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Environmental risk factors for multiple sclerosis. Part II Noninfectious factors

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NEUROLOGICAL PROGRESS
Environmental Risk Factors for Multiple
Sclerosis. Part II: Noninfectious Factors
Alberto Ascherio, MD, DrPH,1–3 and Kassandra L. Munger, MSc1
As discussed in Part I of this review, the geographic distribution of multiple sclerosis (MS) and the change in risk among
migrants provide compelling evidence for the existence of strong environmental determinants of MS, where “environmental” is
broadly defined to include differences in diet and other behaviors. As we did for infections, we focus here primarily on those
factors that may contribute to explain the geographic variations in MS prevalence and the change in risk among migrants.
Among these, sunlight exposure emerges as being the most likely candidate. Because the effects of sun exposure may be mediated
by vitamin D, we also examine the evidence linking vitamin D intake or status to MS risk. Furthermore, we review the evidence
on cigarette smoking, which cannot explain the geographic variations in MS risk, but may contribute to the recently reported
increases in the female/male ratio in MS incidence. Other proposed risk factors for MS are mentioned only briefly; although we
recognize that some of these might be genuine, evidence is usually sparse and unpersuasive.
Ann Neurol 2007;61:504 –513
As described in Part I of this review,1 multiple sclerosis
(MS) frequency among individuals of similar white ancestry increases with increasing latitude worldwide. The
landmark work of Kurtzke2 made it clear that genetic
factors could account for only a small proportion of
these variations, primarily by showing that risk declined twofold with migration from high- to low-risk
areas. Similar conclusions were reached by studies in
Australia and New Zealand.3 Latitude, however, is correlated with many physical, chemical, biological, and
social factors, and for many decades, the true determinants of MS have been hard to pin down. As discussed
later, mounting evidence from experimental and epidemiological studies is now converging to implicate sunlight exposure and the resulting increase in vitamin D
as an important contributor. We also provide a summary of studies relating cigarette smoking to MS risk,
which may explain, at least in part, the recently reported increase in the female/male ratio in MS incidence, and we also present a brief overview of other
potential risk factors.
Sunlight Exposure and Vitamin D
Sunlight Exposure
One of the strongest correlates of latitude is the duration and
intensity of sunlight. Thus, it is not surprising that an inverse correlation between MS prevalence and sunlight was
already noted in early ecological studies; a study among US
From the Departments of 1Nutrition and 2Epidemiology, Harvard
School of Public Health; and 3Channing Laboratory, Department of
Medicine, Brigham and Women’s Hospital and Harvard Medical
School, Boston, MA.
Received Jan 29, 2007. Accepted for publication Feb 9, 2007.
504
veterans found that the average annual hours of sunshine and
the average December daily solar radiation at place of birth
were strongly and inversely correlated with MS (r ⫽ ⫺0.73
and r ⫽ ⫺0.80, respectively)4; similar results were obtained
in Australia5,6 and among immigrants to Israel.7 A link between sunlight radiation and reduced MS risk was further
supported by the finding of an inverse correlation in Switzerland between MS prevalence and altitude, which is also a
marker of sunlight intensity.8
People living in the same area, however, share many characteristics, whose possible contributions to MS risk cannot
be separated in ecological studies. To overcome this limitation, several studies have examined the risk for MS among
people living in a similar environment but exposed to different levels of sunlight. In an exploratory investigation in the
United States based on death certificates, MS mortality in
areas of high and low sunlight was related to the individual’s
usual occupation, classified by an industrial hygienist as indoor, mixed, or outdoor.9 After adjusting for age, sex, and
socioeconomic status, both outdoor work (odds ratio [OR]
⫽ 0.53) and residence in a high sunlight area (OR ⫽ 0.74)
were associated with lower MS mortality rates, consistent
with a protective effect of sunlight exposure. Most importantly, working outdoors was associated with a significantly
lower MS mortality rate in areas of high (OR ⫽ 0.44, compared with indoor occupation), but not low (OR ⫽ 0.89),
sunlight. Mortality from skin cancer, however, followed an
opposite pattern, with outdoor workers in high sunlight areas
having the greatest risk.9 Major limitations of this study include reliance on death certificates, which are an inaccurate
Published online May 10, 2007 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21141
Address correspondence to Dr Ascherio, Department of Nutrition
and Epidemiology, Harvard School of Public Health, 665 Huntington Avenue, Building II, Room 335, Boston, MA 02115.
