Although the strongest risk factor for multiple sclerosis (MS) is a family history, which is not modifiable, there is compelling evidence that environmental factors also are at play in MS development. Addressing these risks may potentially result in reduction of disease incidence, reported Alberto Ascherio, MD, DrPH, associate professor of nutrition and epidemiology and director of the Neuroepidemiology Group at Harvard University in Boston.
Although the strongest risk factor for multiple sclerosis (MS) is a family history, which is not modifiable, there is compelling evidence that environmental factors also are at play in MS development. Addressing these risks may potentially result in reduction of disease incidence, reported Alberto Ascherio, MD, DrPH, associate professor of nutrition and epidemiology and director of the Neuroepidemiology Group at Harvard University in Boston. Of possible modifiable risk factors, vitamin D deficiency may have the strongest impact on MS development, he said in a presentation during a satellite session at the 59th Annual Meeting of the American Academy of Neurology in Boston in early May.
One well-known factor that may be related to the link between MS and vitamin D deficiency is the latitude gradient. The exploitation of the latitude gradient, however, is an impractical way to avoid MS, Ascherio conceded, considering that it requires relocation to the tropics.
MS incidence is low in tropical and subtropical zones, and MS risk has been shown to be low in persons who migrate from Europe to tropical areas, particularly if they migrate during their youth.1-4 Risk is also low among those who migrate from tropical regions to northern Europe. However, for persons born in northern Europe to parents who emigrated there from tropical regions, the risk is the same as it is for the general native population.5-7
"Some of the most compelling data come from the United States," said Ascherio. He cited research by Kurtzke and colleagues,8 published in 1985, which demonstrated that significantly more veterans of World War II and the Korean War who had MS (N = 5305) were born in northern states (particularly in the Northwest) than in southern states. Furthermore, Kurtzke and colleagues found that the incidence of MS among white male veterans who moved from the North to the South was lower than it was among their nonmigrating counterparts. Conversely, those who moved from the South to the North were at higher risk than their fellow Southern veterans who remained close to home.
The trend is changing, though. When Ascherio's team analyzed data from the Nurses Health Study (NHS) I and NHS II, which looked at women born between 1920 and 1946 and between 1947 and 1964, respectively, it found that latitude played a significant role in relative risk of MS in the NHS I study (the older generation of women) but not in the NHS II study (the younger generation of women).9 The group went on to compare these data with data on MS incidence among veterans of World War II and the Korean War and among veterans of the Vietnam War and post- Vietnam War military personnel. Again, geography played a significant role in MS incidence among older veterans and a lesser role among younger veterans.
The cause for this change remains a mystery, although 2 possible hypotheses may account for the role of geography in MS risk. One, as mentioned, is vitamin D deficiency. The other is exposure to childhood infections-or lack thereof-referred to as the "hygiene hypothesis," whereby lack of childhood infections results in immune deviation toward helper T1 (TH1 cells; ie, inflammatory) immune responses, potentially leading to MS development, explained Ascherio.
"We receive most vitamin D from UV light; 80% at least at the latitude of Boston, but exposure to UV light is diminished in the winter, so we all go through a vitamin D deficiency at this time," noted Ascherio. "Because of this, it was proposed over 30 years ago that [the association between MS and] the latitude gradient had to do with vitamin D deficiency."10 Furthermore, although vitamin D has been traditionally thought of as a hormone that aids calcium metabolism, it was recognized in the 1980s that vitamin D receptors are present in immune cells and that vitamin D deficiency is associated with a shift toward TH1 autoimmune responses,11 Ascherio continued.
