Environmental factors and multiple sclerosis

Summary

Studies in Canada have provided strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of multiple sclerosis (MS). However, the available data accommodate more than one type of environmental effect. Migration studies show that changes to early environment can greatly affect risk, and there are recent indications that risk can be altered in situ. The rising incidence rates of MS in Canada implied by longitudinal increases in sex ratio place this effect in temporal context and narrow the candidates for mediating the effect of environment. Similarly, geographical patterns in Australia imply that modifiable environmental factors hold the key to preventing some 80% of cases. Genetic epidemiology provides overwhelming evidence that genetic background has an important complementary role. If genetic factors are held constant, the environment sets the disease threshold. Although these could be independent additive risk factors, it seems more likely that susceptibility is mediated by direct interactions between the environment and genes.

Introduction

Nature versus nurture arguments about the pathogenesis of multiple sclerosis (MS) have given way to evidence that both are important. Independent of seminal South African migration studies by Dean,¹ the low prevalence of the disorder among people of east Asian descent in Canada compared with that in people of north European descent has long been recognised. A similar relative dearth of cases in Queensland is obvious to local practising neurologists familiar with the prevalence of the disorder in Sydney and Melbourne. And these impressions have been confirmed by real data.² It is more timely to ask if and how nature and nurture interact rather than debate their relative importance. Identification of environmental factors might pinpoint biological pathways, and vice versa.

The limited ability of case–control studies to identify differences led to a temporary de-emphasis of the study of environmental factors. The environment does not necessarily differ for affected and unaffected individuals in the same family, and geographically separate regions have the same risk. Several recent studies discussed here refocus attention on environment, which is so clearly important in pathogenesis.

The study of genetic factors, perceived a decade ago to be more tractable than that of environmental influences, has been slow in fulfilling initial promise. Claims for linkage on nearly every chromosomal arm suggest systematic methodological failures.³ Two recent small but confirmed effects leave half of the genetic contribution to MS unexplained.4, 5 Re-examination of the conceptual and practical importance of the environment in the pathogenesis of MS seems timely.

Given that the effect of the environment in MS is not necessarily mediated by singular or discrete events, it may be useful to separate susceptibility, triggering, and outcome. Here we focus on the first of these. Although there is convincing evidence that environment affects outcome and clinical features,⁶ few studies have examined differences in long-term outcome by geographic location.

Non-specific viral (and perhaps bacterial) infections seasonally precede both onset and relapses (and MRI activity) in perhaps a quarter of MS cases⁷ despite common disparity between biological and clinical onset. The relation of relapses to long-term disability is surprisingly unclear⁸ and the dissociation of the two is evident in early studies of interferon.⁹