E-mail: aascheri@hsph.harvard.edu
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
source for both cause of death and occupation, and the possible effects of “reverse causation”; that is, individuals with
MS could preferentially choose an indoor rather than an outdoor occupation.
Another study, conducted in the United Kingdom, used a
record-linkage analysis to compare the observed mortality
from skin cancer among individuals with MS with that expected according to sex- and age-adjusted population rates in
the same districts.10 Skin cancer mortality rate among individuals with MS was found to be about 50% less than expected ( p ⫽ 0.03), a result consistent with a lower level of
exposure to sunlight among people with MS. As in the previous study, however, it remains unclear to what extent this
is the cause or the result of MS, because people with MS are
likely to reduce their sun exposure as a consequence of heat
intolerance and reduced time spent outdoors.
A question on sunlight exposure was included in two early
case–control studies, one conducted in Poland (including
300 cases),11 in which no association with MS risk was
found, and one in Israel (including 241 cases),12 in which,
opposite to expectation, patients with MS reported significantly more time spent outdoors in the summer than healthy
control subjects. More detailed information on exposure to
sunlight before the onset of MS was collected in a recent
case–control study in Tasmania,13 which included 136 patients with MS and 272 age- and sex-matched control subjects. The average time spent in the sun during weekends
and holidays during childhood was assessed using a questionnaire, complemented by an interview and by use of silicon
casts of the skin surface to assess the degree of actinic damage, a marker of cumulative sun exposure. All measures of
sun exposure were consistently associated with a lower risk
for MS. From the questionnaire, the relative risks (RRs) of
MS among subjects who reported an average time in the sun
of 2 hours or more between the ages of 6 and 10 were 0.47
(95% confidence interval [CI], 0.26 – 0.84) for winter exposure and 0.50 (95% CI, 0.24 –1.02) for summer exposure,
although the overall trends were not significant (Fig 1). Inverse but weaker associations were observed with sun exposure at older ages. Stronger associations and significant trends
were found using the interview-based recall of sun exposure.
Although differential reporting of sun exposure between
cases and control subjects, and thus recall bias, cannot be
excluded, such bias could not explain the inverse association
with actinic damage, which was measured objectively. On
the other hand, results based on actinic damage are prone to
error because of reverse causation, a limitation already discussed for the occupation and record-linkage studies, because
actinic damage measures cumulative exposure to sunlight, including the years after MS onset. The persistence of the inverse association between actinic damage and MS risk after
adjusting for self-reported sun exposure after the onset of MS
symptoms, and in analyses restricted to MS cases of more
recent onset,13 provide some evidence against reverse causation, and although bias cannot be excluded, it appears unlikely to fully explain the results.
The association between sun exposure in childhood and
MS risk has also been examined in a study among monozygotic twins discordant for MS.14 Each of 81 twin pairs was
asked about childhood sun exposure and outdoor activities in
comparison with his or her co-twin, and twins with MS reported, on average, lower levels of sun exposure. As for the
study in Tasmania described earlier, recall bias caused by differential reporting of sun exposure between cases and control
subjects cannot be excluded.
Link to Vitamin D
For most people, exposure to sunlight is their major source
of vitamin D.15 Ultraviolet B radiation (290 –320nm) converts cutaneous 7-dehydrocholesterol to previtamin D3,
which spontaneously isomerizes to vitamin D3. Vitamin D3
then undergoes a series of hydroxylations, first to 25hydroxyvitamin D3 (25(OH)D3), the main circulating form
of the vitamin, and then to 1,25-dihydroxyvitamin D3
(1,25(OH)2D3), the biologically active hormone.15 The increase in serum concentrations of 25(OH)D after wholebody exposure to one minimal erythemal dose (a slight pinkness to the skin) is similar to that achieved by taking a single
dose of 10,000 to 25,000IU vitamin D supplements16 (for
comparison, the average intake from diet and supplements
combined in the United States is ⬍400IU/day17). However,
at latitudes ⱖ42° (eg, Boston, MA) in winter, most ultraviolet B radiation is absorbed by the atmosphere, and even
prolonged sun exposure is insufficient to generate vitamin
D.18 Thus, among people living at high latitudes, vitamin D
levels typically decline during the winter, reaching average
levels of 25(OH)D about 40 to 60nmol/L,19 –22 which are
Fig 1. Odds ratios for multiple sclerosis and reported measures of sun exposure in 6- to 10-year-olds. (A) Winter. p for trend ⫽
0.18. (B) Summer. CI ⫽ confidence interval. p for trend ⫽ 0.15. Data from vander Mei and colleagues.13
Ascherio et al: Environmental Risk Factors for MS
505
well less than the 80 to 90nmol/L now considered as the
lower threshold for osteoporosis prevention.23
This connection between sunlight exposure and vitamin
D has been known since the 1930s from studies on rickets,
and more than 30 years ago, Goldberg24 first proposed that
the greater incidence of MS at higher latitudes could be due
to vitamin D deficiency.
