EBV / MS Think Tank

[bromley]

Dear all,

On Friday I am attending the EBV / MS Think Tank which is taking place in London, UK. The event starts at 10.00am and runs to 5.30pm. The morning sessions are presentations covering a range of issues such as "EBV and other putative autoimmune diseases", "Immunology of MS and EBV", and "Anti-viral agents targeting EBV". It's being led by Dr Gavin Giovannoni, Reader in Clinical Neuroimmunology (a recipient of one of the large NMSS grants announced last August which are focusing on neuro-protection and repair).

Over 40 of the great and the good from the UK MS field are attending. Most have the title Professor or Reader etc! And then there's me!

How I got on the list (apart from being a pest) I'll never know. I hope to stick around until mid-afternoon, but do not think I can add much to the breakout groups examing subjects such as "Epidemiology and Genetics".

I'm not sure how the results will be reported i.e. whether Dr Giovannoni will publish something on this issue and I'm not clear what exactly will be presented i.e. whether the aim is to provide data / evidence to demonstrate a definite link between EBV and MS.

I will clear my lines with Dr G and report back in a general way on the event. I hope it proves to be a step forward in the understanding of this disease. Of course EBV may not be the only culprit - some cases may be caused by other viruses or bacteria. But Dr G is a very evidence based researcher and would not be organising such an event and inviting so many specialists in the field without good cause.

Of course, if EBV is shown to be a trigger / cause, my interest is what can be done about it. Is it the virus that causes the 'sick micro-environment' which leads to the death of the myelin producing cells?


I hope something positive comes out of the event. I need cheering up as my football (soccer) team (Arsenal) were beaten by Barcelona in the Champions League final on Wednesday.



Ian

[gwa]

Ian,

There have been a number of articles about the possibility of a cause and effect between EBV and MS. I have never seen anything that told whether a treatment could be developed for MS if it is caused by EBV. I hope that you can glean some information at the meeting about this.

Good luck.

gwa

[Shayk]

Ian

I have every confidence you'll be a great ambassador for people with MS at the EBV/MS think tank. I think it's great you were invited. I'm sorry your soccer team lost but maybe you'll manage to have some fun Friday. I don't know if those neuro types are fun or not though. Maybe not now that I think about it.

Take care--we'll be waiting to hear from you.

Sharon

[dignan]

How I got on the list (apart from being a pest) I'll never know.

At first I just assumed you had some VERY incriminating photos of this Doctor Giovannoni. Then it occured to me that maybe he knows about your on-line activism and is counting on your presence to spread the word in the patient community. I have no idea really. Could just be that you're a hell of a guy.

[Degerlache]

Stick to the numbers !

There are some publications suggesting that nearly all (if not all) MS sufferers are infected by EBV while for the rest of the people the infection level is only at 95-97%. The difference of the 5 à 3% may not look so much, but if it would be confirmed on large scale studies, such a small difference would become "statistically very significant", meaning it can not be explained by hazard, meaning EBV is somehow involved.

My suggestion is to put the reasearchers and the statisticians at work and prove statistically that EBV is implicated.

Best Regard,
Degerlache

[Jaded]

Ian

Being a Highbury girl, I am with you on the footy tragedy.

I hope that today goes well. As someone already said, I am sure you will be a great ambassador. You are very knowledgable on this subject, and given the breadth of research, that is some statement!


I look forward to some good news.

J.

[bromley]

Dear all,

Just returned from the EBV Think Tank - missed the breakout groups as they were a bit too techy.

There were 40 attendees - three of us with MS. I sat next to Professor George Ebers. Pretty much everyone was a medic (neurologist, immunologists, virologists etc - most professors or consultants).

As an overview - EBV was not proved to be the cause. The case was put forward that it might be the cause (in combination with genetics).

There were various presenters on different issues. A summary of what was presented is as follows.

Dr Giovannoni put forward the case for EBV causing MS (in those with genetic susceptibility). Some of his key points were:

- The distribution of MS across the world is similar to the distribution of Glandular Fever (caused by EBV). Glandular Fever same as Mono.

- Every paper on EBV / MS has been 'positive' i.e an association has been found.

- 100 per cent of people with MS test positve for having EBV. For the control group (not have MS), 90 per cent had tested positive for EBV.

- For the 10% of the population who do not get infected with EBV, they are pretty much protected from getting MS.

- Various meta-analyses have been undertaken (pulling together different studies and statistics) which showed that if you had glandular fever / mono (i.e. EBV infection rather than asymptomatic EBV) the risk of getting MS was x 2.5 those who had not had glandular fever / mono.

