Multiple Sclerosis: Ascherio A

Ascherio A. · No affiliation provided · Expert Rev Neurother. · Pubmed #18345964 No free full text.

This publication has no abstract.

Ascherio A, Munger K. · Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. · Semin Neurol. · Pubmed #18256984 No free full text.

Abstract: Although genetic susceptibility explains the clustering of multiple sclerosis (MS) within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographical variations in MS frequency and the changes in risk that occur with migration, which support the action of strong environmental factors. Among these, vitamin D status, infection with the Epstein-Barr virus, and cigarette smoking are emerging as the most consistent predictors of MS risk. In this article, we review the epidemiological data, critically discuss the evidence for causality of these associations, and briefly discuss the possibility of interventions to reduce MS risk.

Ascherio A, Munger KL. · Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. · Ann Neurol. · Pubmed #17492755 No free full text.

Abstract: 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.

Ascherio A, Munger KL. · Department of Nutrition, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. · Ann Neurol. · Pubmed #17444504 No free full text.

Abstract: Although genetic susceptibility explains the clustering of multiple sclerosis (MS) cases within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographic variations in MS frequency and the changes in risk that occur with migration. Epidemiological data provide some support for the "hygiene hypothesis," but with the additional proviso for a key role of Epstein-Barr virus (EBV) in determining MS risk. We show that whereas EBV stands out as the only infectious agent that can explain many of the key features of MS epidemiology, by itself the link between EBV and MS cannot explain the decline in risk among migrants from high to low MS prevalence areas. This decline implies that either EBV strains in low-risk areas have less propensity to cause MS, or that other infectious or noninfectious factors modify the host response to EBV or otherwise contribute to determine MS risk. The role of infectious factors is discussed here; in a companion article, we will examine the possible role of noninfectious factors and provide evidence that high levels of vitamin D may have a protective role, particularly during adolescence. The primary purpose of these reviews is to identify clues to the causes of MS and to evaluate the possibility of primary prevention.

Thacker EL, Mirzaei F, Ascherio A. · Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. · Ann Neurol. · Pubmed #16502434 No free full text.

Abstract: OBJECTIVE: To characterize the association between infectious mononucleosis (IM), a frequent clinical manifestation of primary Epstein-Barr virus infection after childhood, and the risk for multiple sclerosis (MS). METHODS: We conducted a systematic review and meta-analysis of case-control and cohort studies of IM and MS. RESULTS: The combined relative risk of MS after IM from 14 studies was 2.3 (95% confidence interval, 1.7-3.0; p < 10(-8)). Potential sources of heterogeneity (ie, study design, MS definition, and latitude) barely influenced our results. INTERPRETATION: We conclude that Epstein-Barr virus infection manifesting as IM in adolescents and young adults is a risk factor for MS.

Healy BC, Ali EN, Guttmann CR, Chitnis T, Glanz BI, Buckle G, Houtchens M, Stazzone L, Moodie J, Berger AM, Duan Y, Bakshi R, Khoury S, Weiner H, Ascherio A. · Department of Neurology, Partners MS Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Arch Neurol. · Pubmed #19597087 No free full text.

