CIS: risk factors for converting to MS

Risk factors for developing MS: the case for EBV gets stronger. #MSBlog #MSResearch

“The study below was a massive effort by Dr Jens Kuhle, who was generously funded by an ECTRIMS fellowship to do this work. Well done Jens!”

“This work confirms many findings, but also provides new information on an association between oligoclonal bands and raised antibody titres to EBV infection. The whole reason for doing this study was to see if there was a link between EBV infection and OCBs. This study hints at EBV being linked to OCBs. How? Maybe EBV drives the B-cell response in MS. Unfortunately, too few CISers were EBV negative in this study to test to see of EBV-ve CISers were likely to be OCB-ve; even those CISer who were ‘EBV-negative’ using the EBNA-1 antibody screen were positive with more sensitive assays. This confirms  that if you have CIS and are at risk of developing clinically definite MS you are virtually assured or being EBV positive. The corollary to this is that if you are EBV negative you don’t develop CIS or MS. The Billion Dollar question is how do we keep the population EBV negative and is it wise to do so? An EBV vaccination strategy may work, but what will the consequences of getting rid of EBV in the wider population? EBV is part of our metagenome and it is one of the most co-evolved human viruses. This would imply that it must be doing something favourable at a population level for evolution to have moulded such a close relationship between humans and EBV. This is why we are focusing our attention on infectious mononucleosis (IM) which increases your risk of getting MS by a factor of two (2X). How does IM trigger the MS causal pathway? If we prevented and or treated IM would we reduce the risk of you getting MS? These are all very important questions for the future. Someone needs to answer them. If we don’t the next generation of CISers and MSers will ask why we didn’t act given the information we currently have. Despite the firm evidence that EBV plays a role in MS we still get very negative reviews when we submit grant applications to study this further. We must be doing something wrong.”

Epub: Kuhle et al. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Mult Scler. 2015 Feb. pii: 1352458514568827. 

BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort.

METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS.

RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres.

CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting.

CoI: This work was done by TeamG who are also authors on the paper.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Prof G,

    Why do you think that having EBV could also be beneficial. My daughter has had her jab for human papilloma virus in the hope of preventing cervial cancers, we have lots of vaccines as children to prevent viruses, when I had shingles I was treated with an anti-viral and if I get into my 70s there is a vaccine. You are showing too much sympathy for EBV – it cuases various cancers and probably a large number of so called auto-immune diseases. It needs to be erradicated – much like head lice, tapeworms etc. You're goign soft in you old age – time to man up and blitz ebv.

  • I think it would be beneficial to suppress ebv Probably through anti cd20 and good anti herv / ebv anti viral. But I'm not a Dr!

  • Don't think I have ever had EBV/glandular fever. Is there a test to see if you have ever had it ? I only have 'query MS' and I was wondering if the EBV test was negative then I could once and for all tick MS off the list as the possible culprit !

    • I have had RRMS for 2 years and 5 months now and was tested for EBV 17 months ago, I was EBV negative. I had glandular fever when I was in high school.

    • There are a number of tests for Epstein Barr (VCA-IgM, VCA-IgG, EA-D, IgG, EBNA, IgG) if you are negative to them all you have probably never had Epstein Barr. If you are positive to any of them then you have met the virus. If you had glandular fever at high school (assuming a correct diagnosis) then you carry Epstein Barr. There are also subtypes of the virus.

  • OK, so what if us who are EBV +, and OCB -? That's my situation, anyway, and I'm sure I'm not alone. I was diagnosed at age 50, after some 25 years of symptoms.

    • Hi Lisa I am 50 too. Started having symptoms 25 years ago too after radiation treatment. That is a possible cause too. I am OCB negative also but am unsure re the EBV. I would be interested in getting that tested. Limboland sucks as dont know what camp to follow !

    • you can get tested easily by your GP – it's a simple blood test for EBV titers – I had that done before my LP and of course the titers are too high and my OCB are positive.

      My doc got tested too! And his EBV titers were too high as well but he has no MS obviously cos different DNA.

  • In this day and age there should be a big database of all people with MS showing things like OCB and EBV status. In such a way it would be easy to spot links etc. I dont even think most people even have a LP.

  • Oops – that was supposed to say DNA (not DNS). My question to team G is whether I need to track PCR or EBNA titres? My PCR shows EBV below detectable levels (182 copies/ml)

  • We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation. In Epstein Barr cites research findings in their serum levels of Vitamin D3. Forgive me the question but what do you think about the low levels of Vitamin D3? She would have more implication for the conversion of CIS to MS than the virus itself Epstein Barr?

By Prof G



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