- Various studies (nurses, US Army personnel, Swedish study) had shown a link between EBV and MS.

- 3% of people diagnosed with MS are children. In Turkey, a study of children with MS showed that 85% had been infected with EBV and 40% in the control group (those without MS). The children were tested for other viruses but there was no difference in the MS and non-MS groups.

- A similar study in Canada of children with MS showed 80% were infected with EBV and just under 40% in the control group.

- The next bit got very techy discussing what EBV might actually do - molecular mimicry, infect B cells which are immortal and present auto-antigen etc etc.

- Clinical relapses might be due to EBV reactivation in the 'periphery'.

- Mention was made of 'epitope' spreading.

- EBV might also infect myelin making cells (oligodendrocytes).

- Dr G mentioned the Barnett and Prineas work where the 17 year old woman died from a lesion in the brain stem and they undertook a brain autopsy very soon after death. There was evidence of oligodendrocyte apoptosis) and no inflammation (immune system involvement). However, Dr G said that there were other lesions which were classic MS involving T cells and inflammation etc.

- There is also a theory of a dual viral infection (I got lost on this one).

- The hygiene theory was also discussed. Having older siblings made no difference to one's risk, but having younger siblings reduced the risk. The general sense was that being exposed earlier to viruses might be better than be infected later in life.

- Some discussion of the MS clusters / outbreaks. There is a study of a school in rural Denmark where there has been a cluster of cases.

- EBV was the most common virus in the world. But in developing countries usually get infected younger. In China most get infected with EBV by 5 and there is very little Glandular Fever (mono), which tends to come with later EBV infection.

There was a Danish presenter who talked about the Macroenvironment and EBV. The main points were:

- MS a combination of genetics (everyone referred to HLA) and environmental factors.

- He repeated some of the previous mssages : EBV has a world wide distribution, vast majority of people get infected, lower risk if get EBV at younger age, if you move from a high MS risk country to a low risk one before 15 you adopt the low risk of the new country (and opposite applies).

- He discussed MS outbreaks in the Faroe Islands and a County in Norway and a town in Sicily. EBV might be the culprit. But he said that the probability of a cluster was 5% (I assume this means that a cluster could happen by chance).

- He showed a graph of people in Denmark with MS (there is a Danish MS registry). There has been a 'true rise' in incidence among women (but not men).

- In his view there might be other causes that are more importnat than EBV. Epidemiology cannot prove or not prove EBV causes MS.

Professor George Ebers talked about Genetics and the micro-environment:

- He showed a picture of Australia where incidence was higher in the South. In France the incidence of MS was much higher in the North.

- He ran through the various risk of MS among different sorts of twins, siblings etc. The risk of MS for the general population was 1:1000, but 7:1000 if your cousin had MS.

- The greater the genes shared with a relative with MS the greater your chance of getting it.

- Brief discussion of birth month (10% higher risk in May and 10% lower risk in November). Nobody seemed to know why.

- He got very techy with the genes relating to the different chromosomes.

I asked him before coffee what his work could lead to e.g in terms of better treatments. He said that for some diseases a single gene had been identified but no real progress in treatment . For MS he thought the interaction of different genes might lead to molecules which do the damage. These could be blocked without affecting the immune system. He was fairly positive about this (but don't quote me as it's my interpretation of what he was telling me).

Another expert talked about non-genetic MS associted risk factors. In his view Parkinsons tended to affect those with a low-risk life-style (non-smokers, drinkers etc). MS was the opposite. Tended to affect risk-takers (smokers, those who had many sexual partners, heavy drinkers, drug takers). As someone who has lived like a monk all my life I was less than convinced by this!. He talked about Vit D and said that MS tended to affect fair-skin people who did'nt go out in the Sun (I nearly said that it was the bloody medical profession who told me to slap on suncream!). Apparently, skin cancer is low in MS patients!.

He then spoke about MS incidence in 'strict' societies. In some Arab countries (non-alcohol, covered up) incidence of MS was very, very low. He also mentioned the Mormons in Utah and a study which showed that the incidence was much lower than a neighbouring county of non-Mormons. The stats looked impressive but I was that near to shouting Alan Osmond. But the price they pay for clean living is more Parkinsons! (you just can't win can you). I was not impressed by this presentation.