Abstract: BACKGROUND: Although cigarette smokers are at increased risk of developing multiple sclerosis (MS), the effect of smoking on the progression of MS remains uncertain. OBJECTIVE: To establish the relationship between cigarette smoking and progression of MS using clinical and magnetic resonance imaging outcomes DESIGN: Cross-sectional survey and longitudinal follow-up for a mean of 3.29 years, ending January 15, 2008. SETTING: Partners MS Center (Boston, Massachusetts), a referral center for patients with MS. PATIENTS: Study participants included 1465 patients with clinically definite MS (25.1% men), with mean (range) age at baseline of 42.0 (16-75) years and disease duration of 9.4 (0-50.4) years. Seven hundred eighty patients (53.2%) were never-smokers, 428 (29.2%) were ex-smokers, and 257 (17.5%) were current smokers. MAIN OUTCOME MEASURES: Smoking groups were compared for baseline clinical and magnetic resonance imaging characteristics as well as progression and sustained progression on the Expanded Disability Status Scale at 2 and 5 years and time to disease conversion to secondary progressive MS. In addition, the rate of on-study change in the brain parenchymal fraction and T2 hyperintense lesion volume were compared. RESULTS: Current smokers had significantly worse disease at baseline than never-smokers in terms of Expanded Disability Status Scale score (adjusted P < .001), Multiple Sclerosis Severity Score (adjusted P < .001), and brain parenchymal fraction (adjusted P = .004). In addition, current smokers were significantly more likely to have primary progressive MS (adjusted odds ratio, 2.41; 95% confidence interval, 1.09-5.34). At longitudinal analyses, MS in smokers progressed from relapsing-remitting to secondary progressive disease faster than in never-smokers (hazard ratio for current smokers vs never-smokers, 2.50; 95% confidence interval, 1.42-4.41). In addition, in smokers, the T2-weighted lesion volume increased faster (P = .02), and brain parenchymal fraction decreased faster (P = .02). CONCLUSION: Our data suggest that cigarette smoke has an adverse influence on the progression of MS and accelerates conversion from a relapsing-remitting to a progressive course.

Gardener H, Munger K, Chitnis T, Spiegelman D, Ascherio A. · Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA. · Mult Scler. · Pubmed #19389750 No free full text.

Abstract: BACKGROUND: Left-handedness has been studied as a marker for in-utero exposure to sex steroid hormones, and an increased risk of autoimmune and immune disorders among left-handed individuals has been suggested. OBJECTIVE: This study examines the relationship between hand preference and risk of multiple sclerosis, a presumed autoimmune disorder of unknown etiology. METHODS: The study population comprised participants in the Nurses' Health Study, an ongoing prospective cohort study of 121,701 female nurses in the United States with followup from 1976 to 2002. The nurses were asked to report their natural hand preference (right, left, ambidextrous, forced to change). RESULTS: During followup 210 incident cases with multiple sclerosis were confirmed. A 62% increased risk of multiple sclerosis was observed among women who were naturally left handed as compared to those who were naturally right handed (95% CI: 1.04-2.53). CONCLUSIONS: This study suggests a modest increase in risk of multiple sclerosis among left-handed women. Further investigation of this relationship is suggested in other populations including both males and females. While the current results suggest that prenatal exposure to sex hormones may play a role in multiple sclerosis risk, direct examination of the relationship between in-utero hormone exposure and hand preference is necessary before any conclusions can be drawn.

Gardener H, Munger KL, Chitnis T, Michels KB, Spiegelman D, Ascherio A. · Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. · Epidemiology. · Pubmed #19333127 No free full text.

Abstract: BACKGROUND: A potential role of prenatal and perinatal exposures in autoimmunity has been hypothesized, but few studies have examined the relation between various prenatal and perinatal factors and the risk of multiple sclerosis (MS). METHODS: The study population included participants in the Nurses' Health Studies--2 prospective cohorts that together comprise 238,381 female nurses, who self-reported exposure to prenatal and perinatal factors. In addition, 35,815 nurses' mothers participated by providing detailed information regarding experiences surrounding their daughter's birth. The following prenatal and perinatal factors were studied in relation to MS: fetal growth, birth season, preterm birth, mode of delivery, maternal weight gain, medical conditions, medication use, diethylstilbestrol exposure, prenatal health care, maternal activity level, maternal obstetric history, parental age, and prenatal and childhood passive smoke exposure. RESULTS: The sample included 723 confirmed MS cases, including 383 with diagnosis after reporting prenatal and perinatal factors. Few associations were observed. These included an increased risk among women whose mothers reported late initiation of prenatal care (after the first trimester) (27 cases; rate ratio = 1.6 [95% confidence interval = 1.0-2.4]), diabetes during pregnancy (2 cases; 10 [2.5-42]), and maternal prepregnancy overweight/obesity (20 cases; 1.7 [1.0-2.7]). Results also suggested a possible increase in incident MS risk among women with prenatal diethylstilbestrol exposure (9 cases; 1.8 [0.93-3.5]). CONCLUSIONS: This study provides modest support for a role of prenatal factors in MS risk. The results should be interpreted cautiously due to the limited statistical power, potential for exposure misclassification, and possibility of chance findings.