Vitamin D Intake
Although sunlight is for most people the main source of vitamin D, the contribution from diet or vitamin supplements
can be significant, especially in winter and at high latitudes.
As for sunlight exposure, the first observations linking vitamin D intake to MS risk were made in an ecological study.
In Norway, a lower MS prevalence was found in coastal villages with greater fish consumption than in inland agricultural communities.25,26 Traditional fish meals in coastal
communities in Norway are excellent sources of vitamin D,
which contribute to compensation for the low levels of sunlight during the long winters.27 However, it is important to
compare the MS risk of individuals with high and low intake
within the same population, to reduce the effect of potential
confounding factors.
Associations between diet and risk for chronic diseases are
difficult to investigate retrospectively because even a modest
difference in recall between cases and control subjects can
cause a large bias in RR estimates.28 In the case of MS, this
problem is compounded by changes in diet induced by the
disease itself in the early clinical or preclinical phase. These
problems can be circumvented by conducting a longitudinal
study in a large population of healthy subjects to examine
whether diet predicts their future risk for development of
MS.
The only published longitudinal studies on diet and MS
risk are those based on two large cohorts of US nurses.29
Assessment of vitamin D intake among women in these cohorts was based on comprehensive and previously validated
semiquantitative food frequency questionnaires administered
every 4 years during the follow-up.30,31 The information on
current use, brand, and dosage of multivitamin supplements
was collected on each biennial questionnaire. The validity of
vitamin D intake was assessed by comparison with the
plasma concentrations of 25(OH)D among 323 healthy
study participants.32 For plasma collected in winter, which is
more likely to reflect dietary intake, the mean 25(OH)D was
39.8nmol/L among women in the bottom quintile of vitamin D intake and 69.8nmol/L among women in the top
quintile. The validity of estimated vitamin D intake was further supported by its inverse association with risk for hip
fractures.32 Total vitamin D intake at baseline in these cohorts was inversely associated with risk for MS (Fig 2A). The
age-adjusted pooled RR comparing the highest with the lowest quintile of consumption was 0.67 (95% CI, 0.40 –1.12; p
for trend ⫽ 0.03). Intake of vitamin D from supplements
only was associated with a 40% lower MS risk (see Fig 2B).
These RRs did not materially change after further adjustment for pack-years of smoking and latitude at birth. Because multivitamins were the major source of supplemental
vitamin D in this population, confounding by intake of
other micronutrients could not be excluded, but results of
multivariate analyses and biological plausibility suggest that
this is unlikely to fully explain the results.