The best presentation by far was from a virologist who specialised in EBV. The main points were:

- EBV is a unique virus.
- Most common virus (silent in B cells).
- Once infected, you are a life-long carrier.
- Infects B lymphocytes [note: Rituxan targets B cells and is in trials for MS]
- EBV is associated with tumours.
- It lives in B cells but is tightly controlled by T Cells.
- It's a persistent infection controlled by T cells. The problem might be a defect in T cell regulation.
- Roche was looking at an EBV vaccine. In a Phase II trial for Glandular Fever. Anti-virals have not been particularly effective.

The next presenter discussed EBV and other auto-immune diseases such as Rhematoid Arthritis and Lupus. EBV as a cause of RA had come in and out of favour. Data did not support a connection with EBV but seemed to be a link with Lupus and EBV. 99% of those with Lupus had been infected with EBV compared to 94.5% for controls.

Someone from GSK talked about anti-viral therapy. Some trials had involved MS. Acyclovir led to 34% fewer exacerbations but not statistically significant.

The final presentation prior to my departure was Dr G talking about causation. He theorised whether preventing EBV infection would prevent MS.

- He ran through other diseases such as lung cancer where the cause was generally smoking but had taken years to be accepted - way after the medical research. Causation was not a black and white issue. Needed criteria for causation. Need more meta-analyses to see if positive associations consistent. And to assess the strength of the association. Also needed to understand the interaction between EBV and genes.

- He talked about the migration studies. He mentioned Guadalope which was low risk. But those who had gone to France and returned to Guadalope had brought high risk with them and incidence up. Also MS on the increase in the Caribbean where those who moved to the UK had returned and brought high risk with them (? bringing back a virus).

- More needed to be known about the immune response to EBV and whether a strong response could predict MS.

- If EBV caused MS then it would need to fit with the other observations - worldwide distribution of MS, why the current drugs that have some effect on MS might be affecting EBV.

- An EBV vacination might be high risk as may not be life-long.

Summary

It was an interesting day but as with all thing MS - no real answers. The complexity of this disease is a major issue - genes / environment. Dr G put forward a strong case but further research / studies will be required. The real positive was talking to Dr Ebers who seemed pretty upbeat about the possibilities once the genes are identified. On the downside, the brainpower in that room was immeasurable, but I don't think one of them really has a good idea of what this disease is. Thankfully, Dr G is very driven and if anyone is to make some headway I would put money on him.

Hope you find this of some use, even though nothing definite emerged.

Ian

[gwa]

Ian,

Thanks for the narrative about the discussions at the conference. It does sound like the cause of this disease will remain a mystery for a long time.

gwa

[Jaded]

Ian

Thank you for such a comprehensive and readadle report.

It is sad that they are not near an answer, however it is positive, as you say, that such committed and talented people are looking into this disease.

We can only hope.

Thanks again.

J.

[bromley]

Dear all,

EBV might still be the cause - but proving causation is difficult. In my case, I had a bad bout of Glandular Fever at 15 but perfect health until first MS attack at 39. Perhaps I got re-infected or my T Reg cells went wrong and the virus kicked off and started the cascade of events (this is all assuming that EBV is involved).

In some ways identifying the cause will be usful for future generations but may be of little benefit to us with it now. Instead what needs to be identified is what causes the damage - the sequence of events and the immune cells involved. Trials of drugs such as Daclizumab (where T Reg cells increase) and Rituximab (which depletes B cells) should throw new light on the mechanisms / cells involved.

But I was left slightly confused by some of the discussion on genes. I thought the Vikings were to blame but one of the presenters talked about people from India (low risk of MS) moving to Canada and then having the same risk of MS as other Canadians.This certainly points to an infectious agent being involved in some way and individuals losing their protection (whatever that is) when moving from a low risk to a high risk country.

In terms of prevalence - I see that the Canadian MS Society site reports that the estimate of Canadians with MS has increased from 50,000 to 70,000. The Australian MS Society reports that MS incidence is rising by 8 per cent a year. In some areas - Scotland and Colorado, the prevalence is 1:500. Given these figures, MS doesn't appear to be so rare. As a bigger market for treatments emerges, hopefully the drugs companies will invest more to come up with better treatments.

Ian

[Arron]

Ian, thank you for a most excellent summary of intriguing research. It is so typical with MS that no answers could be reached, but the puzzle pieces (and there were obviously many of them presented her), are starting to be elucidated. How they fit is the next step.

[Degerlache]

Thanks for this fantastic piece of information.

Proving causation may not yet be possible, but using basic logical techniques some conclusions can and should already be possible I beleive,

as eg.