Massa J, Munger KL, O'Reilly EJ, Levin LI, Ascherio A. · Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA. · J Neuroimmunol. · Pubmed #19201486 No free full text.

Abstract: We conducted a prospective nested case-control study among military service members to investigate whether antibodies against tetanus or diphtheria predict multiple sclerosis (MS) risk. Paired T-tests were used to compare means of anti-tetanus and diphtheria toxoids among 56 MS cases and 112 matched controls. Conditional logistic regression was used to estimate odds ratios (OR). There were no differences between the mean serum IgG antibodies against tetanus (p-value 0.28) or diphtheria (p-value 0.45) in the baseline samples. The OR of MS associated with 1 standard deviation difference in antibody titers was 0.76 (95% CI: 0.48-1.21) for tetanus (SD=4.71) and 1.03 (0.73-1.45) for diphtheria (SD=0.87). Results of this study suggest serum IgG antibodies against tetanus or diphtheria are not predictors of MS risk.

Wang H, Munger KL, Reindl M, O'Reilly EJ, Levin LI, Berger T, Ascherio A. · Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. · Neurology. · Pubmed #18753473 No free full text.

Abstract: BACKGROUND: It remains uncertain whether the presence of serum anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in healthy individuals contributes to predict their risk of developing multiple sclerosis (MS). METHODS: Prospective, nested case-control study of more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. A total of 126 MS cases and 252 controls matched by age, sex, race/ethnicity, and dates of blood collection were included in the analysis. An ELISA was used to detect IgM and IgG antibodies to MOG. Analyses were conducted with and without adjustment for serum titers of antibodies to the Epstein-Barr nuclear antigen (EBNA), which are an established risk factor for MS. RESULTS: The presence of anti-MOG IgG antibodies in serum was associated with an increase in risk of developing MS (relative risk for anti-MOG IgG+/IgM- vs seronegativity to both anti-MOG IgM and IgG: 2.03; 95% CI: 1.19-3.46; p = 0.01). This association, however, was attenuated and no longer significant after adjustment for titers of antibodies to EBNA, which were higher among individuals positive for anti-MOG antibodies. CONCLUSION: Our findings suggest that although individuals with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have an increased risk of developing multiple sclerosis, this association may at least in part reflect cross-reactivity between MOG and Epstein-Barr nuclear antigen.

Tai AK, O'Reilly EJ, Alroy KA, Simon KC, Munger KL, Huber BT, Ascherio A. · Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts, USA. · Mult Scler. · Pubmed #18701576 No free full text.

Abstract: BackgroundThe human endogenous retrovirus (HERV)-K18 Env is an Epstein-Barr virus (EBV)-associated superantigen. Given the evidence for a role of EBV in the etiology of multiple sclerosis (MS), HERV-K18 Env is a plausible candidate for association with MS.ObjectiveTo assess whether variation in HERV-K18 Env is a risk factor for MS.MethodsWe developed a single nucleotide polymorphism-based genotyping method to determine the distribution of the three alleles of HERV-K18 env. We then conducted a nested case-control study including 207 MS cases and 403 matched controls. Analyses were replicated in an independent series of 909 MS cases and 339 controls.ResultsOverall, there was a significant association between HERV-K18 env genotype and MS risk (chi2 P = 0.03). As compared with K18.2/K18.2 individuals, risk of MS was three fold higher among K18.3/K18.3 individuals (P = 0.03). An increase in MS risk among carriers of the K18.3 allele was also observed in the replication study, but did not reach statistical significance. In pooled analyses, K18.3/K18.3 individuals had a significantly increased risk of MS (relative risks [RR] comparing K18.3/K18.3 vs K18.2/K18.2 = 2.7; 95% confidence interval: 1.1-6.4).ConclusionVariation in EBV-associated superantigen HERV-K18 Env could influence the genetic susceptibility to MS.

