Eight Swallows

Barts-MS rose-tinted-odometer: ★★★★★

How many swallows make a summer? Is eight enough? 

If MS is caused by EBV you would expect there to be clusters of MS potentially linked to a specific subtype of the virus. The best-studied MS cluster is the one from Fjelsø, a small village of 74 families in rural Denmark, where eight people closely linked to each other all developed MS within 13 years of each other. All the subjects had attended the same school. Interestingly all of the people who developed MS had attended the scouts together. 

Danish investigators then typed the variant of EBV these subjects had been infected with and to their surprise, they all had the same subtype of EBV, which importantly was different from controls that were selected from schoolmates and family members. This raises the question of being a scout in Denmark resulted in the transmission of EBV between these subjects. None of these eight subjects reported having had infectious mononucleosis.

What are the chances of getting an eight-person cluster of MS from a group of scouts in a tiny rural village in Denmark? Then on top of this what are the chances of all eight of these people with MS having the same EBV subtype when their family members and schoolmates did not? I suspect the chances are very low.

I don’t think eight swallows are enough to make a summer, but you can’t ignore this cluster when all the other epidemiological evidence points to EBV being causally linked to MS.

The two linked studies below are just a small piece of a large jigsaw puzzle that is gradually being built that I predict will eventually prove EBV is the cause of MS. In the centre of this large jigsaw puzzle are the bespoke pieces for the EBV antiviral and vaccine studies. 

Haahr et al. Cluster of multiple sclerosis patients from Danish community. Lancet. 1997 Mar 29;349(9056):923.

Cluster: We report a cluster of MS in which eight people with verified MS originated from a small Danish community called Fjelsø. All eight had lived within a 2.75 km2 area (2.5 km×1.1 km), where 74 single-family houses, including some farms, were located. The community had a stable population with few migrations into and out of the area. During a 13-year period, all the patients had for 7 years attended the same elementary school with 70-80 pupils. The school had 145 pupils during this period. All those who developed MS had been scouts together, with the older ones being scoutmasters for the younger ones and some of the older ones had also looked after the younger ones. Two cases were siblings and two were aunt and nephew, but MS had not been observed in any of the ancestors of the eight cases or among the school teachers. All cases of MS developed, at various ages and with variable courses, after the eight had left Fjelsø. None of the eight could recall symptoms of infectious mononucleosis.

Munch et al. A single subtype of Epstein-Barr virus in members of multiple sclerosis clusters. Acta Neurol Scand. 1998 Dec;98(6):395-9.

Objectives: Epidemiological studies strongly indicate an infectious involvement in multiple sclerosis (MS). Epstein-Barr virus (EBV), to which all multiple sclerosis patients are seropositive, is also interesting from an epidemiological point of view. We have reported a cluster of MS patients with 8 members from a small Danish community called Fjelsø. To further evaluate the role of EBV in MS we have investigated the distribution of EBV subtypes in cluster members and in control cohorts.

Materials and methods: Blood mononuclear cells were isolated from cluster members, unrelated MS patients, healthy controls, including healthy schoolmates to the Fjelsø cluster patients and finally from persons with autoimmune diseases in order to investigate the number of 39 bp repeats in the EBNA 6-coding region in the EBV seropositive individuals.

Results: We observed a preponderance of the subtype with 3 39 bp repeats in the EBNA 6-coding region both in the MS patients and the healthy controls. In the Fjelsø cluster, all 8 cluster members were harbouring this subtype, which is significantly different from the finding in healthy controls (n = 16), which include 8 schoolmates to the cluster members and 8 randomly selected healthy persons (Fischer’s exact test P = 0.0047), and also compared to all non-clustered individuals studied (P = 0.017).

Conclusion: Infection with the same subtype of EBV links together the 8 persons from the Fjelsø cluster who later developed MS. This finding adds to the possibility that the development of MS is linked to infection with EBV.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

45 thoughts on “Eight Swallows”

  1. Do you think that MS is always caused by EBV? My case would point to the conclusion that it isn’t, I’m 74 and have had MS for 17 years, my sister was diagnosed with Lupus in her 30’s and died from a Lupus related condition in her 50’s. Her son was diagnosed with Crohne’s Disease in his teens and had a colectomy, he’s now 50 and is OK. My cousin was diagnosed with Motor Neurone disease in her 70’s and died from it 2 years later. So in my family’s case it looks like a genetic link, would you think therefore this was a case where EBV isn’t involved?

