
`priate methods for exploring clinically unaffected parts of the
`nervous system. There is a catch, however. Moving straight to
`the clinically unaffected nervous system on the assumption that
`the presenting syndrome is the result of inflammation and
`demyelination runs the risk of missing a local structural lesion.
`Therefore, in this example, the cord should also be targeted to
`exclude other diagnoses.
`In cases where the diagnosis remains in real doubt, it is often
`helpful to answer two questions. First, is there evidence for the
`pathological process of demyelination? This can be inferred
`from the presence of a delayed evoked potential with a well(cid:173)
`preserved waveform, though considerable caution is needed
`when this appears distorted (see Chapter 13). Since demyelina(cid:173)
`tion, axonal loss and gliosis each occur in multiple sclerosis, it
`might be hoped that imaging appearances would suggest the
`diagnosis, but no one morphological component has a specific
`imaging marker and these tissue-based interpretations cannot
`therefore reliably be made. Second, is there an abnormality of
`the immune mechanism in relation to the central nervous
`system? This is most readily judged from examination of the
`cerebrospinal fluid which will provide evidence for intrathecal
`synthesis of oligoclonal immunoglobulin G. This approach is
`particularly helpful in complex cases where considerable doubt
`remains about the disease mechanism, and in patients presenting
`with progressive syndromes attributable to a single site in which,
`over and above exclusion of a structural lesion, other disease
`
`12
`
`

