Ana sayfa | MS’in Derinliği  | MS Slide Resource

In the search for clues to the aetiology of MS, researchers have studied a wide variety of environmental factors. All are tightly interlinked but, for convenience, they can be broadly categorized as geographic, demographic or sociocultural factors.

Geographic

It has long been recognized that MS is unevenly, but non-randomly, distributed throughout the world.^4,12 The pattern of distribution demonstrates the existence of zones of differential risk for MS, which to a large extent relate to geographical latitude. Many researchers consider that this reflects the distribution pattern of some causative factor(s) often attributed to the environment.⁴

Risk zones

Zones of high, medium, and low risk for MS are defined on the basis of disease prevalence.¹³ The high-risk zone, with prevalence rates of >30 per 100,000 population, includes northern Europe, northern USA, southern Canada, southern Australia, and New Zealand. The southern USA, southern Europe and most of Australia fall into the medium-risk zone, where prevalence rates are 5 to 29 per 100,000. The low-risk zone has prevalence rates of < 5 per 100,000 and includes Asia, Latin America, and most of Africa and the Middle East.¹³

This zonal interpretation of geographic variation in MS distribution has several drawbacks:

• important differences in MS prevalence within a zone can be obscured

• re-classification of an area following an apparent change in MS frequency might imply that the aetiological factors that determine disease frequency have altered

• the arbitrary cut-off points can create a false impression that there is a sudden discontinuity in risk between zones.⁵

Latitude

Many epidemiological studies support the existence of a gradient of MS prevalence: with prevalence increasing with distance from the equator in both the northern and southern hemispheres.^4,12 An Australian study provides an excellent example of such a gradient, which is especially valuable since the ethnic distribution appears to be very similar throughout the country. Prevalence is high (76 per 100,000 population) in Hobart, Tasmania (the most southerly area of Australia), then diminishes with progression northwards through Newcastle (37 per 100,000), Perth (30 per 100,000), and finally Queensland (18 per 100,000).¹⁵ Similar gradients are reported in the USA, New Zealand and Japan.^4,16

Conversely, the MS prevalence rate in Rochester, Minnesota, (173 per 100,000 population) is almost four times that found in Newfoundland, (55 per 100,000), which has a higher latitude.^4,16 The validity of the latitude-dependent hypothesis is challenged also by the existence of a two-fold difference in MS prevalence between Rochester, Minnesota (173 per 100,000 population) and both London, Ontario (94 per 100,000), and Vancouver, British Colombia (91 per 100,000), all of which have similar latitudes^.4,16

How useful is the geographical approach?

Prevalence studies do allow some general conclusions to be made about the geographical distribution of MS, despite the severe limitations imposed on their comparability by differences in methodology.

Firstly, prevalence rates for MS tend to be higher in areas that have a temperate climate and are economically developed.¹⁴ Secondly, there is clear evidence to support the existence of latitude-dependent gradients in MS prevalence in several countries where the populations are racially homogeneous.⁴ However, where the population is of mixed ethnic origin the relationship between latitude and MS prevalence is less clear.^4,16

Data from small, but well-conducted national studies reveal the underlying complexity, and sometimes contradictory nature, of the geographical distribution of MS. They show that:

• Regions sharing the same geographical latitude may have very different MS prevalence rates.

[Simultaneous studies by the same research group found markedly different prevalence rates for MS in Malta (4 per 100,000 population) and Sicily (53 per 100,000), which are geographically very close.⁴]

• Regions at different geographical latitudes may have very similar MS prevalence rates.

[MS prevalence rates of 55.2 and 53 per 100,000 population are reported in Newfoundland, Canada, and Enna, Sicily, respectively.⁴]

Demarcating the geographical distribution of MS has done little to identify a causative factor, or why, if such a factor exists, it is distributed unevenly throughout the world. Clearly, there is an environmental component to MS aetiology but exceptions to the geographical explanations show that this is not the only factor operating.

