Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis

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,