Di Pauli F, Reindl M, Ehling R, Schautzer F, Gneiss C, Lutterotti A, O'Reilly E, Munger K, Deisenhammer F, Ascherio A, Berger T. · Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Mult Scler. · Pubmed #18632775 No free full text.

Abstract: BACKGROUND: Cigarette smoking increases the risk for development of multiple sclerosis and modifies the clinical course of the disease. In this study, we determined whether smoking is a risk factor for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome. METHODS: We included 129 patients with a clinically isolated syndrome, disseminated white-matter lesions on brain magnetic resonance imaging, and positive oligoclonal bands in the cerebrospinal fluid. The patients' smoking status was obtained at the time of the clinically isolated syndrome. RESULTS: During a follow-up time of 36 months, 75% of smokers but only 51% of non-smokers developed clinically definite multiple sclerosis, and smokers had a significantly shorter time interval to their first relapse. The hazard ratio for progression to clinically definite multiple sclerosis was 1.8 (95% confidence interval, 1.2-2.8) for smokers compared with non-smokers (P = 0.008). CONCLUSIONS: Smoking is associated with an increased risk for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome, and our results suggest that smoking is an independent but modifiable risk factor for disease progression of multiple sclerosis. Therefore, it should be considered in the counseling of patients with a clinically isolated syndrome.

Morozova N, Weisskopf MG, McCullough ML, Munger KL, Calle EE, Thun MJ, Ascherio A. · Departments of *Nutrition, Harvard School of Public Health, Boston, MA 02215, USA. · Epidemiology. · Pubmed #18300717 No free full text.

Abstract: BACKGROUND: Several dietary factors have been associated with risk of amyotrophic lateral sclerosis (ALS) in case-control studies, but no prospective studies have investigated diet and ALS. METHODS: We prospectively assessed the association of selected foods and beverages with ALS mortality among participants of the Cancer Prevention Study II, a cohort of over 1 million men and women enrolled in 1982. Habitual diet was assessed with a 44-item food frequency questionnaire. Participant follow-up was conducted from 1989 through 2002 for ALS mortality. RESULTS: During the follow-up period, 862 cohort participants died of ALS. The strongest finding was an inverse association between chicken consumption and risk of ALS (P for trend = 0.0006). We also observed an increased risk of ALS among study participants with a high consumption of brown rice/whole wheat/barley (P for trend = 0.006) and decaffeinated coffee (P for trend = 0.01), and a decreased risk of ALS for high consumption of tea (P for trend = 0.02) and French fries (P for trend = 0.02); however, none of these latter associations remained significant after adjusting for multiple comparisons. CONCLUSIONS: Overall, these results do not provide convincing evidence that the investigated food items are related to ALS mortality. The association observed between chicken consumption and ALS mortality should be assessed in other studies.

De Jager PL, Simon KC, Munger KL, Rioux JD, Hafler DA, Ascherio A. · Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. · Neurology. · Pubmed #18272866 No free full text.

