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Lynn I. Levin, PhD, MPH; Kassandra L. Munger, MSc; Mark V. Rubertone, MD, MPH; Charles A. Peck, MD; Evelyne T. Lennette, PhD; Donna Spiegelman, ScD; Alberto Ascherio, MD, DrPH

JAMA. 2005;293:2496-2500.

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.

Author Affiliations: Division of Preventive Medicine, Walter Reed Army Institute of Research, Silver Spring, Md (Dr Levin); Departments of Nutrition (Ms Munger and Dr Ascherio) and Epidemiology (Drs Spiegelman and Ascherio), Harvard School of Public Health, Boston, Mass; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (Dr Ascherio); Army Medical Surveillance Activity, US Army Center for Health Promotion and Preventive Medicine, Washington, DC (Dr Rubertone); US Army Physical Disability Agency, Washington, DC (Dr Peck); and Virolab Inc, Berkeley, Calif (Dr Lennette).

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