What do you know about the MS field hypothesis? #MSBlog #MSResearch
“This study below supports anecdotal clinical evidence of many of my clinical mentors and, now as I have gotten older, my own clinical experience; if you have an MS relapse, or attack, in one particular area of the brain or spinal cord you are more likely to have subsequent attacks in this area. This is the so called field hypothesis, i.e. something locally in a specific anatomical area triggers recurrent attacks in the same site. What underlies the field effect? One explanation is that the area that is damaged by the initial attack is more likely to trigger autoimmune responses in future as a result of the local up-regulation of so called second, or danger, costimulatory signals. The latter occurs in response to the factor produced as part of the initial inflammatory event. For T-cells to become activated they need a antigen-specific signal via the T-cell receptor and additional signal via co-stimulation.”
“Another hypothesis, which I favour, is that there is something in the field that trigger relapses. Possibly a virus? Why do I say this? Firstly, when MSers were treated with interferon-gamma, a cytokine that stimulates immune responses, they all had relapses. The interesting thing about these interferon-gamma induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, who was the principal investigator on the gamma-interferon trial, he thought that this observation was a fundamental observation and was telling us something important about MS. It was after this insight and my discussion with Hillel that led me to formulate my leprosy hypothesis about MS (more on this another time).”
“Another observation that supports the abnormal field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab the field (brain and spinal cord) becomes more abnormal and when you let these cells back in they detect the abnormal field and run amok trying to clear up the field. This is what happens with IRIS (immune reconstitution inflammatory syndrome) and PML. When natalizumab is washed out the immune system finds the JC virus and tries to clear it by initiating an inflammatory process. Some of us think that rebound post natalizumab is simply IRIS in response the virus that causes MS.”
“Another observation comes from serial MRI studies that have shown subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears. This suggests that the primary pathology is something in the nervous system that takes weeks or months to trigger a focal inflammatory lesion. The challenge for us all is to find out what this field abnormality is. I think the best chance we have of doing this is to study the brains of MSers on natalizumab. To do this we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. I think this will work because the viral load is likely to be higher in the absence of inflammation. This is why it is so important for MSers to donate their brains for medical research.”
“If you are interested in more musing about the field hypothesis please read my previous post on the subject.”
Epub: Willis et al. Site-specific clinical disease onset in multiple sclerosis. Eur J Neurol. 2014 Sep 8. doi: 10.1111/ene.12564.
BACKGROUND AND PURPOSE: MS is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes was investigated.
METHODS: Employing prospective clinical database data from 1482 MSers who had experienced one or more consecutive relapses were analysed. Using regression analysis, site and symptom of index event were compared with those of first relapse.
RESULTS: It is demonstrated that following disease ignition subsequent relapses may not be random events but dependent on characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event with a similar association observed when comparing by symptoms.
CONCLUSION: These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.
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What is your leprosy hypothesis? You've mentioned this before but ave never really explained what it is …
I can't remember but this is not M's is caused by the leprosy bacillus. Leprosy comes in two flavours tuberculosis and lepromatous in the former you mount and immune response in the latter you don't
Our was very concerned about the possibility leprosy about MS. I do not think absurd viral hypothesis. As much as it has pursued a pathogen as the cause of MS and have not found does not mean necessarily that it is not there causing the disturbance. I repeat that what is happening here in Brazil with the infection Zika virus and Chycungunia related to microcephaly and Guillain-Barré syndrome has much to say to the field of research in MS. The difficulty to close the pathogenic cycle ZV remains; they know that the virus is there, was found in the brains of fetuses and babies with microcephaly, but why not all babies of mothers who had symptomatic infection ZV developed microcephaly? I am not excluding the autoimmune theory of MS, even think that aberrant autoimmunitt action enables other "facets" of certain viruses and bacteria.I think the same parallel can be made a few viruses for MS, especially Epstein Barr, it is found in virtually the entire population but what he is doing in people with MS and who also had infectious mononucleosis? Will other viruses have the same action "trigger" in relation to MS, as seen in Guillain-Barré syndrome, (here in South America 3 virus, Zika, Dengue and Chycungunia can trigger GBS)?
What about when the immune system repopulates after induction therapies such as Alemtuzumab? Will previous areas of damage be inundated & cause problems? And importantly, is there any reason (theoretical or otherwise) to think that if MS returns after an induction therapy (even many years later), that it will do so more aggressively than before?