Serum Concentrations of 25(OH)D
Serum levels of 25(OH)D are commonly used to measure
vitamin D status for clinical and research purposes because
serum levels of 1,25(OH)2D, the active form of vitamin D,
are tightly regulated and within reference range even in vitamin D deficiency.33 In contrast, 25(OH)D levels are sensitive to both vitamin D intake and sun exposure, and are a
marker of vitamin D availability to tissues, including the immune system.33 Thus, if sun exposure or vitamin D intake
were protective, healthy young adults with high serum levels
of 25(OH)D would be expected to have a lower risk for MS
than those with low levels. Because MS is a relatively rare
disease and because 25(OH)D levels vary over time because
of season and changes in diet and behavior, to determine
whether serum 25(OH)D is a predictor of MS risk requires a
large longitudinal study with repeated collection of blood
samples, such as that recently conducted among US military
personnel with samples stored in the Department of Defense
Serum Repository.34
Since 1990, the Department of Defense Serum Repository
has collected and stored more than 30 million serum samples
leftover from routine human immunodeficiency virus and
worldwide deployment-related blood tests.35,36 Between
1992 and 2004, 257 military personnel with a confirmed
MS diagnosis and at least 2 serum samples collected before
the onset of MS symptoms were identified. For each case,
two individuals of the same sex, age, race/ethnicity, and time
Fig 2. (A) Relative risk (RR) of multiple sclerosis (MS) according to vitamin D intake. p for trend ⫽ 0.03. (B) Relative risk of
MS according to use of vitamin D supplements.p for trend ⫽ 0.006. Data from Munger and colleagues.29
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of collection of the blood samples were randomly selected as
control subjects from the Department of Defense Serum Repository database. Among whites, there was a 41% decrease
in MS risk for every 50nmol/L increase in 25(OH)D (RR,
0.59; 95% CI, 0.36 – 0.97; p ⫽ 0.04). In categoric analyses,
risk for MS was 51% less among individuals with 25(OH)D
ⱖ100nmol/L as compared with those less than 75nmol/L
(Fig 3A). Whether these associations reflect a monotonic decrease in MS risk or whether there is a threshold that has to
be reached before obtaining a benefit remained uncertain,
and a larger sample size will be needed to answer this question. Because childhood and adolescence appear to be important exposure periods for MS, we further examined whether
serum 25(OH)D concentrations ⱖ100nmol/L were more
protective at younger ages. The reduction in risk for development of MS among individuals with 25(OH)D levels
ⱖ100nmol/L was considerably stronger before the age of 20
years (16 –19 years) than at ages 20 or older (see Fig 3B).
Among blacks and Hispanics, however, the associations between 25(OH)D levels and MS risk were not significant, but
power to detect an association was low because of overall low
levels of 25(OH)D and small sample size in these two
groups.
The results from this large longitudinal investigation
strongly support a protective effect of vitamin D on MS risk,
but as in all observational studies, confounding by unknown
factors cannot be excluded. For example, a genetic predisposition to both MS and circulating low 25(OH)D levels could
appear as a protective effect of vitamin D, although it would
not explain the stronger association in younger individuals.
Perhaps the most important potential confounder is sun exposure itself, because sun exposure has immunosuppressive
effects that are in part independent from the synthesis of
vitamin D.37 Whole-body ultraviolet light exposure suppresses experimental autoimmune encephalomyelitis (EAE)
in mice,38 enhances regulatory T-cell function, and increases
production of the immunosuppressive cytokines interleukin-4 and -10.39
Vitamin D and Multiple Sclerosis Immunology
The results of the epidemiological studies described earlier
converge with experimental evidence on protective effects of
vitamin D in animal models of autoimmune diseases.40 The
effects in EAE, an animal model of MS, appear particularly
striking; in several experiments, injection of 1,25(OH)2D
was found to completely prevent the clinical and pathologi-
cal signs of disease.41,42 Furthermore, the onset of EAE was
accelerated in vitamin D–deficient mice42 and was delayed
and attenuated by providing vitamin D supplements.43 The
mechanisms underlying these effects are still under investigation,40,44 – 46 but they are likely to include induction of regulatory T cells.47,48 In an experiment comparing vitamin
D–deficient with vitamin D–supplemented mice, central
nervous system levels of 1,25(OH) 2D, but not blood levels,
were greater in supplemented animals and correlated inversely with disease severity.43 The local increase in
1,25(OH)2D levels is consistent with synthesis in the central
nervous system of 1,25(OH)2D from 25(OH)D by activated
macrophages expressing 1-␣-hydroxylase, resulting in regulation of the tissue-specific immune responses.48
Strength of the Evidence and Implications
As discussed earlier, each individual study is open to an alternative interpretation, but there is no single alternative interpretation that could easily explain the results of all studies
supporting a role of vitamin D in MS prevention. Furthermore, the epidemiological evidence is supported by strong
experimental data in animal models of MS. Thus, overall, it
appears likely that increasing vitamin D levels could reduce
MS risk. If so, it is important to know what the optimal
vitamin D levels are and how many cases of MS could hypothetically be prevented. Answering these questions will provide an assessment of the feasibility of an intervention and its
potential impact on MS incidence. Although an accurate answer would require a better appreciation of the dose–response relation and the importance of age as a potential
modifying factor, a preliminary figure can be obtained for
the relation between 25(OH)D levels and MS risk.
