91 Multiple Sclerosis

Multiple sclerosis is a disease of the central nervous system characterized clinically by recurring epi­sodes of neurological disturbance which, especially early in the course of the disease, tend to remit spontaneously, although as time goes by there is often a gradual accumulation of disability.

Overview

Multiple sclerosis is a remarkable disease. It was first clearly described more than 120 years ago in a way which we would recognize as a modern, patho­logically based account that discusses the clinical features of the illness and their possible patho­physiology (Charcot 1868). It is only since the early 1970s, however, that real progress has been made in understanding its nature, course, and pathogenesis. It was discussed in treatises on pathology by R. Cars­well (1838) and J. Cruveilhier (1835-42), and more knowledge was added by E. Rindfleisch (1873), but the French school did most to delineate the disease. Good descriptions were appearing in standard text­books of neurology before the end of the nineteenth century, and in 1916 J. W. Dawson gave an exhaus­tive account of the pathology of the disease which has remained a standard reference.

Three personal accounts of multiple sclerosis by sufferers are worth reading for the insights that they give into its course and its consequences.

The geography of multiple sclerosis is interesting because it is strange and because understanding it may provide a crucial clue to the nature of the dis­ease (see Matthews et al. 1985; McDonald 1986). Geographic peculiarities were first noted 85 years ago when Byron Bramwell argued that the higher incidence of multiple sclerosis in his practice in Edin­burgh than that of neurologists in New York re­flected a real difference in frequency between the two cities.

Forty years ago, the notion of the relevance of genetic background as well as latitude was pointed out by Geoffrey Dean on the basis of the lower preva­lence of multiple sclerosis among Boers than among British descendants in South Africa; in both groups the prevalence of the disease in Africa was the same as in their countries of origin. The idea that genetic background was important also received support from the discovery of the rarity of multiple sclerosis among the Japanese. In the past 20 years, strenuous efforts have been made to determine the conse­quences of migration at different ages from areas of high to low prevalence, and vice versa. These studies support the general idea of an interaction between latitude and genetic factors determining the geo­graphic distribution of the disease.

Pathology

The characteristic lesion of multiple sclerosis is the plaque of demyelination - a patch varying from a few cubic millimeters to many cubic centimeters in which the myelin sheath of nerve fibers is destroyed, leaving the axons relatively intact.

The outstanding feature of the chronic lesion is the formation of a fibrous scar as a result of prolifera­tion of the astrocytes, one of the supporting cells of the central nervous system. Remyelination, at least in most cases coming to post mortem, is scanty, al­though it is an open question whether it may be more extensive early in the course of the disease.

The plaques are distributed asymmetrically throughout the brain and spinal cord, but there are certain sites of predilection which determine the char­acteristic clinical pattern of the disease. The impor­tant functional consequence of demyelination is block of electrical conduction in the nerve fibers which leads to many of the clinical features of the disease.

Clinical Manifestations

In at least 80 percent of patients, the disease follows a relapsing and remitting course, often in the later stages entering a steadily progressive phase. Fully 5 to 10 percent of patients experience a steadily progressive course from onset. The typical episode of neurological disturbance develops over a matter of days or a week or two, persists for a few weeks, then resolves over a month or two. Common manifesta­tions include reversible episodes of visual loss (optic neuritis), sensory disturbance or weakness in the trunk or limbs, vertigo, and bladder disturbance. Obvious disturbance of intellectual function is un­common, except in severe cases. Recently, however, subtle defects have been demonstrated early in the course of the disease.

Certain special clinical patterns are of interest. Steadily progressive spastic weakness is more com­mon in late-onset cases (older than 40 years). In Orientals generally, severe and persistent visual loss and limb weakness are particularly common. In the same group, a curious form of spasmodic disorder of the limbs is also frequent. The reasons for these well-documented ethnic differences in the pattern of clinical involvement are unknown.

