Figure 2 Factors contributing to genetic susceptibility to multiple sclerosis explored in recent epidemiological studies.

Figure 2 Factors contributing to genetic susceptibility to multiple sclerosis explored in recent epidemiological studies.

among monozygotic twins, range between 31% and 40%, whereas those among fraternal and nontwin siblings are between 3% and 5%, (3,4) demonstrating a significant increase in relative risk with increasing genetic similarity. Because prevalence rates of MS among nonbiological siblings adopted into a family are similar to those found in the general population and are significantly less for biological relatives, familial aggregation of MS is obviously important (3). But the mode of disease transmission shows neither classical recessive nor dominant traits (5) and without a cost-effective means ofpopulation screening, disease penetrance is difficult to estimate.

Within an affected sibship, the initial clinical presentations differ but ultimate concordance for disease course (disability, progression) is likely (6). Familial recurrence rates of 1.9% to 4.7% have been found (7-9). The risk ratio of first-degree relatives compared with the general population was 31 times in one study (9). The risk is highest overall for siblings (4.8%), children (2.3%), and parents (1.3%), with lower rates in second-degree (0.7%) and third-degree (1.8%) relatives. Recurrence is highest for monozygotic twins (8,10). The risk for siblings is influenced by the age at onset and possibly by gender (9); male gender of the probands, female gender of the relatives, and the number of affected relatives in the family significantly increase the risk of MS in relatives (8). There is also a borderline significant interaction between the sex and age at onset of the proband; early age at onset influences sibs' risk only if the proband is female (9). Times to disability do not differ significantly when sporadic, familial and familial subgroups are compared, although the parent of origin may influence disability and disease course as well as increase the risk to additional offspring within the same family (11).

Regional Population Studies

The variation of prevalences within a localized geographical region has been studied and may act as a compass to etiology. A migration model for the epidemiology of MS in Newfoundland and Labrador was recently constructed, which accounts for both country of origin (a possible genetic contribution) and latitude (a potential environmental contribution) (12). This model, based on known migration patterns in a region with a strong founder effect and low intraregional migration, demonstrates that at least a portion of Newfoundland's population prevalence may be accounted for by their country of origin, a pattern that is further refined by the presumed environmental component of latitude.

The developing field of small area analysis has aided in the search for disease clusters in MS. A clustering pattern of prevalent cases (and a west-to-east gradient) has been found in some southwestern Sardinian communes, based on geographic distribution by both current prevalence and residence at the age of 5 to 15 years. Such clustering was found in a common linguistic area, while another adjacent (but genetically distinct) population showed lower figures (13). The authors hypothesized that a widely and evenly spread environmental agent may trigger disease in those subgroups of individuals who are genetically more susceptible.


The occurrence of regional clustering on a defined prevalence day does not distinguish between genetic and environmental influences; the latter would be differentiated by peaks of incidence within a defined geographical area in unrelated people, as in Key West and Sitka, AL (discussed in previous editions of this book). Temporal, as well as spatial cluster analyses may further contribute to the search for environmental causes within a genetically homogeneous population.

Racial Factors

Over the last five years, papers from all inhabited continents have documented the prevalence or incidence and the clinical phenotypes of MS. Thus, among Bantu African Kenyans, MS incidence rates are increasing (14). MS in Japan has a higher age at onset and a higher female-to-male ratio than conventional MS, and opticospi-nal MS is unusually frequent, although in Japanese people born after the 1960s, the ratio of conventional to opticospinal MS has rapidly increased (15) at the same time as there has been increased contact between the Japanese and Western peoples. Of interest is the observation that conventional MS in Japanese people is, like MS in white people, associated with HLA-DRBT1501, whereas opticospinal MS is associated with HLA-DPB1*0501 (16).

In a retrospective study from Manitoba, Canada, seven aboriginals were identified as having MS, giving an unusually low period prevalence rate of 40/105. As in other eastern-derived populations, the clinical features included phenotypes with aggressive disease courses and more frequent involvement of optic nerves and spinal cord compared with nonaboriginal patients. Aboriginals of Algonkian background also seem to be at increased risk for the aggressive type of MS, independent of those HLA alleles known to be associated with MS (17).