How does people in long term remission from alemtuzumab/BMT work with the virus+field theories? These patients have passed 10+ years with no disease activity, to me that's good evidence the problem is autoimmune.
they cause problems when you have alemtuzumab. During the infusion the reason you have steroids is to limit them awakening
Yes but I'm talking years later, when the immune system repopulates & steroids are not being given. Is there any reason to believe (based on the theory outlined in this post) that MS will return more aggressively?
This i can confirm, 1 week post alemtuzumab and I got a milder version of a relapse with many "old" symptoms, started having them on 3 infusion day.
I also think that the current zika epidemic and its neurological implications is something worth thinking about. It could lead to new insights. If proven 100% true we will have another virus causing neurological diseases – coincedence? I don't think so!
Many infectious agents have neurological complications : bacteria, fungi, parasites. because a virus may or may not cause neurological problems it is not ipso facto that a virus in responsible for MS.
Yes, many microorganisms can cause neurological disorders. But what has been seen here are 3 Dengue virus, Chycungunia and Zika, and in particular Zika Virus, probably related to the impressive increase of an autoimmune disorder regarded as including much rarer that MS, which is Guillain Barré Syndrome. As far as I know the GBS is considered one of the 80 autoimunitaris diseases known… Making a parallel with GBS why not a virus, for example, may be performing molecular mimicry and triggering breaking MS through genetic/phenotypic interaction?
Oh wow ProfG! You have read my mind! I have always wondered why I have had only balance issues as symptoms of my last few relapses. Lesions were present everywhere in the first relapse, but since then that hasn't been the case. Everytime there is a relapse it's the same balance issues that come back because of a new lesion in the cerebellum. I always thought there was something "abnormal" with that part of my brain. Are there any imaging studies that could be done on these abnormal fields?
Very interesting. And this sort of theorising may offer an explanation as to why those people whose early symptoms include optic neuritis tend to show less disability?
"Tysabri rebound" logic seems to imply that any immunosuppresive or immunomodulatory DMT is harmful in the long run: immunosurveilance is muted, and whatever virus is causing damage continues to do so unchecked. What's wrong with this conclusion?
If love to hear Prof G's thoughts on this also.
An apparent flaw in your conclusion is that those who get on immunomodulatory therapies early, do better in the long run than those who are not.If the immune system was effective at controlling the virus, and immunomodulatory therapies impeded it from doing so, thereby enhancing the MS damage, the opposite would be true.
Not necessarily. It would depend on how the virus (or pathogens) manifest. If, say EBV, replicates through forcing the immune system to replicate its host (b cells) then immune modulators would have an impact on dampening the disease activity.
Sure. But then immunomodulatory would not be harmful to disease course in the long run, which was the question asked. Rather, it would be beneficial (which is what the clinical trial data suggests).
If the virus replicated through B cell replication, then immunomodulatory therapies will be beneficial in controlling it, not harmful to the disease course. This was the question asked. In support of this, the trial data shows people on these therapies do better. You could argue that there are harmful side effects to tampering with the immune system, but the question here is around impact on disease course.
"If the virus replicated through B cell replication, then immunomodulatory therapies will be beneficial in controlling it, not harmful to the disease course. This was the question asked. " -Thank you, this indeed addresses my original question
Returning to Tysabri, if the "virus" can run amok in the CNS why don't we exhibit symptoms of said virus? This line of thinking would then lead to strong reasoning for extended dosing. The rest makes sense.
Firstly, why wouldn't the virus be detectable in the CSF of a patient who is undergoing natalizumab rebound? Can the agent be detected by elevated IgG in addition to PCR?secondly, maybe the immune reconstitution inflammation is targeting an agent that is not the cause of MS but only appeared following immune suppression by Natalizumab. Also, IRIS can occur in the absence of an infectious agent.
"Some of us think that rebound post natalizumab is simply IRIS in response the virus that causes MS." Although it is not possible or difficult to obtain tissue specimens from the CNS during IRIS is it possible to use MRI as an indicator of the type of IRIS post Natalizumab? Viral-IRIS has distinct MRI from bacterial or fungal IRIS or from non-infectious IRIS? Because immune reconstitution inflammation is more common in HIV patients on HAART can we learn from these MRI profiles?
My wife has relapsing remitting Ms. Diagnosed about 23 years ago…My question is….we are planning a trip to St. Thomas in April, and I can't find any info on zika affect on Ms patient. Should we cancel our trip?
Excellent post. That has always been my hypothesis!