Distribution and Incidence

Multiple sclerosis affects principally individuals of northern European Caucasoid origin living in temper­ate zones, though it does occur infrequently in the tropics and in other racial groups. Because the course of the disease is so prolonged and the manifestations are so variable, it is difficult to determine its true incidence, and prevalence rates are generally used to compare the frequency of the disease in different populations. Females are affected about twice as com­monly as men. The average age of onset is 30 years old, and it rarely starts over the age of 60 or before puberty. In Caucasoid populations, approximately 10 percent of patients have an affected relative. The concordance rate in twins (i.e., the frequency with which both members of a twin pair have the disease) is about 30 percent for identical twins and 2 percent for nonidentical twins, the latter being similar to the frequency in siblings. The difference in concordance rate between identical and nonidentical twins pro­vides strong evidence for the implication of a genetic factor in the etiology of the disease, but the rather low concordance rate in identical twins suggests that an environmental factor is also involved. Further evi­dence implicating both environmental and genetic factors comes from a consideration of the geography and epidemiology of the disease.

Geography and Epidemiology

There are two relevant geographic aspects: the distri­bution of the disease and the distribution of its ge­netic associations. Among Caucasoids the preva­lence of multiple sclerosis is generally higher in higher latitudes.

The influence of migration on risk has been stud­ied in several populations. Migration from high prevalence (e.g., northern Europe and the northern United States) to low prevalence areas (e.g., Israel, South Africa, or the southern United States) before puberty appears to decrease the risk of developing the disease, while migration after puberty does not. The total number of patients involved in these stud­ies is small, but the consistency of the results sug­gests that the observation is significant. Studies of migration from low-risk to high-risk zones (Vietnam to Paris, New British Commonwealth to the Old) are based on even smaller numbers, though they have yielded concordant results. These observations pro­vide further, albeit rather weak, evidence for the operation of an environmental factor in the etiology of multiple sclerosis, although this would seem to be the case if the risk of developing the disease is influ­enced by where individuals spend their first 15 years.

On the face of it, stronger evidence comes from the study of apparent clusters of cases in the Faroe Is­lands in the North Sea. No cases had been identified in the Faroe Islands prior to World War II. But be­tween 1943 and 1973, there were 32 cases; there have been no new cases since. Although it cannot be certain that cases prior to 1943 were not missed, the balance of evidence is in favor of there being an unusual run of them in the 30 years after that date. J.

Multiple sclerosis is much less frequent in non­Caucasoid populations. No postmortem-proved case has yet been described in African blacks, and preva­lence of the disease is lower in American blacks than in whites living in the same areas. The disease is similarly rare among American Indians, the Maoris in New Zealand, the gypsies in Hungary, and Orien­tals living in California and Washington State but not in the larger populations they live among. Multi­ple sclerosis is also rare among the Japanese in Ja­pan; among the Chinese in Taiwan, China, and Hong Kong; and among Indians living in India. It is so far unreported in the Eskimo. In many of these groups (but not Orientals in the United States and Japan), problems of ascertainment may have led to a significant underestimate of the true frequency of the disease. Nevertheless, it is clear that there are real differences in the frequency of the disease in different ethnic groups, again suggesting the opera­tion of a genetic factor in determining susceptibility.

Genetics

The most intensively studied genetic associations of multiple sclerosis are those within the human leuko­cyte antigen (HLA) region of the sixth chromosome. The most frequent association in Caucasoid popula­tions is with HLA-DR2, though others, including DQwl, have been reported. The strength of the asso­ciations varies in different population groups. R. J. Swingler and D. A. S. Compston (1986), though cau­tious in interpreting their data, have reported that in the United Kingdom the north-south gradient of prevalence of multiple sclerosis is mirrored by a simi­lar gradient in the frequency of DR2 in the control population. In the New World, G. C. Ebers and D. Bulman (1986) have shown that in the United States the areas of highest prevalence correspond with the areas of immigration from Finland and Scandinavia (where there is a high frequency of DR2), and D. C. G. Skegg and colleagues (1987) have shown that multi­ple sclerosis is three times less common in the north than in the south of New Zealand - the latter a site of preferential migration for the Scots, who have a par­ticularly high frequency of DR2.