Abstract: BACKGROUND: Individuals with high levels of antibodies to the Epstein-Barr virus nuclear antigen 1 (EBNA-1) have an increased risk of developing multiple sclerosis (MS), but this association could be confounded by genetic susceptibility. METHODS: We conducted a nested case-control study including 148 women with MS (18 with blood collected before disease onset) and 296 age-matched healthy women to determine whether the human leukocyte antigen (HLA) DRB1*1501 allele (DR15) and anti-Epstein-Barr virus (anti-EBV) antibody titers are independent risk factors for MS. RESULTS: The association between anti-EBNA-1 antibody titers and MS risk was not affected by adjustment for DR15 and was similar in DR15-positive and DR15-negative women. The relative risk of MS among DR15-positive women with elevated (>1:320) anti-EBNA-1 titers was ninefold higher than that of DR15-negative women with low (<1:80) anti-EBNA-1 titers. CONCLUSIONS: Anti-Epstein-Barr virus nuclear antigen 1 (anti-EBNA-1) antibody titers are a risk factor for multiple sclerosis (MS), independently from the DR15 allele. Carriers of the DR15 allele with elevated anti-EBNA-1 antibody titers may have a markedly increased risk of MS.

Alonso A, Hernán MA, Ascherio A. · Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. · Acta Neurol Scand. · Pubmed #18095952 No free full text.

Abstract: OBJECTIVE: Previous reports suggested an association between allergy, autoimmunity, and risk of multiple sclerosis (MS), but results have been inconsistent. The present study assessed the association between history of allergy and autoimmune diseases, and the risk of MS. METHODS: We conducted a case-control study nested in the Nurses' Health Study (NHS) and NHS II cohorts. A total of 298 women with MS were matched with 1248 healthy controls and 248 women with history of breast cancer. A mailed questionnaire gathered information about history of allergic conditions and autoimmune disorders. RESULTS: History of allergy was not associated with MS risk [odds ratio (OR) 1.0, 95% confidence interval (CI) 0.8-1.4]. As expected, cases were more likely to have a positive family history of MS than controls (OR 9.7, 95% CI 6.1-15.3). A modest association was found between family history of other autoimmune diseases and MS risk (OR 1.4, 95% CI 1.0-1.8). We obtained similar results when we used women with breast cancer as comparison group. CONCLUSION: Family history of other autoimmune diseases was associated with a higher MS risk, suggesting a common genetic background or shared environmental triggers. There was no clear association between personal history of allergy and risk of MS.

Massa J, Munger KL, O'Reilly EJ, Falk KI, Ascherio A. · Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. · Neuroepidemiology. · Pubmed #17851260 No free full text.

Abstract: BACKGROUND/AIMS: Results of recently conducted prospective studies have demonstrated that the presence of high titers of anti-EBNA-1 or anti-EBNA complex IgG antibodies in healthy individuals is a strong risk factor for multiple sclerosis (MS). Antibodies to BZLF1, the product of the homonymous early lytic gene, have been found to be related to risk of nasopharyngeal carcinoma, but have not been previously measured in MS studies. METHODS: We examined whether high levels of anti-BZLF1 IgG antibodies also predict MS risk in a nested case-control study among women in the Nurses Health Study and Nurses Health Study II cohorts. RESULTS: Results of this prospective study suggest that antibody titers to EBNAs are the strongest predictor of MS risk. CONCLUSION: Little further contribution may be provided by measuring anti-BZLF1 antibodies in regard to MS risk.

Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. · Department of Nutrition, Harvard School of Public Health, and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass 02115, USA. · JAMA. · Pubmed #17179460 links to  free full text