Time trends

Many epidemiological studies suggest that the incidence and/or the prevalence of MS is increasing. It is unclear whether this increase is real or whether it reflects changed diagnostic criteria and/or improved case ascertainment, study design and diagnostic capabilities.⁴ However, there is unambiguous evidence that the incidence of other autoimmune diseases (especially juvenile-onset diabetes) is increasing.¹⁷ In contrast to MS, it is difficult to imagine that this could be related to changes in diagnostic accuracy.

Demographic

Race

The recognition of variability in the geographical distribution of MS prompts the question, 'Is MS prevalence associated with genetically-determined ethnic factors?'. To answer this question, epidemiologists need information regarding the comparative frequency of MS in particular racial groups when living in different countries and when living in the same country.

Whites

MS prevalence is highest in northern Europe and in those countries populated with the descendants of European migrants (e.g. North America, Australia and New Zealand).^4,5 However, this is not inevitably the case, as MS is relatively rare among the whites in South Africa (English-speaking 13 per 100,000 population; Afrikaans-speaking 4 per 100,000) and in the state of Queensland, Australia, and the southern USA.^4,5 Hence, racial susceptibility cannot be the sole factor determining rates of disease either.⁵

Blacks

MS is almost unknown among black Africans, although recently a few cases of probable MS have been reported in Zimbabwe and in South Africa.¹⁸ The prevalence of MS among black males in the USA is higher than that seen in Africa, but lower than that found in American white males (see below for further information).¹⁹

Orientals

MS rates are low in Japan (1 to 4 per 100,000 population) and Korea (~2 per 100,000). The available evidence suggests that MS is rare among other oriental groups.^4,5

Other groups

Amerindians and the Inuit (groups that are both oriental in origin) are almost entirely free from MS.¹⁴ Similarly, Lapps, Maoris, Hungarian gypsies, and other genetically and culturally restricted communities have low rates of MS, even when living in otherwise high prevalence areas.¹⁴

MS in differing racial groups in the USA

The US veterans study provides the most reliable data on the relative risk for MS in the principal racial groups from a single country.¹⁹ The researchers identified 4922 white males, 177 black males and 17 males of 'other' ethnic origin who were diagnosed with MS following military service in World War II and/or the war in Korea.¹⁹ Black American males and those of 'other' ethnic origins (including Amerindians, Hispanics, Japanese, Chinese and Filipinos) had much lower rates of MS than white American males. Relative risks for MS of 0.43 and 0.22 were calculated for black American males and males of 'other' ethnic origins, respectively, compared with white American males.¹⁹

Black and oriental males showed the same north-to-south gradient in risk as white males.^12,19 Although the numbers of 'other' males were too small for confidence, there appeared to be fewer MS cases among Amerindians and American-Japanese than would be expected given the proportions of persons of such origins in the general population.¹⁹

Figure 1.7 Comparative risk for MS among racial groups in the USA19

Gender

Recent population studies show consistently that MS is more common in women than in men, although older studies tend to indicate a more equal sex distribution.^5,20 MS is not the only disease with a sex-related skewed distribution: most autoimmune diseases have an unbalanced sex distribution, and many of these affect women more often than men.²⁰

The ratio of female to male MS patients varies from study to study but is approximately 2:1.^4,10,20 Familial and twin studies provide additional evidence for an increased susceptibility to MS among women.²⁰

In general, the mean age at MS onset is a year or two lower in women than in men.⁴ Men may have a greater tendency to primary progressive MS (i.e. slow, steady decline in neurological function from disease onset).^8,21

In early-onset cases (<16 years of age) the ratio of females to males is ~3:1.²⁰ There is also a preponderance of women among late-onset cases of MS (onset after age 45), with a reported female to male ratio of 2.4:1.²⁰