Conjugal Rates

While Hawkes (18) suggested that family, conjugal pair, twin, and adoption studies are compatible with an infectious cause of MS if this is sexually transmitted, Ebers et al. (3) considered that the low risk for the spouses of MS patients but the high risk in their offspring indicates that the familial risk reflects genetic determination (7), contradicting the supposition that MS is a sexually transmissible disease, at least in the marriage-age group. However, MS may still be interpersonally transmitted during a period of susceptibility that is earlier than the age of marriage, bearing in mind those close, asexual physical contacts that children have (more often with their mothers than with their fathers).

Birth Month

The onset of optic neuritis (ON) and of MS in the northern hemisphere occurs most commonly in spring and least often in winter (19). Seasonal birth studies in MS, amyotrophic lateral sclerosis (ALS), and possibly Parkinson disease also show an excess of spring births (20). However, a Sicilian population of MS patients has shown a highly significant excess of births between June and November (21). Studies of season of birth and risk of MS have been scanty and controversial until the recent demonstration (22) of a significant increase in the numbers of MS patients born in May compared with the numbers born in November, in the northern hemisphere. There is no obvious reason why differing nine-month calendar periods of intrauterine development should influence MS incidence two decades or so later; speculations about incident radiation (e.g., UV radiation generates vitamin D which modulates helper T2 lymphocytes to counterbalance the activity of helper T1 lymphocytes) can be constructed but are as yet unsubstantiated. Should future studies reveal that the more frequent months of birth are inverted in the southern hemisphere, the construction and testing of theories of causation based on these findings will be of paramount importance.

Mortality Studies

MS reduces life expectancy. Among 1614 Finnish MS patients, survival rates 40 years after diagnosis were 64% for MS-related deaths (c.f. 53% for all deaths). The proportions of violent deaths and neoplasms were higher in the general population, but that of cardiovascular deaths was relatively low (23).

In Canada, over the 30 years from 1965, the highest average annual MS mortality rates were in Quebec (4.4/105) and Ontario (3.9), while the western provinces had an intermediate rate (2.1) and the Atlantic provinces the lowest rate (1.2). The overall average annual MS mortality rates in Canada have fluctuated during the past 30 years, but there is no apparent relationship between prevalence and mortality rates among the Canadian provinces (24).

In a Danish study of 9881 patients, of whom 4254 had died before the end of follow-up, the median survival time from onset was approximately 10 years shorter for MS patients than for the age-matched general population, and MS was associated with an almost threefold increase in the risk for death (25). MS patients also had excess mortality rates from other diseases, except cancer, and from accidents and suicide. On the brighter side, the 10-year excess mortality rate was almost halved in comparison with that of the middle of the 20th century.

In a large study of U.S. veterans (26), median survival times from onset of MS were 43 years for white females, 30 years for black males, and 34 years for white males, whereas crude 50-year survival rates were 31.5% for white females, 21.5% for black males, and 16.6% for white males; only the figures for white females and white males differed significantly. Standardized mortality ratios utilizing national U.S. data (for 1956-1996) showed a similar marked excess for all three race-sex groups of MS cases but with a decreasing excess over time. Relative survival rates, comparing the survival of veterans with MS and those without, differed significantly by socioeconomic class but not by sex-race group, suggesting that the significant difference in survival between male and female MS cases results in part from gender rather than disease.

Tassinari (27) computed standardized mortality ratios in Italy for the period 1974-1993. Age-adjusted rates per million inhabitants were 4.1 for males and 5.0 for the period females. Northern Italian regions had higher MS mortality rates than central and southern regions and Sicily, particularly for females. Over these years, a statistically significant increase was seen for both males (+2.14%) and females (+3.09%) in the south and Sicily.

During a 10-year observation period, 21% of MS patients died but only 70% of them had an entry denoting MS in the death statistics (28). Because only a few papers provide details of the causes of death, and because of the notorious unreliability of death certificates, calculations of incidence or prevalence rates on the basis of death certificates appear unprofitable (29) and will not be discussed here. Although the quality of the data and their interpretation are open to question, they still remind us that depression, suicide, infections, and motor impairments in MS patients constrain living and truncate life.

0 0

Post a comment