Based on our study, the potential for MS prevention is
striking. In the United States, nearly half of white and twothirds of black adults have 25(OH)D levels less than
70nmol/L,49 and levels among adolescents are only slightly
greater,50 results consistent with our observation that only
about 20% of whites have 25(OH)D greater than
100nmol/L. Thus, if increasing serum concentrations of
25(OH)D from less than to more than 100nmol/L in young
people truly reduced MS risk 10-fold, as suggested by results
in Figure 3B, then up to 72% of MS cases could be prevented (ie, 90% of the cases among the 80% of subjects with
25(OH)D ⬍ 100nmol/L); if the reduction in risk was only
twofold, still 40% of MS cases could be prevented. According to studies among individuals with low sun exposure, sup-
Fig 3. (A) Rate ratios of multiple sclerosis (MS) by category of serum 25(OH)D level for whites. *p ⫽ 0.02. (B) Rate ratios of MS
comparing 25(OH)D ⱖ100 versus ⬍100nmol/L by age at blood collection for whites. Data from Munger and colleagues.34
Ascherio et al: Environmental Risk Factors for MS
507
plements providing 1,000IU/day of vitamin D would increase circulating 25(OH)D levels to 80 to 100mol/L,51,52
and 4,000IU/day would maintain levels greater than
100nmol/L.53,54 These amounts do not cause hypercalcemia
or other known adverse side effects in healthy individuals,
and would result in circulating levels of 25(OH)D still less
than the average levels among individuals with regular high
exposure to sunlight.53 Because of these important public
health implications, there is an urgent need to determine in
a large randomized trial whether vitamin D supplements can,
in fact, contribute to MS prevention. Because of the rarity of
MS, a randomized, controlled clinical trial assessing whether
vitamin D supplementation in the general population prevents MS would have to be large, but the sample size could
be reduced by enriching the study with individuals at high
risk, such as first-degree relatives of individuals with MS.
Vitamin D and Multiple Sclerosis Progression
The protective effects of 1,25(OH)2D in EAE also suggests
that vitamin D may be beneficial in individuals with MS.
Whereas there is evidence of high levels of vitamin D deficiency among MS patients,55 and many would benefit from
vitamin D supplements for prevention of osteoporosis and
fractures, whether high doses of vitamin D can affect MS
progression remains unknown. The safety and tolerability of
high doses of vitamin D (1,25(OH)2D) in individuals with
MS has been recently established in a phase 2 trial,56 and a
larger investigation is being planned. Results from studies on
seasonal fluctuations in number of MS lesions are conflicting.57– 60
Vitamin D, the Latitude Gradient, and Other
Features of Multiple Sclerosis Epidemiology
Although the hypothesis that high vitamin D levels reduce
MS risk may explain several features of MS epidemiology,
such as the latitude gradient and the change in risk among
migrants, it falls short in explaining other important features,
such as the recent decline in the latitude gradient within the
United States, discussed in the first part of this review.1 A
decline in sun exposure because of increased awareness of the
risk for skin cancer or the widespread use of vitamin D–supplemented milk could be invoked as possible explanations,
but neither appears likely to explain the rather dramatic disappearance of a threefold difference in incidence among
white women. Also, the fact that blacks, despite having much
lower levels of vitamin D than whites, have a low risk for
MS is a clear reminder of the multifactoriality of MS and the
importance of genetic factors. Finally, neither the Faroe island epidemics61 nor the strong association between Epstein–
Barr virus (EBV) infection and MS1 can be explained by
vitamin D.
Cigarette Smoking
Although cigarette smoking cannot explain the latitude
gradient of MS or the changes in risk with migration,
it is an important risk factor because of the strength of
the evidence, the implications for individuals at risk for
MS, and possible insights into MS pathogenesis.
