A new meta-analysis of 39 studies (n=10,864) has concluded that there is an association between Epstein-Barr virus (EBV) seropositivity and MS (Almohmeed et al. PLoS One 2013;8:e61110; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3621759/pdf/pone.0061110.pdf). Seroprevalence was determined for three anti-EBV antibodies: anti-EBV nuclear antigen 1 (anti-EBNA-1) or EBNA complex; antiviral capsid antigen (anti-VCA); and anti-Early Antigen (anti-EA).
The median seroprevalence of anti-EBNA IgG was 98% in MS patients compared to 88% in controls (odds ratio 4.7). The median anti-VCA IgG seropositivity was 99% in MS patients versus 92% in controls (OR 4.51). In contrast, the median seroprevalence for anti-EA IgG was similar in cases and controls (18% vs. 16%; OR 1.4), which may suggest that recent EBV infection is less relevant to MS.
The association of anti-EBNA and VCA IgG with MS was more robust for confirmed MS cases compared to cases of probable MS or clinically isolated syndrome. Odds ratios for EBNA and VCA antibodies were 5.25 and 6.23, respectively, in confirmed MS cases.
The meta-analysis did not examine antibody titre levels or the potential importance of the timing of rising antibody levels. Anti-EBNA antibody titres have been reported to be significantly higher in MS patients compared with matched controls (DeLorenze et al. Arch Neurol 2006;63:839-844). A further observation is a two- to three-fold elevation in antibody titres to EBNA-1 after age 25, which may herald the onset of MS (Levin et al. JAMA 2005;293:2496-2500). One suggestion is that increased anti-EBNA-1 activity may indicate an altered immune response to EBV in the years preceding MS onset (Sundstrom et al. Neurology 2004;62:2277-2282).
Comment
Dr. François Grand’Maison: There is no doubt that EBV infection is a significant risk factor for the development of MS. Anti-EBNA negative teenagers and young adults eventually develop MS only after having mounted an immune response related to infectious mononucleosis or other EBV-mediated infection. Basically, there are two main schools of thought on the pathogenic role of EBV in MS: EBV triggers the MS immune cascade peripherally through molecular mimicry; or centrally when EBV-infected B cells are targeted by CD8+ lymphocytes. However, EBV infected cells have not been uniformly detected in the CNS. Nevertheless, EBV infection may play a role in the formation of follicle-like structures in the meninges that are thought to be involved in the pathogenesis of MS (Serafini et al. J Neuropathol Exp Neurol 2010;69:677-693). A vaccine against EBV in young children may reduce the incidence of MS significantly.