The nature of multiple sclerosis

Abstract

Multiple sclerosis (MS) has recently been classified according to its clinical course. Despite relapses and remissions, its course is invariably progressive, and the observed progression from the remitting-relapsing to the secondary progressive form represents the accumulation of permanent damage to the nervous system. Discussions of the nomenclatural position of Schilder’s, Marburg’s, and Baló’s diseases, ignore the fact that the unique, pathognomonic, sharp-edged plaque of MS, is also the pathologic end-result in the three variants. Devic’s disease or neuromyelitis optica (NMO) is quite different and with some exceptions, is a particular form of disseminated encephalomyelitis (DEM). There is no evidence that the ‘oriental form of MS’ is anything but NMO. The suggestion that MS and DEM are variants of the same condition is contradicted by the fact that the pathological characteristics of the two are quite different. While it is probable that the two share aspects of pathogenesis, the patients differ because of their genetic endowment. This was dramatically demonstrated in a group of Japanese patients who died after anti-rabies vaccination and were found to have the typical sharp-edged lesions of MS. The genetic determinant was also crucial in the marmoset in which EAE uniquely resulted in a chronic relapsing-remitting (RR) disease characterized by the classic sharp-edged lesions of MS. The question ‘ADEM: distinct disease or part of the MS spectrum?’ can be answered with a resounding no. A new classification is proposed separating the different forms of MS from the various types of DEM.

Introduction

Since there is no identified etiological agent, nor a fully established pathogenesis, several different definitions and classifications of multiple sclerosis (MS) have been published, but the matter remains controversial. In 1952, Adams and Kubik [1] published a classification (Table 1) that remained in use for a long time. It was based on the morbid anatomy of what were designated as demyelinative diseases, since they shared demyelination as a common pathological substrate. Not surprisingly, Schilder’s encephalitis periaxialis diffusa and metachromatic leucoencephalopathy were grouped together as ‘cerebral sclerosis of the demyelinative type’. More recently, the problem has been stated somewhat differently, by asking the question, ‘MS: one disease or many?’ [2]. Over the years, some clarification occurred and the various nomenclatures have been restricted to what have more correctly been called idiopathic inflammatory diseases of the central nervous system (CNS).

The concept of a spectrum of diseases has been advanced (Fig. 1) [2] based on purely clinical considerations of chronicity and severity. As a result, Marburg’s disease and acute disseminated encephalomyelitis (ADEM) are grouped together, as are Devic’s and Baló’s diseases, and relapsing myelitis. For some reason, benign MS and relapsing-remitting (RR) and secondary progressive MS (SPMS) are considered to be different.

In regard to MS itself, Lublin and Reingold [3], reflecting the results of an international survey, defined it strictly in terms of its clinical course (Table 2). It is, however, more logical to look upon the clinical manifestations of MS as the externally observable parts of an underlying, essentially continuous process [4], somewhat like the Hawaiian Islands, which are the summits of a chain of active undersea volcanoes [5]. It is also easy to understand the conversion of RR to SPMS simply as resulting from the accumulation of damage to the nervous system [6] (Fig. 2).