There are fewer data for non-Caucasoid popula­tions. In a small study, multiple sclerosis was found to be associated with the Dw2 (related to DR2) in blacks in Philadelphia. Among the Arabs, multiple sclerosis is associated with DR2 in some groups, and DR4 in others. No HLA association has been found in the Japanese and Israelis.

It should be noted that multiple sclerosis is rare in two populations in which DR2 is common: the Hun­garian Gypsies (of whom 56 percent of controls are DR2 positive) as well as the Maoris - raising the possibility of the existence of an overriding genetic protective effect. Protective genes have also been postulated in Mongoloid and Caucasoid populations. Moreover, current research suggests that multiple sclerosis may be associated with peculiarities in the structure of certain genes in the HLA region.

What is one to make of this mass of confusing and sometimes conflicting data? The frequency with which some association with the HLA system is found suggests that the observations are significant. Yet it is clear that none of the factors so far identified alone confer susceptibility to the disease. The simplest ex­planation would be that DR2 is acting as a marker for another gene (or genes) conferring susceptibility, and that other genetic factors are involved as well.

Other possible genetic associations have been little studied, although there is evidence for an association with genes concerned with the control of antibody structure located on the fourteenth chromosome. A consistent pattern has not yet emerged. What is com­mon to all the genetic associations so far identified is that they are concerned in one way or another with the genetic control of the immune response.

Pathogenesis and Etiology

In considering how the geographic, epidemiological, genetic, and pathological data might fit together, it must be stressed that there is no wholly satisfactory framework within which to incorporate all the data.

Pathogenesis

Much evidence has accumulated suggesting an im­munologic basis for the disorder in patients with multiple sclerosis. There is abnormal synthesis of antibodies, both inside and outside the brain; there are changes in the number and functional activity of peripheral blood lymphocyte subsets in active dis­ease; and there are immune-competent cells around the venules in the lesions and in the brain itself. The occurrence of such changes in the retina (where there is no myelin) is evidence that the vascular events are not secondary to myelin breakdown pro­duced in some other way. This, combined with the results of recent functional vascular studies and other evidence, suggests that a vascular change is a critical early event in development of the new lesion.

Etiology

These processes provide a plausible though incom­plete explanation for the development of the lesions in established multiple sclerosis. What of its initia­tion? There is good evidence from family studies and epidemiology that an environmental trigger, proba­bly infective, is required in the genetically suscepti­ble individual. The most likely infective agent would be a virus, though interest in spirochetes has been revived recently on rather slender grounds.

Two possible mechanisms for demyelination fol­lowing viral infection are now known that occur only in genetically susceptible hosts. With visna, a retro­virus infection of certain strains of sheep, there are recurring episodes of demyelination of the central nervous system dependent on a direct attack of the virus; the remissions are due to the formation of neutralizing antibodies, whereas the exacerbations are due to mutations that lead to the loss of antibody control and renewed multiplication of the virus (Johnson 1982). There are, however, a number of important clinical and pathological differences be­tween visna and multiple sclerosis, including the consistent failure to isolate, reproducibly from the latter, a virus or fragments of one.

The second plausible mechanism involves the de­velopment of an autoimmune form of demyelination (after complete elimination of the virus) in mice inocu­lated intracerebrally with corona virus (Watanabe, Wege, and Ter Meulen 1983). The limitations of this model are that it is not known whether the process occurs after a natural route of infection, and whether in appropriate strains of animals a spontaneously relapsing and remitting disease can develop.

In conclusion, a solution to the problem of the nature and cause of multiple sclerosis would seem to be within sight. When we understand the reasons for the peculiar distribution of the disease, we are also likely to understand its etiology and pathogenesis.

W. I. McDonald

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