Recently there was an hype on (my) LinkedIn about a new paper published in Science that claims a causal link between Epstein-Barr-Virus (EBV) infection and development of Multiple Sclerosis (MS).

What is so extraordinary about this paper that one can claim causation instead of correlation?

Long story short, and in my opinion, the most extraordinary is the number of samples studied. The scientists had access to samples collected by the US-military who, on average, collected 62 blood samples per person, for each of the 10 million people enlisted over a period of 20 years. In context, scientists had access to a study group the size of Portugal’s population.

Where these samples representative?

From the enlisted population, about 95% had previously contracted an EBV infection (in line with the prevalence of EBV in the general population) and in total 955 people went on to develop Multiple Sclerosis. If we simplify and assume 48 new MS patients per year, this is lower than the average annual incidence in the UK. Moreover, in the general population, 1 in 3 MS patients are men whereas in this study the ratio is the exact opposite (see study design below).

Is this a good paper?

Technically, the paper is not very elaborated (note that I did not look at the supplementary material), it checks serum levels of anti-EBV antibodies, antibodies against several other viruses for control, the presence of soluble Neurofilament L (sNfL), and EBV antigens. But the techniques applied are adequate.

What are the main conclusions?

The results are discussed assuming that sNfL is the earliest molecular marker of MS. Because, in these patients, detection of antibodies against EBV in serum (seroconversion) occurs before detection of sNfL, it is concluded that first there is an EBV infection and only then MS development.

The authors check the levels of antibodies against other viruses and see no differences between MS patients and the control group before and after disease onset, suggesting that no other viral infection precedes disease onset.

Importantly, the authors say that the absence of differences, comparing to the control group, in the response against other viruses before and after disease onset suggests that MS does not cause a susceptibility to viral infections; and specifically, that MS does not cause susceptibility to EBV infection, as the responses against this virus does not change before and after onset in the patient group.

Figure 1 from the paper, with the study design


K. Bjornevik et al., Science 10.1126/science.abj8222 (2022).

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