    1. Pakpoor et al. The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis. Mult Scler. 2013 Feb;19(2):162-6.

      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. 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.

    2. A genetic link does not disprove an infectious cause/trigger HLA-DR is the main MS link, if you have the MS varint gene then EBV is 4 times more infective to theise B cells so a genetic risk to an infectious trigger

  2. The findings of this research could lead to an answer to the million dollar question for me (SPMS) and my only sibling, my sister (PPMS). Why both of us? Having been brought up with plenty of sunshine and on a healthy Mediterranean based diet, non smokers and plenty of exercise, we both know (although never tested) we had symptoms of the EBV in childhood.

  3. I think think this is fascinating and really hope that more research can be done in this area.

    A vaccine for EBV would be fantastic.

    My diagnosis letter says that my blood was tested for EBV, JC etc and there were no signs. Would that have meant just on that day or in general? I’m not sure how these things work. Do you have to do special tests to find out if the virus is still lurking somewhere?

      1. Do you know of someone involved in MS research that got in touch with moderna since they have a RNA vaccine in their early pipeline? I think MS researchers could team up with oncologists given that EBV is also involved in some cancers.

  4. I’m not disagreeing but it’s not only EBV that causes mono, though it is the most common cause.
    Other causes of mono include adenovirus and CMV, plus a few other viruses.

      1. Thanks. My thinking was, I had mono in my teens I remember that and was very unwell but I was not tested for virus at the time, no blood test. I had the white in my throat was very fatigued.

        So I can’t be sure if it was EBV mono or another other mono virus.
        The same I’m sure with other people.

  5. What was the gender ratio? What was their diet? Denmark is a dairy producing country but Freidrikhaven is clearly a port with this name and its locus. Did the study focus only on EBV? Were factors like latitude and diet considered? I know this is very promising research for your theory. It suggests a strengthening of evidence. A creeping forward towards some degree of certainty.
    I recollect that, in the Faerøes, the incidence of MS is lower than in the Orkneys, despite its being further north. The study concludes that the Faerøese diet is rich in fish and the Orcadian diet, rich in dairy, slightly negating latitude.
    .I only throw this into the mix because of the need to hold other components of the context in mind. Still excited by the study though. Fits well with my own disease course.

  6. Hey prof g ! I commented earlier in the week on another post about ebv and my partners infection. she had active mono this year and has ebv anti bodies and i believed this to have been when my ms gave me my first attack , well long story short i went to my gp last week and they done a full ebv pannel and found no antibodies or infection. How would this work ? If we believe ebv to be linked to ms, as i definatley have ms how could i have it without ebv anti bodies ?

      1. Hey my doctor said i had not had ebv and had no evidence of it in the pannel they done which was a full ebv one, but the hypothesis is that ebv infecfion is linked to ms so that doesnt make sense to me ?

      2. How would you suggest they look harder ? They done a full ebv panel and are really good at doing tests, what would yoi suggest ?

    1. We found 32 people in over 1000 subjects who were EBV negative. When we sent these specimens for more detailed testing with more sensitive EBV assays 32 came back positive and one as borderline. In other words 100% positive.

      1. Oh wow i dont think my local gp would be able to do that lol! but if barts would like to do the testing and prove the point i would be happy to supply a blood sample, please let me know who to contact and send it to 🙂

      2. We sent our samples to a specialist EBV lab in Amsterdam. Very few routine labs do immunofluorescence antibody assays; only research labs.

  7. Smaller scale, but myself and a co worker also male, got diagnosed with MS within a year of each other, maybe coincidence maybe not, will never know.
    Good luck with your hypothesis, real life evidence supports the EBV + other viruses being complicit in the development of MS.
    Hopefully a treatment prevails

  8. Is there any posibility that MS can “shift gears” according to repeated infections by EBV? So whilst someone may have only clinically silent MS following EBV infection in childhood, the disease only breaks out fully following re-infection as an adult?

    1. I have no idea. But there is some circumstantial evidence that active EBV infection may be associated with MS disease activity. This is why we want to test antiviral agents as DMTs in MS.

  9. Interesting, thanks for sharing. I am also convinced by this being a big factor. Me and my sister are 1 year apart in age but we were like twins growing up, we did everything together. We both developed MS within months of each other as adults. No other genetic links in our family. We didn’t have mono or glandular fever growing up but I really do think it has to be something we were exposed to or our lifestyle

    1. This has been done using old technology and the results were equivocal. I agree we need to do it with new deep sequencing technology. But which compartment do interrogate; the brain, lymph nodes, blood, saliva, spleen, bone marrow, CSF, etc.. ?

