MedPage Today Action Points Advise patients who ask that the etiology of multiple sclerosis is unknown, but has been associated with a heightened antibody response to Epstein-Barr virus (EBV). Note that this study shows that high antibody levels to EBV occur many years before the onset of MS, suggesting it is an early event in the pathogenesis of the disease. Review Gerald DeLorenze, Ph.D. Kaiser Permanente Division of Research OAKLAND, Calif., April 11 - A powerful antibody response to Epstein-Barr virus (EBV) may predispose people to develop multiple sclerosis years later, according to researchers. The risk of developing multiple sclerosis doubles for every four-fold increase in antibodies to EBV, Gerald DeLorenze, Ph.D., an epidemiologist at the Kaiser Permanente Division of Research here, reported in the April 10 online issue of Archives of Neurology. EBV, the widely disseminated herpesvirus that is the primary agent of infectious mononucleosisis, is spread by intimate contact between susceptible persons and asymptomatic EBV shedders. The majority of primary EBV infections are subclinical. Approximately 90% to 95% of adults are EBV-seropositive. It has been known for several years, Dr. DeLorenze said in an interview, that elevated antibody responses to EBV occur in patients who go on to develop MS, "but it was not clear whether the increases in antibody titers to Epstein-Barr were prior to developing MS or were a consequence of the development of MS, with its heightened immune activity." In fact, Dr. DeLorenze said, "the elevation does precede the MS," often by decades. Dr. DeLorenze and colleagues reported a prospective case-control study -- using a long-standing database that included blood samples taken between 1965 and 1974 -- that aimed to try to clear up the link between EBV and MS. "Our study," Dr. DeLorenze said, "had the potential for blood samples to be collected up to 34 years before the onset of first MS symptoms." In one case, he said, a blood sample taken 32 years before a patient developed MS showed high levels of EBV antibodies. By contrast, he said, earlier studies that highlighted the link between the two illnesses - such as the Nurses' Health Study - had short follow-up periods of only a few years on average. Kaiser Permanente has maintained medical records of all health plan members who provided blood samples and who were members for all or some of the time between giving the sample and 1999, for a maximum possible follow-up of 34 years, Dr. DeLorenze said. From those records, he and colleagues found 42 confirmed cases of MS. For each case, the researchers selected three controls, matched by age at the time of blood collection, by sex, and by date of blood collection. The blood samples were analyzed for levels of antibodies to Epstein-Barr Nuclear Antigen (EBNA) and one of its components, EBNA-1. Analysis showed: The median age at onset of MS was 45 and the median time between baseline blood collection and onset of MS was 15 years. For every four-fold increase in antibodies to EBNA, the relative risk of MS doubled. The hazard ratio was 2.1, with a 95% confidence interval from 1.1 to 3.8. For every four-fold increase in antibodies to EBNA-1, the risk of MS also rose. The hazard ratio was 1.8, with a 95% confidence interval from 1.1 to 2.9. The implication, Dr. DeLorenze said, is that a heightened antibody response to EBV is probably an early event in the pathogenesis of MS, although exactly what happens is not yet clear. One possibility, he said, is that the active immune response to EBV creates a T-cell response that cross-reacts with myelin antigens, kick-starting the degradation of myelin that is characteristic of MS. Also, he said, it is known that EBV infects B-lymphocytes, which might also lead to an auto-immune response. The central clinical message of the study, he said, is the hope that better understanding of the etiology of MS will lead to better treatments. "Now we want to throw it back to the basic scientists and say, find the mechanism," he said. He suggested that vaccines against EBV, which affects about 90% of the adult population, might also be a valuable tool.