Accumulation of irreversible disability in multiple sclerosis: From epidemiology to treatment
Introduction
The course of multiple sclerosis (MS) may be looked upon as the interaction between two clinical phenomena, relapses and progression, the latter being defined as a steady worsening of symptoms and signs over a minimum of 6 months [1], [2], [3], or even 12 months according to recent definitions [4], [5]. It is also an interaction between two biological phenomena in the central nervous system (CNS), i.e. inflammation, which is focal, disseminated, acute and recurrent, and degeneration, which is diffuse, early, chronic and progressive. There is strong evidence that relapses are the clinical counterpart of acute focal inflammation of the CNS [6]. There is also growing evidence that progression is the clinical counterpart of chronic and progressive neurodegeneration [7], [8]. One of the central issues with respect to outcome in MS is the mechanism of accrual of irreversible disability [8], [9], [10]. It may be the result of relapses with sequelae (“relapse-driven”) as well as from progression (“progression-driven”). The question arises about the respective contributions of relapses and progression, and of focal inflammation and diffuse degeneration in this cumulative process. The classical view is to consider MS as an organ-specific autoimmune disease. This means that inflammation is responsible for the initiation of the degeneration of the CNS. Does this mean that inflammation is also responsible for the perpetuation and progression of neurodegeneration? In such case, the relapses might be the major cause of the accumulation of irreversible disability in MS.
Section snippets
Relapses are a major cause of irreversible disability
At first glance this assertion is attractive. Relapses may be an important cause of disability in MS. This is a charcateristic of borderline forms of MS, such as Devic's neuromyelitis optica, transverse myelitis, acute disseminated encephalomyelitis and Marburg disease, although it is precisely because they are so devastating that they are not considered as typical MS. Relapse-driven irreversible disability may also be a feature of more classical cases of MS. Clinicians are familiar with
Relapses are not the major cause of irreversible disability
The actual contribution of relapses to disability accumulation is not clear. Inflammation also has some beneficial effects, the best evidence being that remission is the rule following a relapse. Some experimental data have also shown that inflanmation may have a neuroprotective effect [18]. Other evidence comes from the primary progressive forms of MS: progression of irreversible disability occurs without superimposed relapses [19] and without clearcut inflammation as seen pathologically and
Is there a dissociation between relapses and progression of disability, and between focal inflammation and diffuse degeneration?
All these observations are, in fact, rather puzzling. Clinicians learn directly from patients and are apt to recall the most striking experiences; thus all neurologists will remember the patient with MS who had a relapse with a permanent deficit. There are many instances in medicine in general, and in MS in particular, of anecdotal, experience-based clinical impressions that have been clearly refuted by appropriate large-scale epidemiological studies. With respect to MS, the influence of
Conclusion
Does this mean that inflammation and relapses do not deserve consideration? Obviously not. Assuming that the disease were detected at the very beginning of the autoimmune process, immunoactive drugs might be administered immediately and could presumably show a dramatic efficacy. Unfortunately, when MS becomes clinically apparent, the disease, in most cases, is already well-established. Currently approved immunoactive drugs can help control inflammation and relapses, but even powerful agents,
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