The reason for this sex-related skew in early- and late-onset MS is unclear, but the increased susceptibility of women at the relevant ages may be related to puberty and to menopause.²⁰ Sex hormones, which are thought to influence the immune response, may be involved.²⁰

Age

MS onset occurs between the ages of 20 and 40 years in most patients (~66%), with the mean age of onset from 29 to 33 years (slightly younger in females).^4,5,10 MS onset is infrequent in the young and the elderly; only ~0.3% of patients are younger than 10 years at disease onset, and it is rare in those over 59 years but can occur as late as the eighth decade.^4,10 For research protocols, an age of onset range of 10 to 59 years is used, as this includes almost all MS patients.^4,5

The age-specific incidence curve for MS has some unusual characteristics. It is basically unimodal, with a 'shoulder' that reflects the unexpectedly high proportion of patients with onset between the ages of 41 and 45 years.

The shape of the age-specific incidence curve for MS appears to be the same world-wide, regardless of differences in disease frequency.⁵ In three Australian cities with widely differing MS incidence, the mean age at onset and the age-specific incidence curve show little difference.¹⁵ The observation appears to hold true in the most extreme of cases. For example, a simple adjustment to the scale of the vertical axes of the graph allows the age-specific incidence curves for Japan and Denmark to be superimposed, despite a 50-fold difference in prevalence.⁵

Migration

Migration studies should, in theory, resolve the debate over the relative importance of environmental and genetic factors in the aetiology of MS. The incidence of diseases that are purely genetic in origin will be unaffected by migration, while the incidence of diseases with an environmental cause may change to reflect that of the adoptive country.^4,5

Therefore, by comparing the rates of disease in a migrant population with those seen in:

• their country of origin, and

• the native-born population in the host country,

it should be possible to make the distinction between genetic and environmental causes.⁵

Furthermore, if an environmental factor is involved, it may be possible to determine when the disease (or the potential for the disease) was acquired. This could be achieved by examining disease risk in groups who migrated at different ages, given a sufficiently large migrant population for whom age at migration is known.⁵

In practice, there are several difficulties with this approach:⁵

• Migrants are not necessarily typical of the general population in their country of origin in age, social class, or health status.

• The host country may place restrictions (age, education, occupation, health status) on who they will accept as immigrants.

• Migrants are not necessarily exposed to the same environmental conditions as the indigenous population in their adoptive country. They are unlikely to be distributed evenly throughout the country, and may choose to form their own communities and retain their own lifestyle rather than integrate into the host society.

Hence, migrants may not be directly comparable to either the population in their native country or the indigenous population of their adopted country.⁵ Several additional factors further weaken the validity of migration studies. These include:

• the small size of migrant populations

• difficulty in estimating the size of the population at risk

• difficulty in comparing studies done at different times.^4,5,1

Nevertheless, migrant studies can provide useful information.

Migration from high-risk to low-risk areas

The earliest study examined the effect of migration from northern Europe, a high-risk area for MS, to South Africa, a low-risk area.²³ The MS prevalence rate of 36 per 100,000 population found among the migrants contrasted sharply both with those seen in their region of origin (50 to 100 per 100,000) and in native-born South African whites (11 per 100,000).³³ Age at migration was not considered in this study.

These results show that groups with the same ethnic background can have very different MS prevalence rates when they live in widely separated geographical areas.⁴ In addition, they suggest that migrants tend to adopt the MS frequency of their new country of residence.⁵ Australian and Israeli migrant studies tend to support this hypothesis.⁵

Except in the areas of highest MS risk, immigrants to Australia have similar MS prevalence rates to those with a European ethnic background who are born there.¹⁵ MS prevalence among immigrants in Hobart, Tasmania (103 per 100,000 population), the area of highest risk, is significantly higher than that in the local population (70 per 100,000), but is similar to MS prevalence in the UK and Ireland, the countries from which most of the immigrants came.¹⁵

The gradient in MS prevalence that exists among the Australian-born population (see above) is apparent also in the immigrant population.¹⁵