Several early reports have described an aggravation of
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MS symptoms after smoking,62– 68 and a positive association between cigarette smoking before age of onset
and risk for MS was found in some,12,69 but not
all,70,71 case–control studies and in a survey of the general population of Hordaland County, Norway, comprising 23,000 individuals of which 87 had MS.72
Most notably, a positive association was found in
each of the four prospective studies that have addressed
this question. In the Oxford Family Planning Association Study, more than 17,000 British women attending family planning clinics between 1968 and 1974
were followed for MS incidence through 1991; based
on 63 incident MS cases, the RR for women smoking
15 or more cigarettes per day as compared with never
smokers was 1.8 (95% CI, 0.8 –3.6; p for trend over
number of cigarette smoked at baseline ⫽ 0.05).73 In
the Royal College of General Practitioners’ Oral Contraception Study, conducted between 1968 and 1996,
114 new incident cases of MS were documented in a
cohort of 46,000 British women; the RR for women
smoking 15 or more cigarettes per day as compared
with never smokers was 1.4 (95% CI, 0.9 –2.2).74 In
the third study, conducted among more than 200,000
US women participating in the Nurses Health Study
and Nurses Health Study II, the RR was 1.7 (95% CI,
1.2–2.4; p ⬍ 0.01) for women who smoked 25 or
more pack-years as compared with never smokers; this
association was not explained by latitude or ancestry.75
Finally, in a nested case–control study based on the
General Practice Research Database including 201
cases, the RR of MS comparing ever to never smokers
was 1.3 (95% CI, 1.0 –1.7).76 Although a clearly significant association was found only in one of the studies above, the results are quite consistent across cohorts,
and summary estimates of the RRs are highly significant (Fig 4).
Although confounding cannot be excluded, the combined evidence from these studies and the lack of convincing alternative explanations suggest that smoking
increases the risk for MS. Furthermore, smoking has
been associated with an accelerated transition from
relapsing-remitting to secondary progressive MS.76 The
possible mechanisms that relate cigarette smoking to
MS risk or progression have been little investigated.
These could include neurotoxic77 effects of components of cigarette smoke, as indirectly supported by the
association of cigarette smoking with optic neuropathy78 or immunomodulatory effects,79,80 as suggested
by the association of cigarette smoking with an increased risk for development of other autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Graves’ hyperthyroidism, and primary
biliary cirrhosis.81 Finally, cigarette smoke increases the
frequency and duration of respiratory infections,82
which have been linked to MS risk.
Cigarette smoking is thus emerging as a modifiable
Fig 4. (A) Relative risk of multiple sclerosis (MS) by smoking status. *Past smoking not available for Thorogood and Hannaford.74
†1–14 or ⱖ15 cigarettes/day for Villard-Mackintosh and Vessey73 and Thorogood and Hannaford.74 (B) Relative risk of MS by
duration/frequency of smoking. *1–9 pack-years for Hernàn and colleagues75; 1–14 cigarettes/day for Villard-Mackintosh and Vessey73 and Thorogood and Hannaford74; not available for Hernan and colleagues.76 †10 –24 and ⱖ25 pack-years for Hernàn and
colleagues75; ⱖ15 cigarettes/day for Villard-Mackintosh and Vessey73 and Thorogood and Hannaford74; not available for Hernan
and colleagues.76 ‡p ⬍ 0.01.
risk factor for MS. Furthermore, differences in smoking habits across populations could explain some of the
variation in MS incidence, particularly variation in the
sex ratio, such as the increase in the female/male sex
ratio in Canada over the past 50 years.83
Diet, Hormones, and Other Factors
Although several other risk factors for MS have been
proposed, evidence remains mostly thin and unpersuasive, and only a brief mention is included in this review.
Dietary Fat
Results of ecological studies25,84 – 88 and one case–control investigation89 have suggested that diets high in
animal/saturated fats and low in polyunsaturated fats
may increase MS risk. As discussed earlier, however,
these study designs are prone to confounding or bias,
and results should be interpreted cautiously.28 In the
only prospective study on dietary fat and MS, neither
animal nor saturated fats were associated with an increased risk for MS, but a possible inverse association
with intake of the n-3 polyunsaturated fat linolenic
acid could not be excluded.90 Results of randomized
trials of n-691 or n-392,93 polyunsaturated fat supplements in MS patients suggested a possible modest reduction in the severity and duration of relapses. Overall, further research is needed to establish whether
dietary fats may influence MS risk or progression.
