99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Epstein-Barr virus and multiple sclerosis: epidemiological evidence

Abstract

While the causes of multiple sclerosis (MS) are unknown, there is strong evidence that infection with Epstein-Barr virus (EBV) is an important factor. In this review, we discuss the epidemiological evidence and argue for a causal role of EBV in MS aetiology. One of the most striking and consistent observations is that MS is extremely rare among EBV-negative individuals. Further, the timing of EBV infection appears to be critical, with individuals who are infected during adolescence and young adulthood, when the infection is more likely to manifest as mononucleosis, having a two- to threefold greater risk of MS compared to individuals infected in early life. These observations challenge the hygiene hypothesis which states that being in a high hygiene environment in early life increases future risk of MS - if this general formulation were true, EBV-negative individuals would be expected to have an increased risk of MS. Additional support for the causal role of EBV comes from longitudinal, prospective studies which show remarkable consistency, in that antibodies against EBV are elevated prior to MS onset. However, while infection with EBV is consistent with many observations of MS epidemiology, there are some that remain unexplained, suggesting that other factors are also involved in determining risk.

Fig. 1

Relative risk of multiple sclerosis (MS) for white male veterans of World War II or the Korean conflict by tier of residence at birth and at entry into active duty (EAD) (coterminous United States only). Data from [6]. Reprinted with permission from Thieme Medical Publishers, Inc., Ascherio and Munger, Semin Neurol 2008; 28:17–28. P for no change in birthplace risk: all = 0·0003; north = 0·003; middle = 0·002; south = 0·57.

Fig. 3

Odds ratio of paediatric multiple sclerosis (MS) associated with remote Epstein–Barr virus (EBV) infection. Data from [–24]. For Pohl, 2006, odds ratio estimated by the authors based on data provided in the original paper.

Fig. 2

Relative risk (RR) of developing multiple sclerosis (MS) according to Epstein–Barr virus (EBV) infection and history of mononucleosis. Bars represent the 95% confidence intervals of the RR estimates. Data from [7,21] Reprinted with permission from Thieme Medical Publishers, Inc., Ascherio and Munger, Semin Neurol 2008; 28:17–28.

Fig. 4

Relative risk of multiple sclerosis (MS) according to serum levels of anti-Epstein–Barr virus EBV nuclear antigens (EBNA) antibody titres an average of 4 years before the onset of symptoms. Data from [28].