Research: EBV is the cause of MS

R
Epub: Pakpoor et al. The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis.  Mult Scler. 2012 Jun 11.

BACKGROUND: Epstein-Barr virus (EBV) infection is widely considered to be a risk factor for multiple sclerosis (MS). A previous meta-analysis estimated an odds ratio (OR) for MS in individuals seronegative for EBV of 0.06. 


“This meant that if you were found to be EBV negative your chances of getting MS were very close to being zero compared to somebody who is EBV positive; a 94% lower risk. This study is a timely update of this previous analysis.”

Given the potential importance of this finding, we aimed to establish a more precise OR for adult and paediatric onset MS in EBV seronegative individuals.

METHODS: PubMed and EMBASE searches were undertaken to identify studies investigating the association between MS and EBV. Twenty-two adult and three paediatric studies were included. ORs were calculated using a fixed effects model. A sub-group analysis based on the method of EBV detection was performed.

RESULTS: The OR for developing adult MS in EBV seronegatives was 0.18 (95% confidence interval (CI) 0.13-0.26)) and for paediatric MS was 0.18 (95% CI 0.11-0.30). Sub-group analysis on EBV detection method showed that studies which used immunofluoresence generated an OR=0.07 (95% CI 0.03-0.16); for those that used enzyme-linked immunosorbent assay (ELISA) OR=0.33 (95% CI 0.22-0.50) and for studies which used ELISA and immunofluoresence OR=0.00 (95% CI 0-0.43).

CONCLUSION: The sensitivity and specificity of the assay used to measure EBV antibody titres have an influence on the association between MS and EBV. Looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. This has implications for future studies of EBV in MS. MS patients without EBV infection, if they truly exist, should be studied in more detail.

“This study tells us two things. (1) The assays we use to assess whether or not you have had EBV are not that sensitive. In other words being negative on one assay means you may still have had EBV infection in the past; a false negative test. When you are negative using two different assays you are more likely to be EBV negative, a true negative test. This is a very important observation and has major implications on how we interpret the EBV data. (2) If you are EBV negative on two different assays your risk of getting MS is zero compared to someone who is EBV positive. This observation indicates that EBV is likely to be the cause of MS or at least fall in the causal pathway. This is why we need to focus our research attention on EBV; how does EBV trigger and/or drive MS disease activity? Hence my frustration when our recent grant application was turned down to test an anti-EBV drug in MS. Don’t worry we are not giving up; we are going to generate some more basic lab data and when we go back for funding the case will be water tight. We do need your help; if you get the chance please keep letting the World and MS stakeholders know how important the Charcot Project is.”


CoI: This work is from Team G and was done as part of an MRC funded grant. I would also like to point out that Julia Pakpoor is a medical student. It is unusual for someone in medical school to publish such an important paper. 
Well done Julia!

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.

26 comments

  • According to Wikipedia, "In the United States, about half of all five-year-old children and 90 to 95 percent of adults have evidence of previous infection [of EBV]." Certainly, 90 to 95 percent of the adult population does not have MS. I find a causal relationship between EBV and MS, therefore, less than convincing. Susceptibility after the fact, maybe.

  • "if you get the chance please keep letting… MS stakeholders know how important the Charcot Project is."

    Any recommendations on how we could do this?

  • Judy, I think it would be causal if Team G could show that those people who have MS also have higher EBV antibodies with no exception to the rule and that is what they are up to. Then you could say that given a genetic susceptibility those with EBV are going to get/have got MS.

    It would be even better if they could find a gene linked to EBV in people with MS who at the same time had higher antibodies – that would be hyper-causal so to speak.

  • I think Prof G means networking. Someone who knows someone – e.g. perhaps someone is from Edinburgh Uni and knows a tutor of J.K. Rowling's? Also, Oxford tutors (humanities) are quite good points of contact if you want to drum some support from writers.

    I can think of one writer in Oxford who potentially could be approached & who knows a lot about MS – so calling on some Oxford bloggers……..

    As I said before contact Ozzy O. Perhaps through the Iron Maiden guy who got the PhD from MD.

  • Heard a nice talk about how EBV could be causa. When asked why this logic falls on deaf ears in the immunology community….the answer was EAE is the problem…Me thinks it is not EAE that is the problem but how people you use EAE think…Normally in a blinkered way:-)

  • Just because the virus is common in most people who do not have MS, is not a reason why it is not causal. We know other factors, genetics environmental alos have to fall into place.

  • Re: " 90 to 95 percent of the adult population does not have MS."

    You may have missed the important observation that all the people destined to develop MS are in this 90-95% group. The only factor that protects you from developing MS is not having EBV. How do we stop people getting EBV? That is a very difficult problem.

  • I wonder about the consequences of this study on therapy options.

    E.g. chemotherapeutic agents like Cyclophosphamide and Mitoxantrone.

  • Re: "I wonder about the consequences of this study on therapy options. E.g. chemotherapeutic agents like Cyclophosphamide and Mitoxantrone."

    All the chemotherapies that work in MS seem to target B-cells; the cell in which EBV lives. I have proposed many times that these agents are working via a EBV mechanism. Interestingly agents that target T-cells selectively have little of no effect in MS, e.g. anti-CD4. The most exciting results in the recent past is anti-CD20 therapies (rituximab and ocrelizumab) these target B cells exclusively.

