Elsevier

The Lancet

Volume 359, Issue 9313, 6 April 2002, Pages 1221-1231
The Lancet

Seminar
Multiple sclerosis

https://doi.org/10.1016/S0140-6736(02)08220-XGet rights and content

Summary

Multiple sclerosis is the prototype inflammatory autoimmune disorder of the central nervous system and, with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. As with all complex traits, the disorder results from an interplay between as yet unidentified environmental factors and susceptibility genes. Together, these factors trigger a cascade of events, involving engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration. The sequential involvement of these processes underlies the clinical course characterised by episodes with recovery, episodes leaving persistent deficits, and secondary progression. The aim of treatment is to reduce the frequency, and limit the lasting effects, of relapses, relieve symptoms, prevent disability arising from disease progression, and promote tissue repair. Despite limited success in each of these categories, everyone touched by multiple sclerosis looks for a better dividend from applying an improved understanding of the pathogenesis to clinical management.

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:

  • 1

    immune engagement

  • 1

    acute inflammatory injury of axons and glia

  • 1

    recovery of function and structural repair

  • 1

    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:

  • 1

    reduce relapse rates

  • 1

    prevent fixed disability directly attributable to relapse

  • 1

    provide symptomatic management of fixed neurological deficits

  • 1

    prevent disability acquired through progression

  • 1

    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

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.

References (81)

  • J Homes et al.

    The cost of multiple sclerosis

    Br J Med Econ

    (1995)
  • WI McDonald et al.

    Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis

    Ann Neurol

    (2001)
  • PA Brex et al.

    A longitudinal study of abnormalities on MRI and disability from multiple sclerosis

    N Engl J Med

    (2002)
  • DH Miller et al.

    Nuclear magnetic resonance monitoring of treatment and prediction of outcome in multiple sclerosis

    Philos Trans R Soc Lond B Biol Sci

    (1999)
  • BG Weinshenker et al.

    The natural history of multiple sclerosis: a geographically based study, 2: predictive value of the early clinical course

    Brain

    (1989)
  • BG Weinshenker et al.

    The natural history of multiple sclerosis: a geographically based study, 1: clinical course and disability

    Brain

    (1989)
  • C Confavreux et al.

    Relapses and progression of disability in multiple sclerosis

    N Engl J Med

    (2000)
  • C Confavreux et al.

    Vaccinations and the risk of relapse in multiple sclerosis

    N Engl J Med

    (2001)
  • A Ascherio et al.

    Hepatitis B vaccination and the risk of multiple sclerosis

    N Engl J Med

    (2001)
  • C Confavreux et al.

    Rate of pregnancy-related relapse in multiple sclerosis

    N Engl J Med

    (1998)
  • A Compston

    The genetic epidemiology of multiple sclerosis

    Philos Trans R Soc Lond B Biol Sci

    (1999)
  • A meta-analysis of genome screens in multiple sclerosis

    Muliple Sclerosis

    (2001)
  • Sawcer S, Meranian M, Setakis E, et al. A whole genome screen for linkage disequilibirum in multiple sclerosis confirms...
  • S Sriram et al.

    Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis

    Ann Neurol

    (1999)
  • T Derfuss et al.

    Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response

    Brain

    (2001)
  • PB Challoner et al.

    Plaque-associated expression of human herpesvirus 6 in multiple sclerosis

    Proc Natl Acad Sci USA

    (1995)
  • EJ Redford et al.

    Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible

    Brain

    (1997)
  • JD England et al.

    Changed distribution of sodium channels along demyelinated axons

    Proc Natl Acad Sci USA

    (1990)
  • DJ Werring et al.

    Recovery from optic neuritis is associated with a change in the distribution of cerebral response to visual stimulation: a functional magnetic resonance imaging study

    J Neurol Neurosurg Psychiatry

    (2000)
  • KJ Smith et al.

    Electrically active axons degenerate when exposed to nitric oxide

    Ann Neurol

    (2001)
  • BD Trapp et al.

    Axonal transection in the lesions of multiple sclerosis

    N Engl J Med

    (1998)
  • C Bjartmar et al.

    Axonal loss in normal-appearing white matter in a patient with acute MS

    Neurology

    (2001)
  • JH Simon et al.

    Transcallosal bands: a sign of neuronal tract degeneration in early MS?

    Neurology

    (2001)
  • BA Barres et al.

    Proliferation of oligodendroctye precursor cells depends on electrical activity in axons

    Nature

    (1993)
  • A Wilkins et al.

    A role for oligodendrocyte-derived IGF-1 in trophic support of cortical neurons

    Glia

    (2001)
  • CL Karp et al.

    Interferon-beta in multiple sclerosis: altering the balance of interleukin-12 and interleukin-10?

    Curr Opin Neurol

    (2001)
  • LD Jacobs et al.

    Intramuscular interferon beta-la for disease progression in relapsing multiple sclerosis

    Ann Neurol

    (1996)
  • DW Paty et al.

    Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial

    Neurology

    (1993)
  • Randomised double-blind placebo-controlled study of interferon beta-la in relapsing/remitting multiple sclerosis

    Lancet

    (1998)
  • PRISMS-4: long-term efficacy of interferon-beta-la in relapsing MS

    Neurology

    (2001)
  • Cited by (1805)

    View all citing articles on Scopus
    View full text