We did a computer-aided search of PubMed to March, 2002, for aspects of multiple sclerosis pertinent to this review, to supplement our existing awareness of the primary literature. Because of limitations on the number of citations, we made selections from the 11 648 reports published on multiple sclerosis in the past decade to support our interpretations with criteria for assessing experimental studies and evidence-based medicine.
SeminarMultiple sclerosis
Section snippets
Pathological physiology and anatomy
The oligodendrocyte, a principal target of immune attack in multiple sclerosis, synthesises and maintains the myelin sheath of up to 40 neighbouring nerve axons in the central nervous system. Compact myelin consists of a condensed membrane, spiralled around axons to form the insulating segmented sheath needed for saltatory axonal conduction: voltage-gated sodium channels cluster at the unmyelinated nodes of Ranvier, between myelin segments, from where the action potential is propagated and
How is the disease diagnosed?
Revised diagnostic criteria classify individuals in the categories of multiple sclerosis, not multiple sclerosis, or possible multiple sclerosis, and incorporate evidence from MRI.2 As with the previous diagnostic criteria, individuals must have a minimum of two attacks, affecting more than one anatomical site, but, assuming an initial presentation suggestive of multiple sclerosis, the second lesion need not necessarily be clinically expressed (figure 2).
Investigations are done for four main
The natural history of multiple sclerosis
Multiple sclerosis affects twice as many women as it does men; this unexplained bias mimics that seen in other putative autoimmune diseases. The disease has an incidence of about seven per 100 000 every year, prevalence of around 120 per 100 000, and lifetime risk of one in 400. 80% of patients present with relapsing/remitting disease and, typically, the illness passes through phases of relapse with full recovery, relapse with persistent deficit, and secondary progression. In about a quarter of
What causes multiple sclerosis?
Multiple sclerosis is caused by an interplay between genes and the environment. The disease predominantly affects northern Europeans. There is a familial recurrence rate of about 15%. The age-adjusted risk is higher for siblings (3%), parents (2%), and children (2%) than for second-degree and third-degree relatives. Recurrence in monozygotic twins is around 35%. The risk for half-siblings is less than for full siblings. Recurrence is higher in the children of conjugal pairs with multiple
Evolution of the plaque
Maturation of the individual lesion involves several stages:
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immune engagement
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acute inflammatory injury of axons and glia
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recovery of function and structural repair
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post-inflammatory gliosis and neurodegeneration.
Healthy individuals harbour autoreactive myelin T cells, normally kept in check by regulatory T cells. One hypothesis to explain the breakdown of immune regulation in autoimmune diseases is molecular mimicry, which suggests that peptide (the environmental factor), presented in the groove
Treatment of multiple sclerosis
Against this background, our analysis of treatments follows a mechanistic approach rather than clinical pragmatism. The aims of treatment are to:
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reduce relapse rates
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prevent fixed disability directly attributable to relapse
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provide symptomatic management of fixed neurological deficits
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prevent disability acquired through progression
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treat established progression.
Reducing relapse rates in multiple sclerosis
Since permanent disability can be caused by incomplete recovery from episodes, relapse frequency is bound to correlate with accumulation of disability during the relapsing-remitting phase of multiple sclerosis. The dividend from reducing the relapse rate is best shown by use of the beta interferons: interferon beta-la (Avonex, Biogen, and Rebif, Ares-Serono), and interferon beta-1b (Betaferon and Betaseron, Schering), which has one aminoacid substitution and is non-glycosylated. These type-1
Prevention of disability attributable to relapse
Corticosteroids, bound to their cytoplasmic receptors, enter the cell nucleus and inhibit transcription of proinflammatory cytokines, such as interleukin 1, interleukin 2, tumour necrosis factor-α (TNF-α) and proinflammatory enzymes, including collagenase, elastase, and plasminogen activator. These anti-inflammatory effects have long been used for acute treatment of multiple sclerosis relapses—conventionally given as intravenous methylprednisolone over 1–5 days,42 although oral steroids might
Symptomatic management of fixed neurological deficits
Fixed neurological deficits in multiple sclerosis are best managed by a multidisciplinary team, attending to physical therapies, psychological, and social interventions supplemented by medical treatments. The benefits of intense inpatient rehabilitation outlast the duration of therapy by up to 9 months.48 The symptoms that are most amenable to treatment are spasticity and sphincter dysfunction (figure 1). Spasticity causes discomfort and hinders care. It is usefully treated by baclofen, which
Prospects for improved treatment of disease activity
In view of the fact that the ability to suppress relapses and limit their consequences is partial, no informed analyst could reasonably conclude that (despite their achievements) the beta-interferons are a definitive therapy in multiple sclerosis. The pharmaceutical industry has responded by sponsoring studies with combinations of established drugs (such as beta interferon and cyclophosphamide) without compelling evidence for synergistic benefit to date, together with a significant investment
Prevention of disability acquired through progression
There have been three trials of interferon beta in secondary progressive multiple sclerosis. One, involving 718 patients treated with Betaferon, was stopped early because a significant effect on disability was achieved; treated patients took 9–12 months longer to reach a sustained increase in disability (by one Kurtzke point) than did controls.61 This study led to extension of the European licence for Betaferon for patients with secondary progressive multiple sclerosis. However, a larger study62
Can surviving axons be remyelinated?
The informed patient often expresses disappointment that management aims merely to limit further damage without seeking to restore the neurological past. Endogenous remyelination is limited to the acute inflammatory phase, and this timing raises the issue of whether, paradoxically, anti-inflammatory treatment might contribute to the failure of repair. For those axons that degenerate early as a direct result of the inflammatory process, efforts at remyelination might have little to offer;
Is multiple sclerosis more than one disease?
A major part of future studies will be to resolve the question of disease heterogeneity.78 Because primary progressive multiple sclerosis affects an older (predominantly male) population, has a less favourable prognosis, and is associated with fewer radiological and histological inflammatory lesions—such that these patients are disenfranchised with respect to clinical trials of immunomodulatory drugs—this type of multiple sclerosis is considered by many to be a separate disorder.79 Harding's
The past and future of multiple sclerosis
Within 40 years of its first depiction, the clinical and pathological details of multiple sclerosis had been adequately characterised. Over the past 120 years, ideas have consolidated on the cause and mechanisms of inflammatory demyelination and axonopathy. In the past 10 years, therapies have emerged that modestly affect the course of the illness. Current research is increasingly seen as coherent and focused on the hot topics that need to be solved to limit, repair, and prevent the damage
Search strategy
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