Dietary Antioxidants
Low antioxidant activity in white matter may lead to
increased lipid peroxidation by reactive oxygen species
and subsequent damage.94 Significant inverse associations with vitamin C and juice intake, but not intakes
of vitamin E, ␤-carotene, or fruits and vegetables (good
sources of antioxidants), were reported in one case–
control study.95 No significant associations with fruit
or vegetable consumption were also found in other
studies of similar retrospective design.12,70,96 In the
only prospective study,97 we did not find significant
associations between intakes of vitamins C or E, carotenoids, or fruits and vegetables and risk for MS, but
CIs were wide and moderate effects cannot be excluded.
Sex Hormones
Estrogens in high levels appear to shift the immune
response from the proinflammatory type 1, dominant
in MS, to the noninflammatory type 2.98,99 This effect
may explain the decrease in the number of MS relapses
in pregnancy, when estrogen levels are high, and its
rebound in the puerperium.100 Risk for MS may follow a similar pattern,101 but any benefit from estrogen
appears to be transient, because neither oral contraceptive use73,74,102 nor parity73,74,101,102 or age at first
birth102 are associated with long-term risk. In a cohort
of British women, recent use of oral contraceptives was
associated with a reduced risk,101 a result also consistent with a transient benefit from high estrogen levels.
Other Factors
In several investigations, a positive association has been
found between higher education and MS risk, as discussed in the first part of this review1; this association
is consistent with the hygiene hypothesis and with a
late age at infection with EBV.
Observations during a mass immunization campaign
in France prompted concerns that the hepatitis B vaccine may increase the risk for MS,103 but the results of
subsequent studies were largely null. In a case–control
study of first central nervous system demyelinating
event in France, there was a nonsignificant increase in
risk after vaccination.104 No increased risk for demyelinating events or MS after hepatitis B vaccination was
found among subjects included in a US health care da-
Ascherio et al: Environmental Risk Factors for MS
509
tabase,105 in a study based on two large US nurse cohorts in which history of vaccination was confirmed
from vaccination records,106 or in a large case–control
study in the United States.107 Furthermore, no associations were found between hepatitis B vaccination and
MS in adolescents108 or with MS relapses.109 One exception has been a case–control study in the United
Kingdom, in which vaccination history was determined
from computerized medical records.110 Overall, although the hypothesis cannot be dismissed, evidence is
insufficient to support a causal relation between hepatitis B vaccination and MS risk.
Other environmental risk factors that have been proposed to increase MS risk but for which there is insufficient evidence include occupational exposures, particularly to organic solvents111–115 and physical trauma.116 In contrast, stronger evidence from a large longitudinal study supports an increased MS risk after
psychological stress (bereavement).117 In contrast, environmental factors that have been proposed to reduce
MS risk include tetanus toxoid vaccination,118 use of
antibiotics,119 and antihistamines,120 and increased
blood levels of uric acid,121,122 but the roles of these
factors remain to be elucidated.
Conclusions
There is compelling evidence that strong environmental risk factors for MS exist. As discussed in the first
part of this review,1 infection with the EBV plays an
important role in MS cause, but by itself cannot explain some aspects of MS epidemiology, including the
reduction in risk among migrants from high- to lowrisk areas. However, this could be clearly explained by
a protective effect of vitamin D, which is emerging as
an important cofactor. What are the implications for
MS prevention? Currently, EBV infection cannot be
avoided; although infection in early childhood is associated with lower MS risk relative to infection later in
life, attempts to anticipate age at infection are also not
practical on a large scale. In contrast, low circulating
levels of vitamin D (and cigarette smoking) are clearly
modifiable and could be targeted by public health interventions. Whereas large longitudinal investigations
may contribute to strengthen the evidence of causality,
refine estimates of dose–response, and identify genetic
and nongenetic factors that may modify susceptibility,
a case can be made for intervention studies to address
the possibility that increasing vitamin D levels among
adolescents and young adults could reduce MS risk.
Considering that levels of circulating vitamin D associated with protection could be achieved with doses of
vitamin D supplements largely regarded as safe, and
the potential for preventing a large proportion of MS
cases, in addition to the potential benefits for bone
health and other chronic diseases,23 there appears to be
no reason to wait. However, we should remain aware
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that we are facing a disease caused by a complex interplay of genetic and environmental factors, and that undoubtedly more challenges lie ahead on the road to MS
prevention.
We thank L. Unger for technical support.
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