If 100% of persons with MS test positive for EBV, while only 90% of the overall population tests EBV positive and
if the 10% of the EBV negative persons are 100% MS negative,

only 1 logical conclusion seems possible and this conclusion is that EBV is a "necessary but unsufficient condition" in the development of MS.

One can not already go so far that a cause is identified but a step in that direction should be possible if the above assumption are correct.

Degerlache.

[bromley]

Degerlache,

I agree that this is a very interesting area.

The data on children with MS also points to EBV as having a role. At the think tank, mention was made of further research coming out this year showing a strong association.

Of course it's all complicated by genes. There appears to be two issues relating to genes (i) suceptibility genes (ii) genes which influence how the disease progresses i.e. mild, severe. During the discussions the claim was made that African-Americans often have a more severe course. I assume this related to genes!

Ian

[mrhodes40]

Great post and here is another thought to add to the works:

RESULTS: Serological evidence for remote EBV infection was present in 83% of pediatric MS patients compared with 42% of emergency department and healthy controls (P<.001). Five pediatric MS patients were negative for all 3 EBV antigens. Pediatric MS patients were less likely than controls to have been exposed to herpes simplex virus (P =.003), while seropositivity for cytomegalovirus, parvovirus B19, and varicella zoster did not differ between MS patients and controls. CONCLUSION: These results suggest an association between EBV infection and pediatric MS

From the pediatric MS study on relationship to ebv. based on this,
it appears that MS is not 100% associated with EBV as was suggested by the other paper. Clearly since kids (God bless them) are the youngest persons with MS, unless we believe it to be a different disease, their profile should be the least impacted by other factors and later infections and thus the most pure data. Of course MS could be several diseases

But one other thing that is true is that once one has had EBV the b cells are infected and carry it for life. This paper was on serological evidence not CSF so my comment here may seem immaterial but as other papers point out the EBV presence in CSF I'd like to point out that it may be possible that the "MS process" whatever it is brings thusly ebv infected b cells into the CNS and thus causes the apparent issue of CNS infection.

I have RA and there was excitement about EBV being causal in that arena some years back as it was present in the joints of people with RA very frequently and not in healthy joints . Since b cells are infected for life once one has EBV, b cell presence in joints with active immune involvement was eventually thought to be the cause of the presence of the ebv in the joints rather than causal of the RA.

Back on to the brain, activated microglia "invite" b cells into the CNS

Despite what appears to be a marvelous strategy for keeping microbes out of the brain parenchyma, when looked at from the perspective of the large number of viruses, bacteria, fungi, parasites, and proteinacious pathogens that are "neurotropic," i.e., that have a predilection for infecting the nervous system (Table 3), the brain could be considered an "immunologically underprivileged" organ. Thus, an evolving concept of microglia is that when it comes to defense of the CNS against invading microorganisms, they do not function on their own but rely on their ability to "call in the troops," i.e. lymphocytes, monocytes, and neutrophils

from this terrific review on microglia here http://cmr.asm.org/cgi/content/full/17/ ... _Microglia.

My bias is that CPn or another stealth pathogen like Lyme is a plausible cause in MS and therefore ebv presence is not at all unexpected as a secondary phenomenon since it causes lifelong infection of the b cells. in my view it is possible that the microglia, activated by apoptosis of oligodendrocytes caused by Lipopolysaccharide (LPS) presence which is secondry to death of a gram negative bacteria like chlamydia pneumoniae, call in the troops of the peripheral nervous system to help clean up the mess and thus ebv is brought along by the b cells entering in response. You could then culture the ebv in the CNS in much higher numbers than in healthy people.
Even if you believe the autoimmune idea then the presence of b cells in the CNS means that an ebv infected person will have ebv in the cns.
It is a very complex issue
Marie

[bromley]

Marie,

The issue of children with MS was discussed at the Think Tank. Apparently, a diagnosis is more difficult when dealing with children. Some children get a clinically isolated syndrome and do not go on to develop MS or develop another neurological illness.

Another point made was that some cases of chronic fatigue syndrome end up turning into MS. Whether the fatigue was MS to start with who knows. But I think I've read that CFS can be viral.

On the genes front - I already said that there were likely to be genes which make one susceptible and genes which affect the course of the disease. Interestingly, reference was made to families with more than one case of MS. Examples were given of one sibling having RR and another PP - I still don't think the experts are clear whether its a different version of the same disease of a different disease altogether.

As you say Marie - this is very complex probably involving various pathogens.

Ian