April 2003 Journal Scan
Medscape Infectious Diseases 5(1), 2003.
From JAMA March 26, 2003 (Volume 289, Number 12)
Multiple Sclerosis and Epstein-Barr Virus
Levin LI, Munger KL, Rubertone MV, et al.
The Epstein-Barr virus (EBV) would win the prize for most versatile virus if Academy Awards were given to microbes. Both acute and chronic infections produce a wide variety of symptoms from minor illness to fulminant malignancy. The repertoire of the virus is extended to chronic neurologic disease in this brief report by investigators at the Walter Reed Army Institute of Research and collaborators at the Harvard School of Public Health and Virolab Inc. (Berkeley, California). The investigators showed a relationship between titer of serum IgG antibodies to viral capsid antigen (VCA) or EBV nuclear antigen (EBNA) complex and subsequent diagnosis of multiple sclerosis (MS). The relative risk is plausible, graded, and substantial. Although not proving causation, this study suggests the possibility of new ideas to prevent and treat multiple sclerosis.
The investigators used the extensive US Defense Department serum bank, which contains samples from more than 3 million persons collected at entry into service and approximately every 2 years starting in 1988. They identified cases of MS (defined as certain or probable on the basis of diagnostic criteria that included MRI and examination by a neurologist) from records of the US Army Disability Agency. Cases were each matched to 2 controls by age, sex, race/ethnicity, and date of blood draw. Samples were subjected to IgG and IgA antibody tests for VCA, anti-early antigen complex (EA-D and EA-R), and IgG antibodies against EBNA complex and EBNA-1 and EBNA-2. IgG antibodies to cytomegalovirus (CMV) were also measured in all cases and controls. Finally, cases and controls were compared using geometric mean antibody titers against all of the antigens.
There were 83 cases and 166 controls. All cases and 98% of the controls had evidence of exposure to EBV at entry into the service. Mean age of onset of MS was 27 years, with diagnosis considered certain in 64% and probable in 36%. A mean of 4 years elapsed between first blood draw and onset of illness. The baseline geometric VCA and EBNA complex IgG antibody levels were significantly higher in cases than in controls. Additionally, the risk of MS rose significantly as the titer increased. The relative MS risk of subjects with highest compared to lowest VCA and EBNA IgG titers were 19.7 and 33.9, respectively. There was no association of risk to CMV antibodies, race, age, or sex. Using simultaneous regression analysis, only high EBNA complex antibody and EBNA-1 antibody correlated to risk. Interestingly, the VCA and EBNA antibody levels remained stable across time, even after the onset of disease.
The investigators state that the pattern of high VCA, high EBNA seen in the patients with MS suggests recent EBV infection or reactivation with vigorous cellular immune response. They also suggest that this pattern has been associated with greater risk of Hodgkin's disease and nasopharyngeal cancer. Could the high titer represent continued viral replication in the central nervous system? With new anti-herpes medications potentially achieving sufficient activity against EBV in the central nervous system, it might be time to see whether anti-EBV therapy is beneficial for this dreaded disease. On the other hand, it increasingly looks like a vaccine against EBV given early in childhood might be a good thing.
© 2003 Medscape