Abstract: CONTEXT: Epidemiological and experimental evidence suggests that high levels of vitamin D, a potent immunomodulator, may decrease the risk of multiple sclerosis. There are no prospective studies addressing this hypothesis. OBJECTIVE: To examine whether levels of 25-hydroxyvitamin D are associated with risk of multiple sclerosis. DESIGN, SETTING, AND PARTICIPANTS: Prospective, nested case-control study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. Multiple sclerosis cases were identified through Army and Navy physical disability databases for 1992 through 2004, and diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and dates of blood collection. Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum samples collected before the date of initial multiple sclerosis symptoms. MAIN OUTCOME MEASURES: Odds ratios of multiple sclerosis associated with continuous or categorical levels (quantiles or a priori-defined categories) of serum 25-hydroxyvitamin D within each racial/ethnic group. RESULTS: Among whites (148 cases, 296 controls), the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio [OR] for a 50-nmol/L increase in 25-hydroxyvitamin D, 0.59; 95% confidence interval, 0.36-0.97). In categorical analyses using the lowest quintile (<63.3 nmol/L) as the reference, the ORs for each subsequent quintile were 0.57, 0.57, 0.74, and 0.38 (P = .02 for trend across quintiles). Only the OR for the highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L, was significantly different from 1.00 (OR, 0.38; 95% confidence interval, 0.19-0.75; P = .006). The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. Among blacks and Hispanics (109 cases, 218 controls), who had lower 25-hydroxyvitamin D levels than whites, no significant associations between vitamin D and multiple sclerosis risk were found. CONCLUSION: The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis.

DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. · Kaiser Permanente Division of Research, Oakland, Calif, USA. · Arch Neurol. · Pubmed #16606758 links to  free full text

Abstract: OBJECTIVE: To determine whether serum titers of anti-Epstein-Barr virus (EBV) antibodies are elevated in blood specimens collected up to 30 years prior to onset of multiple sclerosis (MS). METHODS: Individuals with MS were identified among members of the Kaiser Permanente Northern California health plan who participated in the multiphasic examinations administered between 1965 and 1974. Stored serum samples were used to compare anti-EBV antibody titers in 42 individuals who developed MS with age-matched and sex-matched controls. RESULTS: The geometric mean titers of antibodies to the Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 were significantly higher in the MS cases when compared with matched controls. The relative risk of MS associated with a 4-fold increase in antibody titers was 2.1 (95% confidence interval, 1.1-3.8) for the EBNA complex and 1.8 (95% confidence interval, 1.1-2.9) for EBNA-1. Elevations of antibody titers to the EBNA complex and EBNA-1 among MS cases first occurred between 15 to 20 years before the onset of symptoms and persisted thereafter. CONCLUSION: The elevation of anti-EBV titers is probably an early event in the pathogenesis of MS and is unlikely to be the result of an aspecific immune dysregulation.

Alonso A, Jick SS, Olek MJ, Ascherio A, Jick H, Hernán MA. · Department of Epidemiology, Harvard School of Public Health, Brigham and Women's Hospital, Boston, MA 02115, USA. · Arch Neurol. · Pubmed #16157743 links to  free full text

Abstract: BACKGROUND: Exogenous estrogens affect the onset and clinical course of experimental allergic encephalomyelitis. Oral contraceptives, a frequent source of exogenous estrogens in humans, could have a role in the development of multiple sclerosis (MS). OBJECTIVE: To examine whether recent oral contraceptive use and pregnancy history are associated with the risk of MS. DESIGN AND SETTING: A case-control study nested in the General Practice Research Database. This database contains prospective health information (drug prescriptions and clinical diagnoses) on more than 3 million Britons who are enrolled with selected general practitioners. PARTICIPANTS: One hundred six female incident cases of MS, younger than 50 years, with at least 3 years of continuous recording in the General Practice Research Database before the date of first symptoms (index date), identified between January 1, 1993, and December 31, 2000, and 1001 controls matched on age, practice, and date of joining the practice.Main Outcome Measure Incidence of first symptoms of MS, confirmed through medical records. RESULTS: The incidence of MS was 40% lower (odds ratio, 0.6; 95% confidence interval, 0.4-1.0) in oral contraceptive users compared with nonusers during the previous 3 years. The risk of MS increased in the 6 months after pregnancy (odds ratio, 2.9, 95% confidence interval, 1.2-6.6), but it was not otherwise related to parity. CONCLUSIONS: The hormonal changes that occur during oral contraceptive use and pregnancy may be associated with a short-term reduction in the risk of MS, and the postpartum period may be associated with a short-term increase in the risk of MS.

Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A. · Division of Preventive Medicine, Walter Reed Army Institute of Research, Silver Spring, Md, USA. · JAMA. · Pubmed #15914750 links to  free full text

Abstract: CONTEXT: Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear. OBJECTIVE: To determine whether antibodies to EBV are elevated before the onset of MS. DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected. Serial samples collected before the onset of symptoms were available for 69 matched case-control sets. MAIN OUTCOME MEASURES: Antibodies including IgA against EBV viral capsid antigen (VCA), and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus. RESULTS: The average time between blood collection and MS onset was 4 years (range, <1-11 years). The strongest predictors of MS were serum levels of IgG antibodies to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody titers to EBNA complex were similar to those of controls before the age of 20 years (geometric mean titers: cases = 245, controls = 265), but 2- to 3-fold higher at age 25 years and older (cases = 684, controls = 282; P<.001). The risk of MS increased with these antibody titers; the relative risk (RR) in persons with EBNA complex titers of at least 1280 compared with those with titers less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase in anti-EBNA complex or anti-EBNA-1 titers during the follow-up was associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0; 95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was found between cytomegalovirus antibodies and MS. CONCLUSION: These results suggest an age-dependent relationship between EBV infection and development of MS.

Hernán MA, Jick SS, Logroscino G, Olek MJ, Ascherio A, Jick H. · Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. · Brain. · Pubmed #15758034 links to  free full text

Abstract: An increased risk of multiple sclerosis among smokers has been found in several prospective epidemiological studies. The association between smoking and progression of multiple sclerosis has not been examined. We identified patients who had a first multiple sclerosis diagnosis recorded in the General Practice Research Database (GPRD) between January 1993 and December 2000. Their diagnosis and date of first symptoms were confirmed through examination of medical records. Smoking status was obtained from the computer records. To assess the association between smoking and risk of multiple sclerosis, we conducted a case-control study nested in the GPRD. Up to 10 controls per case were randomly selected, matched on age, sex, practice, date of joining the practice and availability of smoking data. To assess the association between smoking and progression of multiple sclerosis, we conducted a cohort study of multiple sclerosis cases with a relapsing-remitting onset. Our nested case-control study included 201 cases of multiple sclerosis and 1913 controls. The odds ratio [95% confidence interval (CI)] of multiple sclerosis was 1.3 (1.0-1.7) for ever smokers compared with never smokers. Our cohort study included 179 cases with a mean (median) length of follow-up of 5.3 (5.3) years. The hazard ratio of secondary progression was 3.6 (95% CI 1.3-9.9) for ever smokers compared with never smokers. These results support the hypothesis that cigarette smoking is associated with an increased risk of multiple sclerosis, and suggest that smoking may be a risk factor for transforming a relapsing-remitting clinical course into a secondary progressive course.

Wagner HJ, Munger KL, Ascherio A. · Center for Gene and Cell Therapy, Baylor College of Medicine, Houston, TX, USA. · Eur J Neurol. · Pubmed #15667414 No free full text.

Abstract: Elevated antibody titers to Epstein-Barr virus (EBV) have been found prior to the onset of multiple sclerosis (MS) and EBV has been found in serum of patients with MS exacerbations. We conducted a prospective, nested case-control study in the Nurses' Health Study and Nurses' Health Study II cohorts to determine whether plasma EBV viral load in healthy adults predicts the risk of MS. MS cases with blood collected before onset (n = 18) or diagnosis (n = 13) and 62 healthy controls were matched by age and time of blood collection. EBV viral load in plasma was measured by real time polymerase chain reaction. Presence of EBV in plasma was associated with an increased risk of MS (relative risk = 2.5, 95% CI 0.78-7.8, P = 0.12). Adjusting for smoking, ancestry, and latitude of residence at birth did not materially change this result. However, no association was found between the EBV viral load and risk of MS. These results support a role for EBV in the etiology of MS, but need to be confirmed in a larger study.