Data from studies of immigrants to Israel are difficult to interpret, partly because of the unusual and rapidly changing age structure of the population, and partly because of the diversity of ethnic origins.^4,5 However, comparison of age-specific prevalence rates shows that, at all ages, MS is less common in European immigrants to Israel than in the countries of northern Europe.⁵

Migration from low-risk to high-risk areas

A study of first generation immigrants to the United Kingdom (UK) from the West Indies (a low-risk area for MS) showed that the immigrants had an MS risk only one-eighth that of the native-born population.⁵ This suggests that the move from a low-risk to a high-risk area has no immediate effect on the risk of disease.⁵

A strikingly higher rate of disease was seen in a follow-up study of the UK-born children of these West Indian immigrants.⁵ However, case ascertainment was not population-based.⁵

An excellent example of the effects of confounding factors is provided by a study to compare MS risk in Vietnamese immigrants to France with that of the population who remained in Vietnam.⁴ An increase in MS risk was reported among the immigrants: a finding that lent support to the hypothesis that MS risk increases in migrants from a low-risk to a high-risk area.

However, it was not taken into account that the migrants were all of mixed race, each having one French parent. Therefore, they were not comparable to the Vietnamese population, and the 'expected' prevalence for MS in the immigrant group was invalid.⁴

Effect of age at migration

Several migrant studies suggest that the potential for developing MS may be established early in life, and possibly by the age of 15 years.^5,10 Although this impression may be false, there is clear and consistent evidence that migration from a high-risk to a low-risk area while young results in a reduction in MS risk.⁴ There is less evidence that an increase in MS risk is associated with migration from a low-risk area to one of high-risk, and any such increase in risk may be less marked than in the reverse case.⁵

Clusters and epidemics

Numerous reports describe MS clusters, where several cases arise at the same time in the same location, or patients have lived or worked in close proximity in the past.⁴ Reported instances are difficult to verify and, in most cases, rigorous statistical analysis of data has failed to find positive evidence of geographical or temporal clustering^.4,5 A possible exception to this is the clustering found among MS patients at about 21 years before disease onset and just prior to onset on three of the Orkney Islands off the Scottish coast.⁵

It is often impossible to determine whether clusters occur more frequently than could be expected simply by chance.^4,5 Nevertheless, reports of clustering merit consideration as they could help to clarify the cause of MS.⁴

Putative 'epidemics' of MS have been reported in several locations. The most well-known of these occurred in the Faroe Islands following World War II.^4,5,13 Three successive 'epidemics' have been identified in the thirty-year period between 1943 and 1973, and the possible occurrence of a fourth was reported recently.¹³

There were said to be no cases of MS in the Faroes before 1943, and the appearance of MS cases correlated strongly with the stationing of British troops in the Faroes from 1940 to 1945.⁵ Investigators suggest that asymptomatic British troops introduced the first epidemic, and that subsequent epidemics were transmitted by asymptomatic Faroese.⁵

A similar relationship has been proposed between the presence of British, American and Canadian troops in Iceland during World War II, and the occurrence there of an 'epidemic' of MS between 1945 and 1954.⁵ It remains unclear whether or not this 'epidemic' was real.²⁴ MS was already prevalent in Iceland before the War, and the annual average incidence increased from 2 per 100,000 population to 3.5 per 100,000 between 1945 and 1954.^5,24 This apparent increase in incidence may reflect improved case ascertainment, since the first neurologist in Iceland was appointed in 1942.^4,5

An influx of outsiders into a newly-built army training camp was implicated in the introduction of MS to Macomer in Sardinia.⁵ In a population said to be previously MS-free, six cases of MS were identified between 1952 and 1960, and seven more between 1964 and 1980. The mean time between first contact with the outsiders and onset of disease in the first six cases was more than 12 years.⁵