Animal studies have demonstrated inflammatory autoimmune responses in the absence of vitamin D and a reversal when the deficiency is corrected.12 Two studies in humans have shown similar results,13,14 but equivocal factors about the study design rendered the findings questionable, noted Ascherio. His team's analysis of NHS data, however, found a modest reduction in risk of MS development in women who, according to information about diet, took in more vitamin D, typically in the form of a supplement.9
"We went on to see whether we could predict development of MS in young adults if we measured serum 25-hydroxy vitamin D [25(OH)D], which is the immediate precursor of the active form of the vitamin," said Ascherio. His team sorted through over 30 million blood samples of more than 7 million military personnel collected since 1990 and focused on 257 cases of MS and 514 matched controls.
Of the patients with MS, average age at onset was 28.5 years, most (73%) had relapsing-remitting disease, and symptom onset occurred at an average of 5.3 years from the time the first blood sample was drawn. It was determined that those persons who had very high levels of 25(OH)D (greater than 100 nmol/L) were at lesser risk for MS development. "The association was greatest in those whose blood samples were taken before age 20 years," said Ascherio, suggesting that the amount of vitamin D a person absorbs in childhood may be predictive of MS risk. He added that the data were specific to white persons, namely because high melanin levels, which are characteristic in dark-skinned populations, block absorption of vitamin D. Thus, serum 25(OH)D levels are naturally not particularly high in African Americans, a phenomenon that was evidenced in the study. "Serum 25(OH)D did not exceed 90 nmol/L among black participants in the study," reported Ascherio.
The implication is that if vitamin D has a protective effect on MS risk, supplementation in young persons could help ameliorate MS incidence. "The Institute of Medicine now recommends only 200 IU/d of vitamin D in persons younger than 50, but most experts believe that this dose is far too low. You can give a dosage of 4000 IU/d, increasing the serum 25(OH)D up to 100 nmol/L without adverse effects," Ascherio said. In his opinion, a large, population-based, randomized trial is urgently needed to ascertain whether vitamin D is protective against MS. "It would be interesting to look at persons with clinically isolated syndrome to see the effect of vitamin D supplementation on disease progression," he said.
"It has been hypothesized that exposure to childhood infections primes the immune system to make MS development less likely," explained Ascherio. Lack of exposure to childhood infections may have the opposite effect. Evidence for the hygiene hypothesis is the observation that incidence of MS is low in developing countries, the population of which is assumed to have been exposed to numerous childhood infections, and is increased in affluent, well-educated populations in which exposure to infections is presumed to be low because of better health hygiene.15,16
Another factor at play in the hygiene hypothesis is that risk of MS is high among persons who have a history of mononucleosis, a phenomenon confirmed in 2 studies conducted by Ascherio and collaborators.9,17 Furthermore, although it has been assumed that persons who are negative for the Epstein-Barr virus (EBV) should be within the category of those at high risk for MS, recent studies showed that EBV seronegative status confers protection against MS.17-19
These 3 studies, 2 of which were coauthored by Ascherio, suggest that risk of MS development is particularly high among persons who are EBV-positive and have a history of mononucleosis, especially if they became infected with EBV in adulthood; relatively high in persons who became EBV-positive in childhood but do not have a history of mononucleosis; and very low in persons who are EBV-negative. The mechanism behind the association between EBV and MS, however, is unknown and demands study, Ascherio commented.
The final modifiable risk factor in MS development discussed by Ascherio was cigarette smoking. He reminded the audience of the strong correlation between cigarette smoking and MS, citing the 4 longitudinal studies on the subject.20-23 Furthermore, a study in which he was involved showed that cigarette smoking is associated with accelerated transformation from relapsing-remitting to secondary progressive MS.23 Indeed, ever-smokers had more than a 3-fold higher risk of MS progression than patients who had never smoked cigarettes, Ascherio reported.
He urged researchers to look into the mechanism behind smoking and MS risk, noting that nicotine may compromise immune function and that toxins in cigarettes may contribute to demyelination.
In conclusion, Ascherio reiterated that modifiable environmental factors-namely vitamin D deficiency, EBV infection, and cigarette smoking-play a role in MS development. Recognition and further research may result in preventive measures and new therapeutic approaches to the treatment of MS.
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