PAPER: ACCUMULATION OF IRREVERSIBLE DISABILITY IN MULTIPLE SCLEROSIS - LESSONS FROM NATURAL HISTORY STUDIES AND THERAPEUTIC TRIALS

Abstract

There is good evidence that relapses in multiple sclerosis (MS) are the clinical counterpart of acute focal inflammation of the central nervous system (CNS), whereas progression is that of chronic diffuse neurodegeneration. The classical view is to consider MS solely as an organ-specific auto-immune disease, i.e. inflammation is the cause of neurodegeneration.

Recurring relapses eventually lead to accumulation of disability, and clinical progression could also result from subclinical relapses. Recent observations suggest that this classical concept should be challenged. In particular, striking results have come from the study of the natural history of MS in the Lyons MS Natural History Cohort.1 Progression of irreversible disability from the assignment of a score of 4 on Kurtzke's disability status scale (DSS) to the assignment of a score of 6 or 7 is unaffected by the presence or the absence of a relapsing-remitting phase before the chronic progressive phase of MS. The same observation is true regarding the presence or absence of superimposed relapses during the progressive phase, either primary or secondary. Beta interferons lead to a 30% reduction in the relapse rate and to a more than 50% reduction in conventional magnetic resonance imaging (MRI) activity. Despite this effect on inflammation, the effect of interferons on disability is only marginal and this small effect may be relapse-reduction-driven. Administration of Campath-1H to MS patients with very active disease, results in a profound and prolonged lymphopenia, and the suppression of clinical and MRI activity. In spite of this, progression of clinical disability and cerebral atrophy still occurs. These observations support the view that in MS, relapses and focal inflammation do not influence the rate of progression of irreversible disability and diffuse neurodegeneration. They are consistent with what was shown in individual patients in the 1970s by performing serial quantitative neurological examinations over several years, and with what is emerging currently from early and serial structural brain MRI studies.