      1. In order of complexity 🙂 I would start easy and (maybe) cheap and then increase in complexity. Lymph, bone marrow, brain are not easy to access, so I would start with blood, saliva and CSF when it is picked in diagnostic routine. I think data size could reach significance in few years for saliva and blood based on the number of new diagnosis per year.

        If nobody start this research we will never know 🙁

  10. Well I know for sure that I’ve had EBV as I went to my GP as I was so tired all the time. Full range of blood tests and was positive for Glandular fever. Never know tiredness like it before or after, I was just exhausted all the time. At the time I was in my late twenties, approx 15 years later received a ms diagnosis. Although I do have fatigue with my ms,currently it’s nothing like it was with the glandular fever and I hope it doesn’t progress to be either. I remember at one point having to sleep all day it was so debilitating, and struggling to haul myself out of bed just to eat on others.

    1. So interesting this connection with EBV and possible genetic links. My mother had progressive MS, so Ive always presumed there was a genetic contributor to my own MS years before it was considered acceptable science. I had prolonged debilitating fatigue with mono diagnosis at 17, followed by some MS type symptoms. About 10 yrs later my Fatigue, MS type symptoms, and many punctAte brain lesions on MRI were labeled “possible” MS, followed after another 9 yrs with a definite MS diagnosis due to an undeniable severe disabling MS flare and lesions on MRI. I’ve believed all along that mono somehow triggered MS in my body, which I was predisposed to genetically. How fantastic if a vaccine or treatment can be created to prevent triggering MS immune response. I can hope it is way to protect those not affected yet, such as my beautiful healthy children.

  11. No smoking gun is needed. There’s a lack of urgency in tackling MS. How much brain damage is a lot of brain damage? I would say any brain damage is TOO much. Let’s start trials with the same urgency as the COVID-19 trials. They said the vaccine would take 2 to 3 years to develop, 9 months later here it is.
    Nevertheless, in my opinion the biggest issue in the HAART trial besides lack of funding would be the fact 90% of all the patients (Placebo&Drugs) would get better since everyone here thinks they’ve caught mono and are huge supporters of the EBV=MS school. So while we need to do it ASAP, we can’t rush it.

  12. I’ve already mentioned this but ascorbic acid (vitamin C) shows a reduction in EBV over time.
    Prof G, surely it would be an idea to research this for MS and the EBV theory? I know pharma probably wouldn’t be interested as there wouldn’t be much profit.

    1. What is also interesting is that RRMSers when relapsing often have low vitamin C levels. What can cause this?
      And also it’s interesting that vitamin C is needed for myelin sheath formation…..

      1. https://www.sciencedirect.com/science/article/pii/S2405650218300078
        A review on potential roles of vitamins in incidence, progression, and improvement of multiple sclerosis.

        ‘high levels of vitamin C can be potentially harmful for patients due to promoting Fenton’s reaction, a reaction that produces hydroxyl radicals in iron-rich tissues such as brain or spinal cord white matter. As the reduced form of iron ion, ferrous, is a part of this reaction, high concentrations of anti-oxidants such as vitamin C can promote it and as the result, may worsen inflammatory state due to radical production [113], [114], [115]. As a result, using vitamin C in therapeutic doses may worsen inflammatory diseases such as MS by promoting the Fenton’s reaction [116]. It is reported that administration of vitamin C, not only shows no protective role against EAE development, but also worsens lipid peroxidation both in vivo and in vitro in the presence of Fe3 +[112].’

  13. As you feel so strongly about it’s, would it be possible for the MS society to supply funding for this, it’s that what the moneys for?

    Respected neurologists have their theory’s and they get out to the test with willing participants.

    Pre existing drugs have already passed trials and if proven to work, if the safety profiles are justified, i don’t see the issue or is it more complicated than that?

    Could the MS society collaborate with other MS charity’s to spilt the costs, the end results the same.

    Hope this is not something that becomes a headline grabber from the charity’s in 10/15 years time going into a trail when it’s known about now.

    People treated with HAART for other illnesses have less chance of developing MS and reports of people on HAART therapy given to people for other illnesses who happened to have MS improved, less disability, less brain and spinal lesions etc. Seams a worth cause to peruse to me.

  14. Clozapine is a inhibitor of EBV reactivation. There was a small MS trial for clozapine, as a DMT for MS in New Zealand but the trial was halted, due to the side effects of falls and dizziness.

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