Multiple sclerosis MS is the most common chronic inflammatory disease of the CNS with more than 2 million individuals affected globally. In this article, Dr Aju Mathew discusses a study and explains the relationship between EBV in multiple sclerosis.

Multiple sclerosis

Multiple sclerosis (MS) is characterised by fully or partially reversible episodes of neurological disability. The incidence is relatively low in India with preliminary epidemiological studies in India reporting an incidence of 8.3 per 100,000 people. 

Various genetic and environmental risk factors have been proposed for MS, but its aetiology is still unknown. As is common in autoimmune diseases, roughly three-quarters of people with MS are women. There is an increased risk within families. Previous research identified the HLA DRB1*1501 haplotype as the most significant genetic risk factor for MS as it increases the risk of MS by three times. 

Role of Epstein Barr Virus (EBV) in Multiple sclerosis

Patrick F. Bray et al, were one of the first to describe the causative role of EBV in MS. They found a significantly increased prevalence of EBV infection in MS patients as compared to controls. They also described a negative relationship between CMV infection and MS. Later, Thacker et al stated that the risk of MS is extremely low in people who have not been infected with EBV and also that the risk for MS doubles after EBV infection.

Hence, they concluded that EBV infection in the form of infectious mononucleosis in adolescents increased the risk of MS in adults. The relationship between EBV antibody titers and the onset of MS was described by Levin et al in 2005. They found that the relative risk of developing MS was almost 9 times higher in study participants with higher EBV titers compared to baseline. Furthermore, EBV was isolated from MS demyelinated lesions in patients in 3 different pathological studies. However, evidence of a causal relationship between EBV and MS is still inconclusive.

The abundant nature of EBV, which infects ~95% of adults, and the fact that MS is a relatively rare disease, has until now impeded such an investigation.

The study

In a novel study, throughout a 20-year collaboration with the US military, Bjornevik et al identified cases of MS in a cohort composed of >10 million active-duty US military personnel between 1993 and 2013. Out of these, 5.3% of individuals were EBV negative on initial sampling and hence were included in the study. Samples were obtained at first contact, just before MS diagnosis, and then one in between. 

Samples of 801 MS cases and 1566 controls were taken and assessed for EBV infection. Comparing them based on EBV positivity showed that individuals infected with EBV were 26 times more likely to develop MS compared to those who were negative [95% CI: 3.7 to 191.6; P = 0.001]. At the time of the first sample, 35 MS cases and 107 controls were EBV-negative.

Nearly all cases became infected with EBV during the follow-up, and all seroconverted before the onset of MS. The nearly complete seroconversion rate among individuals who developed MS during follow-up (97%) contrasts with the 57% rate of seroconversion observed among individuals who did not develop MS. Also, EBV seroconverted individuals were 32 times more likely to develop MS compared to individuals who were seronegative throughout the study (95% CI: 4.3 to 245.3, P < 0.001).

This means that all patients with MS had been infected with EBV before the pathological sign of MS manifested. CMV was used as a negative control since it displays socioeconomic and racial/ ethnic disparities in age at infection similar to those of EBV. MS risk was lower among CMV-positive than among CMV-negative individuals, consistent with a previous report and suggesting that the immune response to CMV nullifies the adverse effects of EBV.

Conclusion

The findings of this exciting new study demonstrate EBV to be the most important cause of MS. There is evidence that EBV may be acting synergistically with HLA DR15 mutation to cause MS. It is thus all the more imperative to find vaccines to prevent EBV infection. Anti-CD20 antibodies are the most effective treatments for MS currently because they deplete circulating memory B cells which may harbour EBV viruses. However, therapies which directly target EBV could be just as effective without the additional side effects.

Disclaimer- The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Edwin Saji is a research associate at Kerala Cancer Care, Kochi, India.

Dr Aju Mathew is a medical oncologist, haematologist, internist and epidemiologist practising in Kochi.