  • Re: "Is PPMS a B cell disease?"

    In my opinion yes; the CSF has OCBs or oligoclonal IgG bands and the pathology shows B cell follicles and plasma cells (mature immunoglobulin factories). Interestingly, there is a hint that some PPMSers respond to anti-CD20 treatment.

  • in another publication on the blog, we talk about a study that people with low vitamin D is more likely to have veb. therefore, because msers always have lower vitamin D are more susceptible to EBV. This could go? I would also like to explain the epidemics of multiple sclerosis with veb, if bev is spread throughout the world for a long time. thank you very mucha, alvaro

  • This is interesting. Prof G – would you consider a clinical trial that looks at the impact of raltegravir on MS patients?

  • Sorry – scrap that idea. It kills mice with autoimmune disorders… http://www.ncbi.nlm.nih.gov/pubmed/19923437

    But it seems a likely area to look at, no?

    Te drawback to the current generation of antiviral drugs are that they are fraught with side effects.

    Foscarnet is extremely nephrotoxic; Ganciclovir and Valganciclovir (Valcyte) causes myelosuppresion, GI symptoms, as well as neurological symptoms; and Valacyclovir and famciclovir lack broad spectrum anti-viral efficacy. Many taking Valcyte report nasty side effects.

    Cure the illness, kill the patient…

    I don't like the sound of that one.

  • Re: "This is interesting. Prof G – would you consider a clinical trial that looks at the impact of raltegravir on MS patients?"

    Why raltegravir?

  • Prof G – it was this article that made the connection.

    http://www.ncbi.nlm.nih.gov/pubmed/21871974

    If HHV 6 is a trigger of EBV reactivation, perhaps targetting HHV 6 is the key?

    Interferon acts as a viral suppressant too. Perhaps a trial combining BInterferon and aciclovir might have an impact?

    The trail of MS to the door of HHV6 seems so compelling. Why are more neurologists not looking at this? There are some strong, new anti virals…. But where are the studies?

    Interestingly, HHV6 thrives on cholesterol. Perhaps that's why statins showed promise.

    HHV6 is implicated in Vit D disregulation….

    Why can't we as MSers access anti viral drugs to improve our outcomes?

    You rightly attack CCSVI. But those who only focus on inflammatory reducers are as guilty of the same myopia.

    You though Prof G are onto something. Please let me be on a trial!!!!

  • Re: "Why can't we as MSers access anti viral drugs to improve our outcomes?"

    We need data; if anti-CD20 is working via EBV you will may have access to it within 5 years.

  • @ Iain O

    University of Gothenburg, 1997 "Acyclovir treatment of relapsing-remitting multiple sclerosis"

    If I remember right there was also a second study with more participients. But I can't remember the title. But it was before 2001/2002.

  • Thanks for that anonymous.

    in the Gotenburg study "there were no convincing signs of reduced neurological deterioration in the acyclovir group. " is something to focus on. Perhaps acyclovir isn't potent enough for HHV6. But it might retard progression…. Not inflammation. That's why an anti viral AND an anti inflammatory hold promise IMHO.

    I will continue to post about this with the zealous dedication of a CCSVI convert. 🙂

  • Your welcome Iain,

    Acyclovir targets Herpes Simplex and VZV.

    Correct me Prof G if I am wrong 😀

    So I guess it's no so much about the potency.

    But however this will be going on, maybe they will find something against Herpes Virusus too. These viruses are responsible for so many sh***** errrr….. I mean diseases…… 😀

    So however this EBV thingy is going on, I am quite sure it will have a positive effect. If not for MSers maybe for ppl. with other diseases related to EBV, VZV an other HHV.

  • EBV infection is causal in MS only if it precedes the onset of MS. The following research says that this is really the case:

    http://msj.sagepub.com/content/17/10/1185.full
    "Anti-Epstein–Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel "

    However, while the time of EBV infection can be straightforwardly pinpointed between a negative and a positive blood sample, the same does not hold for the time of MS onset. In fact, no one really talks about the onset of MS but rather about the onset of MS symptoms. The exact point in time when MS begins its destructive action is only a vague notion. No one can ever tell with certainty when a specific instance of MS really begun. Most, if not all, MS symptoms are not MS specific. The is no way to tell if an innocent childhood event can in fact be an early sign of MS. It is well known that sufficient damage must take place in the CNS before first symptoms arise.

    So, unless there is a way to unmistakeably find the exact point in time when CNS damage commences due to MS, there is no point in comparing it to the time of EBV infection.

  • Re: "Acyclovir targets Herpes Simplex and VZV."

    yes that is correct. It does not work against EBV or HHV6.

  • Re: "I will continue to post about this with the zealous dedication of a CCSVI convert."

    Please do; no one can be sure that MS is not due to a virus. Part of the proof or dis-proof is testing anti-virals in MS. Hence the Charcot Project.

  • I am currently trying to get my neuroligist on board wtih prescribing my Acyclovir to help with the positive viruses in my body. I have several but I see that you said Acyclovir doesn't help with EBV…do you know any antivirals that do help with EBV? I think all MS patients should be on some antiviral…if we can get the viruses contained and put back in the box, we might actually feel better overall. What can I do to help?

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