`

`

`

`

`

`

`

`

`

`Magnetic resonance imaging
`
`Figure 7.10 Multiple sclerosis. Ti-weighted MRI shows a lesion
`with alternating bands of high and normal signal (Balo's
`concentric sclerosis). From Kastrup et al (2002) with permission.
`
`Figure 7.9 Multiple sclerosis. Ti-weighted scans showing large
`cerebral hemisphere lesions with mass effect. Kindly provided by
`Dr Claudia Lucchinetti.
`
`fast spin echo (fast STIR) imaging has a slightly higher sensi(cid:173)
`tivity than fast or conventional spin echo in detecting some cord
`lesions but this gain is offset by more frequent occurrence of
`artefacts (Bot et al 2000). Fast STIR has not become a part of
`the standard protocol for detecting spinal cord lesions.
`Abnormalities in the cord may be seen when none are
`detectable in the brain, a finding of particular importance in
`primary progressive multiple sclerosis where cerebral lesions are
`less extensive than in other forms of the disease, and may even
`be absent (Kidd et al 1993). Thorpe et al (1996b) emphasized
`the value of cord imaging in 20 patients with clinically suspected
`multiple sclerosis but normal or near normal brain MRI. All 20
`patients exhibited at least one focal cord lesion (median 2; range
`1-6) . The value of other laboratory investigation in such cases
`was also emphasized by the presence of cerebrospinal fluid
`oligoclonal bands in 13/15 and delayed visual evoked potentials
`in 10/18 subjects. Diffuse hyperintensity on proton density
`weighted images of the cord may also be seen, more so in
`primary progressive than in other forms of multiple sclerosis
`(Lycklama et al 1998).
`
`Figure 7.11 Multiple sclerosis. Ti-weighted sagittal MRI of the
`spinal cord shows multiple, small intrinsic lesions (arrowed).
`
`As with the corpus callosum, the cord is rarely involved by
`vascular disease and, unlike the cerebrum, asymptomatic areas
`of high signal are very uncommon as an incidental finding with
`increasing age (Thorpe et al 1993) . A recent study compared
`brain and spinal cord MRI in 25 patients with clinically definite
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`Magnetic resonance imaging 3
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`Figure 7.13 Serial monthly gadolinium
`enhanced T,-w eighted brain MRI over
`6 months (starting at the top left and
`ending at th e bottom right) in a patient
`with relapsing- remitting multiple
`sclerosis. Severa l new enhancing lesio ns
`appear each month and cease enhancing
`1 or 2 months later. Some lesions show
`homogeneous enhancement while others
`display rin g enhancement.
`
`Fi.,;ure 7.14 (A) Ti-weighted image showing multiple lesions in clinically definite mu lti ple sclerosis; note that no ab normality is visible at
`the t ip of the arrow. (B) Gadolinium-enhanced T1-weighted image. Note that there are several areas of enhanceme nt, one of which is
`at the tip of the arrow. Thi s image was taken a matter of minutes following the Ti-weighted images. (C) Ti-weighted image some
`Weeks later, now showin g a lesion visibl e at the tip of the arrow.
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`3 CHAPTER SEVEN The diagnosis of multiple sclerosis
`
`used to a limited extent to investigate the pathophysiology of
`central nervous system dysfunction in a variety of disorders,
`including multiple sclerosis (J.B. Baker et al 1968; Halliday and
`Wakefield 1963; Namerow 1968b). The systematic exploitation
`of evoked potential techniques as diagnostic aids began, how(cid:173)
`ever, with the pattern reversal visual evoked potential in optic
`neuritis, which at once revealed a dramatic increase in latency,
`detectable in 90% of cases (Halliday et al 1972). More modest
`delays were soon found to be characteristic findings in
`somatosensory (Desmedt and Noel 1973; Fukushima and
`Mayanagi 1975; Small 1976; D.G. Small et al 1978; Trojaborg
`and Petersen 1979) and auditory evoked potentials (Chiappa
`1980; Eisen and Odusote 1980; Robinson and Rudge 1977).
`Delays in the motor response evoked by electrical (Cowan et al
`1984; Marsden 1980; Merton and Morton 1980a; 1980b;
`Merton et al 1982; Mills and Murray 1985; Rossini et al 1985)
`or magnetic (Barker et al 1985a; 1985b; 1986; Hess et al
`1986; Ingram et al 1987) stimulation of the cortex were later
`observed.
`Application of evoked potential techniques to the clinical
`assessment of patients with multiple sclerosis began right away
`(Halliday et al 1973b), and their value was at once apparent. As
`already pointed out, the principal contributions of evoked
`potentials have been to answer the questions:
`
`•
`•
`
`Is a clinically silent lesion present?
`Is the process of demyelination present?
`
`One selects a pathway for the evoked potential that assesses
`an asymptomatic region of the nervous system. The result of the
`examination may of course answer both questions but, if not, a
`clinically affected part of the central nervous system may then
`be chosen for interrogation. Although the introduction of MRI
`from the 1980s has substantially reduced the frequency with
`which evoked potentials are ordered as diagnostic tools in
`cases of suspected multiple sclerosis, they are still of use when
`there is diagnostic difficulty. This applies especially to use of
`the visual evoked potential. A report of the Quality Standards
`Subcommittee of the American Academy of Neurology has
`recently evaluated the utility of evoked potentials in identifying
`clinically silent lesions in patients with suspected multiple
`sclerosis (Gronseth and Ashman 2000). They produced the
`following recommendations.
`
`• Visual evoked potentials are probably useful to identify
`patients at increased risk for developing clinically definite
`multiple sclerosis.
`• Somatosensory evoked potentials are possibly useful to
`identify patients at increased risk for developing clinically
`definite multiple sclerosis.
`• There is insufficient evidence to recommend brainstem
`auditory evoked potentials as a useful test to identify
`patients at increased risk for developing clinically definite
`multiple sclerosis.
`
`1
`
`This sensibly conservative approach has been further tem(cid:173)
`pered by the subsequently published new diagnostic criteria for
`multiple sclerosis, which rely more heavily on MRI evidence of
`dissemination in space and time to enable the diagnosis (WI.
`McDonald et al 2001).
`
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`
`Evoked potentials have been infrequently used to monitor the
`course of established multiple sclerosis, and the advent of MRI
`has probably inhibited efforts to investigate serial changes in
`evoked potential measures. A 2-year study of a mixed cohort of
`30 patients with relapsing-remitting or secondary progressive
`multiple sclerosis showed a modest relationship between
`changes in disability and visual and motor evoked potential
`measures but also concluded that a reliable prediction of the
`course of multiple sclerosis is not possible from the evoked
`potential measures (Fuhr et al 2001). The introduction of evoked
`potentials has been of great value in understanding the patho(cid:173)
`physiology of central nervous system demyelination in patients,
`and in confirming that the detailed findings from experimental
`studies are reproduced in humans. We will consider each
`modality used for evoked potentials in some detail, partly
`because of their historical contribution to our understanding of
`multiple sclerosis, and in part because of their remaining utility
`(Figure 7.40).
`
`Visual evoked potentials