True-EBV negative MS is not MS

I have almost completed a paper with a colleague and friend Viqar Chamoun. He was a contemporary of mine when I did my PhD. Chamoun and I worked in the same laboratory and we spent many hours chewing the cud together. Chamoun is a very deep thinker and got me interested in medical philosophy and the application of logic to defining a disease. Chamoun worked on neurosarcoidosis and developed a set of logical steps to show that contemporary diagnostic criteria for neurosarcoidosis were based on tautology. Despite his logical approach we never got his seminal paper published. The plan is to publish it now and in parallel with a paper defining MS as a biological disease and setting-out the principles of how we should incorporate biomarkers into the diagnostic criteria to improve both the sensitivity and specificity of the current criteria.

Viqar Chamoun - thinker extraordinaire

 

Surprise, surprise one of the biomarkers we want to explore is EBV seropositivity. However, to validate a new set of diagnostic criteria to define MS as biological rather than a clinico-radiological construct will require a post-mortem study and will take decades to complete. I am also not sure the wider MS community is ready for us to redefine MS as a biological disease.

I am not surprised by the study below that found paediatric anti-MOG syndrome masquerading as MS. Diagnosing MS is always difficult in children. Please remember even if you fulfil the contemporary definition of having MS at post-mortem about 1 in 20 of you will not have MS and I suspect this will be even higher in children with MS. I have been saying for years that true EBV negative MS is not MS. When I say true EBV-negative MS is that you have to remember that standard diagnostic assays for detecting anti-EBV antibodies are not 100% sensitive. In summary, it is very difficult to find true-EBV negative people with MS.

I have had a recurring dream of finding and studying a cohort of true EBV-negative MS patients, but there are too few such patients to study. When we found 32 patients, in our large international CIS study of over 1000 patients, who were seronegative for EBV we shipped their samples to Jaap Middledorp’s EBV laboratory in Amsterdam for more detailed testing. When the results came back 31 of the 32 were positive and one was equivocal with Jaap’s more sensitive assays.

So yes I think ‘true-EBV negative MS is not MS’ and that applies to paediatric MS as well. The data below is very important and strongly supports EBV as being the cause of MS and is screaming out for us to start our EBV-vaccine MS prevention study ASAP. Do you agree?

Bardia Nourbakhsh et al. MS is rare in EBV-seronegative children with CNS inflammatory demyelination. Ann Neurol. 2021 Mar 11. doi: 10.1002/ana.26062. Online ahead of print.

Although Epstein-Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV-seronegative. When re-evaluating 25 EBV-seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti-myelin oligodendrocyte glycoprotein (MOG) antibody in 11/25 (44%) EBV-seronegative, but only 9/164 (5.5%, p < 0.001) EBV-seropositive patients. After critical review, MS remained a plausible diagnosis in only four of 14 EBV-seronegative/MOG antibody-negative patients. In children with an MS-like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG-antibody disease. This article is protected by copyright. All rights reserved.

CoI: multiple

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