Munger KL, DeLorenze GN, Levin LI, Rubertone MV, Vogelman JH, Peck CA, Peeling RW, Orentreich N, Ascherio A. · Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. · Neurology. · Pubmed #15159481 No free full text.

Abstract: BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent in multiple sclerosis (MS). However, previous studies were cross-sectional and could not assess whether Cpn infection preceded the onset of MS. METHODS: The authors conducted a prospective nested case-control study among 3 million US Army personnel and 121,466 members of the Kaiser Permanente Medical Care Program (KPMCP) cohort. Serum samples collected prior to onset of MS symptoms were available for 83 MS cases in the Army and 46 in the KPMCP cohort. Two controls were matched to each case on age, sex, and date of blood collection. Microimmunofluorescence was used to measure serum immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody titers to Cpn; IgG titers > or 1:16 were considered positive for past Cpn infection. RESULTS: Seropositivity for Cpn was not significantly associated with risk of MS in either cohort (Army: OR = 1.0; 95% CI 0.6, 1.8; KPMCP: OR = 1.5; 95% CI 0.7, 3.1) or in the pooled analysis (OR = 1.2; 95% CI 0.8, 1.9). Serum levels of anti-Cpn IgG antibody were also not associated with an increased risk of MS in the Army (OR for a fourfold difference in antibody titers = 0.9; 95% CI 0.7, 1.2) or in the pooled analysis (OR = 1.2; 95% CI 0.9, 1.4), but a significant increase in risk was seen in the KPMCP cohort (OR = 1.7; 95% CI 1.2, 2.5). The difference between these results in the Army and the KPMCP cohort was significant (p = 0.01). CONCLUSIONS: Neither Cpn seropositivity nor serum anti-Cpn IgG antibody titers predicted risk of developing MS. However, due to the heterogeneity of results between cohorts, we cannot exclude the possibility that infection with Cpn may modify the risk of MS.

Munger KL, Zhang SM, O'Reilly E, Hernán MA, Olek MJ, Willett WC, Ascherio A. · Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA. · Neurology. · Pubmed #14718698 No free full text.

Abstract: BACKGROUND: A protective effect of vitamin D on risk of multiple sclerosis (MS) has been proposed, but no prospective studies have addressed this hypothesis. METHODS: Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women: the Nurses' Health Study (NHS; 92,253 women followed from 1980 to 2000) and Nurses' Health Study II (NHS II; 95,310 women followed from 1991 to 2001). Diet was assessed at baseline and updated every 4 years thereafter. During the follow-up, 173 cases of MS with onset of symptoms after baseline were confirmed. RESULTS: The pooled age-adjusted relative risk (RR) comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 (95% CI = 0.40 to 1.12; p for trend = 0.03). Intake of vitamin D from supplements was also inversely associated with risk of MS; the RR comparing women with intake of >or=400 IU/day with women with no supplemental vitamin D intake was 0.59 (95% CI = 0.38 to 0.91; p for trend = 0.006). No association was found between vitamin D from food and MS incidence. CONCLUSION: These results support a protective effect of vitamin D intake on risk of developing MS.

Riise T, Nortvedt MW, Ascherio A. · Department of Public Health and Primary Health Care, Section of Occupational Medicine, University of Bergen, Norway. · Neurology. · Pubmed #14581676 No free full text.

Abstract: The authors determined the relationship between tobacco smoking and the risk of developing multiple sclerosis (MS) in a general population of 22,312 individuals living in Hordaland, Norway in 1997. A total of 87 individuals reported having developed MS. The risk of MS was higher among smokers than among never-smokers (rate ratio 1.81, 95% CI 1.1 to 2.9; p = 0.014). Studies on how smoking interacts with disease onset may contribute to determining the causal agents of this disease.