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Epstein-Barr virus is a necessary causative agent in the pathogenesis of multiple sclerosis: Yes

A number of genetic and environmental risk factors have been implicated in multiple sclerosis (MS) risk, of which Epstein-Barr virus (EBV) is the leading candidate of proposed infectious agents. A role for EBV in MS pathogenesis fits many of the enigmatic features of the disease such as the geographical distribution and the change in risk with migration.1,2 The timing of EBV infection is likely to be important in determining MS risk and may in part explain why MS is virtually non-existent in many developing countries. Most individuals worldwide are infected with EBV at an early age in childhood, but a late adolescent age of EBV infection is common in the developed world (thought to be a consequence of increased hygiene). Infectious mononucleosis (IM) is an atypical symptomatic presentation of EBV infection and is characteristic of an adolescent age of infection. IM has been consistently associated with an increased MS risk (a metaanalysis of thousands of patients yielded a relative risk of 2.17).3 Many of these studies were questionnaire based and thus could have been afflicted by recall bias. However, Nielsen et al. investigated a cohort of patients with serologically tested EBV-related IM and still found an increased MS risk, suggesting that bias cannot explain the association between MS and IM. The increased risk of MS after IM was shown to remain for more than 30 years after IM and was independent of sex, age or severity of IM.4 The high seroprevalence of EBV in the general population has in the past made it difficult to determine whether EBV is causally related to MS. Meta-analysing all available data on EBV seroprevalence showed that ‘nearly all’ (99%) of MS patients have evidence of EBV infection, as compared to approximately 90% of controls. Whilst the increased seroprevalence of EBV in MS patients suggests that EBV influences MS risk, the ‘nearly all’ finding is of intrigue. Is EBV needed for MS to develop? Indeed some studies have shown a 100% seroprevalence in MS patients. It has recently been demonstrated that variability of studies appear to arise, at least in part, from different methodological assays. A meta-analysis showed that when studies used two different assays of EBV detection (enzyme-linked immunosorbent assay (ELISA) and indirect immunofluoresence (IIF) and/or anti-complement immunofluoresence (ACIF)), in contrast to either on its own, 100% of MS patients are EBV seropositive, as compared to less than 100% of controls, giving an odds ratio of 0 for someone who is EBV seronegative developing MS.5 Criteria commonly used to establish causality of an infectious agent are the consistency of the association, the temporal relationship of the infection and pathogenicity of the infectious agent. Temporal consistency was shown in a landmark study by Levin and colleagues. Anti-EBV antibody titres both before and after MS onset in serum samples from the American Department of Defense Serum Repository were measured.6 Of individuals who were initially EBV seronegative and subsequently went on to develop MS, 100% seroconverted prior to MS onset in contrast to seroconversion of only 35.7% of the EBV seronegative controls. The data further supports the hypothesis that EBV infection is a prerequisite of MS. As EBV is near ubiquitous in the general population but pathogenic in only a minority of individuals who are infected, other factors, as well as the potential influence of EBV strain variation, must contribute to causation. EBV is necessary but not sufficient for MS development. The key may be in the timing. In a longitudinal study of the US military cohort mentioned above, antibody titres to the EpsteinBarr nuclear antigen (EBNA) complex were found to be similar in cases and controls younger than 20 years, but a significant rise in serum antibody titres occurred in those who would go on to develop MS at age 25 years or older with antibody titres two to three times greater than their control counterparts.7 It remains an important consideration that the onset of MS may substantially precede the onset of MS symptoms, rendering it possible that the association between EBV and MS is secondary to an early MS immune alteration. This is unlikely in light of the fact that the Epstein-Barr virus is a necessary causative agent in the pathogenesis of multiple sclerosis: Yes