One common factor emphasized in these reported epidemics was the arrival, in relatively isolated communities, of a large number of newcomers. Investigators have tended to interpret this as evidence that MS is a transmissible disease.⁵ Before this explanation can be accepted, other factors or events that may have influenced recognition of MS (e.g. improved diagnostic facilities), and came into operation at the same time as the influx, must be investigated.⁵

Sociocultural

The sociocultural factors that may affect the epidemiological patterns of a disease are concerned with differences in the way in which groups of people live.^5,12 This may relate to diet and nutrition, hygiene and sanitation, or to urbanization, industrialization and 'Westernization'.^5,12

The studies examining the effects of sociocultural factors on MS have produced conflicting results.¹⁰ Simple correlations between MS risk and socioeconomic status are not easy to interpret.

Figure 1.12 Sociocultural factors affecting MS epidemiology

Diet and nutrition

Some investigators suggest that specific dietary factors, deficiencies, or excesses may be risk factors for MS.¹⁰ They suggest also that MS patients may differ from the general population in the composition of their diet.¹⁰

Fat in the diet, in terms of both amount and type, has been implicated in the aetiology of MS.¹⁰ Studies were done to correlate changes in dietary intake of fat before, during, and after World War II with the yearly incidence of MS during the same period. These suggested that the incidence of MS in particular populations may be related directly to the amount of fat (particularly saturated fat) in the diet.¹⁰ It was proposed that diets high in saturated fats would have a relative deficiency of essential fatty acids, and that this may affect myelin function.²⁵

Reports suggest that MS patients may benefit from a low-fat diet, with fewer deaths, less disability and fewer exacerbations occurring over a 20-year observation period.¹⁰ Further support for the suggestion that high fat consumption might be significant in causing MS comes from empirical studies in Israel, and review of dietary and prevalence data in many other countries.¹⁰

However, at least one study reports satisfactory results in MS patients given a high-fat diet.¹⁰ Furthermore, it has already been established that MS is uncommon among Afrikaans-speaking white South Africans, who eat a very high-fat diet.¹⁰

Investigators have suggested several other dietary factors that might be involved in the epidemiology of MS. These include cereal crops, gluten-containing grains, vitamin D and calcium, selenium and vitamin E, and vitamin A.

Hygiene and sanitation

A considerable body of evidence exists to correlate the levels of hygiene and sanitation with the frequency of MS in a community.¹⁰ Little evidence is available to rebut the connection.¹⁰

Numerous reports show that high MS rates tend to be found among groups that live in an environment where sanitary standards are high.¹⁰ If there is a real relationship between MS frequency and sanitation levels, then in technologically advanced countries where sanitation is poor MS rates should be low. This situation has been observed in both Japan and Mexico.¹⁰ In contrast, an increase in MS frequency should occur where sanitation levels are improved, which has been reported to be the case in Israel.¹⁰

It is known that cleanliness can be an important factor in the development of experimental autoimmune disease. A relationship between disease penetrance and increased cage cleanliness has been established in non-obese diabetic mice - an animal model of spontaneous autoimmune disease.¹⁶

Urbanization

Several investigators have failed to correlate MS risk with either rural or urban living.^5,10 In contrast, studies in the USA and Israel provide convincing data to connect MS risk with an unidentified factor related to urbanization.¹⁰ The series of Israeli studies linked MS with a Westernized, technologically developed way of life.¹⁰ This hypothesis merits further investigation, since other diseases (e.g. diabetes, hypertension) are associated with the changes in lifestyle that develop in parallel with the processes of urbanization and technological development.¹⁰

Any or all of the above-mentioned sociocultural factors, and many others such as socioeconomic status and religious practices, may influence MS risk. However, their complexity and variability, together with methodological inconsistencies in studies, make it difficult to draw any but the most general conclusions regarding their effects on MS epidemiology.

Bu sayfadaki bilginin en son güncellendiği/doğrulandığı tarih:

11/09/2001

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