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A Prospective Study

Alberto Ascherio, MD,DrPH; Kassandra L. Munger, MSc; Evelyne T. Lennette, PhD; Donna Spiegelman, ScD; Miguel A. Hernán, MD,DrPH; Michael J. Olek, DO; Susan E. Hankinson, ScD; David J. Hunter, ScD

JAMA. 2001;286:3083-3088.

Context  Epidemiological studies suggest an association between infection with Epstein-Barr virus (EBV) and risk of multiple sclerosis (MS).

Objective  To determine whether elevation in serum antibody titers to EBV viral capsid antigen (VCA), nuclear antigens (EBNA, EBNA-1, and EBNA-2), and diffuse and restricted early antigen (EA-D and EA-R) as well as to cytomegalovirus (CMV) precede the occurrence of MS.

Design, Setting, and Subjects  Prospective, nested case-control study. Of 62 439 women participating in the Nurses' Health Study (aged 30-55 years in 1976) and Nurses' Health Study II (aged 25-42 years in 1989) who gave blood samples in 1989-1990 and 1996-1999, respectively, and were followed up through 1999, 144 women with definite or probable MS and 288 healthy age-matched controls were included in the analysis.

Main Outcome Measure  Serum antibody titers to the specific EBV and CMV antigens, compared between cases and controls.

Results  We documented 18 cases of MS with blood collected before disease onset. Compared with their matched controls, these women had higher serum geometric mean titers (GMTs) of antibodies to EBV but not CMV. Elevations were significant for antibodies to EBNA-1 (GMT, 515 vs 203; P = .03), EBNA-2 (GMT, 91 vs 40; P = .01), and EA-D (15.9 vs 5.9; P = .04). The strongest association was found for antibodies to EBNA-2; a 4-fold difference in titers was associated with a relative risk (RR) of MS of 3.9 (95% confidence interval [CI], 1.1-13.7). The corresponding RRs were 1.6 (95% CI, 0.7-3.7) for VCA, 2.5 (95% CI, 1.0-6.3) for EBNA, 1.8 (95% CI, 1.0-3.1) for EA-D, and 1.0 (95% CI, 0.6-1.7) for CMV. Significant but generally weaker elevations in anti-EBV antibodies were also found in analyses of 126 cases of MS with blood collected after disease onset and their matched controls.

Conclusions  Our results support a role of EBV in the etiology of MS.

Author Affiliations: Departments of Nutrition (Dr Ascherio and Ms Munger), Epidemiology (Drs Ascherio, Spiegelman, Hernán, Hankinson, and Hunter), and Biostatistics (Dr Spiegelman), Harvard School of Public Health, Center for Neurological Diseases–Multiple Sclerosis Unit (Dr Olek), and Channing Laboratory, Department of Medicine (Drs Hankinson and Hunter), Harvard Medical School and Brigham and Women's Hospital, Boston, Mass; and Virolab Inc (Dr Lennette), Berkeley, Calif.

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