Introduction

In the last edition of this handbook, this chapter concluded with the statement that epidemiology is inferential—its role is to provide etiologic clues, but it cannot prove nor refute causality. Multiple sclerosis (MS) is a complex trait that appears to be determined by both genetic and environmental factors. It exhibits a changing incidence over time in an uneven geographic distribution. The evidence of these spatial and temporal trends from migrant studies affirms the etiological relevance of environmental factors, although their nature remains mysterious and is undoubtedly complex. A best summarizing guess at the causality of the disease was proffered, supposing that all MS patients possess one of the range of genotypes that confer susceptibility, that different genotypes are associated with different phenotypes, and that about one-third of those susceptible will develop the disease while the remaining two-thirds will not— either because they possess inhibitory or protective genes or because they do not come into contact with the necessary triggering factors in their internal or external environments.

The task for classic, inferential epidemiology is yet to standardize case findings, diagnostic criteria, and other methodological considerations to elucidate the contributory factors. Over the last five years, further epidemiological data that help in the understanding of the nature and cause(s) of MS have been published; a selection of these are reviewed here. During this period, Rosati (1) has noted that the influence of genetic factors in MS acquisition has been suggested by its rarity among certain races and by the relatively high risk among others. Such findings clearly indicate that the different susceptibilities of distinct racial and ethnic groups contribute to determining the uneven geographic distribution of the disease. The distribution of MS in Europe, however, shows many exceptions to the enigmatic north-south gradient and requires more explanation than a simple prevalence-latitude relationship.

In order to present an organized discussion of current clues to etiology, we have constructed a framework for the natural history of MS (Fig. 1) in the context of the various epidemiological observations toward the search for etiology thus far.

Figure 1 A proposed template for the natural history of multiple sclerosis including genetic factors that affect an individual's susceptibility from birth, multiple environmental exposures, a critical age of sufficient exposure, unknown induction period length, an estimated latency period, and a heterogeneous disease presentation.

Figure 1 A proposed template for the natural history of multiple sclerosis including genetic factors that affect an individual's susceptibility from birth, multiple environmental exposures, a critical age of sufficient exposure, unknown induction period length, an estimated latency period, and a heterogeneous disease presentation.

A natural history of the disease would begin with genetic or familial factors conferring susceptibility or protection to an individual at conception. It is likely that multiple genetic factors contribute to such susceptibility and that different combinations of such factors affect the length of the induction period (from the first disease trigger to a sufficient disease trigger), but the number and nature of the environmental exposures required for disease initiation or clinical progression remain speculative. The environmental contribution to disease initiation may occur either in utero or after birth. Different environmental factors (e.g., an exposure to a disease-triggering event) and multiple exposures may be necessary, again depending on the genetic susceptibility of the individual.

Susceptibility to disease induction in an individual may depend on a critical age of susceptibility or on a specific milestone (e.g., the evolution to puberty). This age of susceptibility may be variable, given selected genetic factors. Following this critical age, a latency period ensues before the clinical expression of the disease. To add further complexity to the model, different clinical forms of MS have been described, with different clinical courses, natural histories, ages of onset, rates of progression, and male-to-female ratios. Therefore, any etiological hypotheses drawn from epide-miological observations should be made in the context of the specific disease subtype.

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