The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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Summary of Research

Discussion in 'General ME/CFS Discussion' started by dlap4, Aug 8, 2014.

  1. dlap4

    dlap4

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    Hi guys,

    This is my first time posting but for a month now I've been reading a bit on CFS/ME and I think it's time I finally ask a question.

    Some researchers say that CFS/ME is "3" different illnesses (I think Klimas said this in 2009 with no elaboration I could immediately find). Others say "10-15" different illnesses comprise CFS/ME, with no elaboration either. They say they present in a similar way.

    What exactly do they mean? Is it publicly available how these subsets are defined? Does anyone have a guess? How exactly could 10-15 different illnesses possibly cause the same thing? Do they just mean that there's 10-15 different TRIGGERS? Or do they literally mean very different processes are happening in different sufferers bodies. I don't really understand.

    Is there some sort of summary of all the research to date? I'm confused how all the different findings mesh together and how they possibly could.

    An example of a complete contradiction I've come across is that some people say mitochondrial dysfunction is from oxidative stress from low blood flow. (Newton I think?) But then another doctor in the past has suggested low-blood volume and low blood flow are reactions to cellular acidosis from an already existing mitochrondrial dysfunction. (Cheney I think)

    So which is it? It can't be both. Either mitochrondrial dysfunction is a result or cause of POTS/Low-Blood-Volume/Low-Blood-Flow. It can't be both.

    I'm very confused when I come across such contradictions and there seems to be little chatter nowadays (perhaps there was more in the past) about how such contradictions could be resolved.

    There are many other findings like low cytoxicity of killer T-Cells and NK cells and low molecular weight RNase-L. One suggests a TH2-dominated humoral immune activation causing TH1 suppression while the other suggests some sort of hypoimmunity causing the TH1 response's inability to clear viruses. Which is it? Can it really be both? What are your thoughts? What is the latest news on these contradictions?

    So if someone could link me to a recent summary of all this research I'd be interested. It's hard to see how all this fits together coherently without contradiction. There's so many findings from the past and new ones now: POTS/Low-blood-volume/low-blood-flow/cellular acidosis/muscle cell acid buildup/mitochrondrial dysfunction/diastolic dysfunction/TH1 suppression/TH2 activation/microglial neuroinflammation/etc.

    I'm confused!

    Thanks if you can help I'd appreciate it as an interested layman.
     
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  2. MikeJackmin

    MikeJackmin Senior Member

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    I'm a layperson, so others here might be better informed.

    My understanding is that CFS/ME is a syndrome, literally, a collection of symptoms. Different diseases can present with very similar symptoms, so whenever you have a situation like ours, where the cause is unknown, it's possible that different CFS patients are actually suffering from entirely different diseases.

    There are two good reasons to think this is the case. The first is that there are so many differences among us - for example, some of us have gotten sick after a specific event, while others sort of gradually drifted into trouble. Some recover, some stabilize, some just keep getting worse. Some respond to certain therapies, others don't.

    The second reason is that, if we are in fact suffering from multiple diseases, it would explain why the research is just all over the map. If, for example, a mitochondrial disease is responsible for the illness experienced by 15% of us, that small group gets mixed in with the remaining 85% who have some other problem. A researcher who is trying to find evidence of a mitochondrial issue will never get a good fix on their data - the signal just gets washed out in the noise.

    This is made worse by the shocking complexity of the human body, and our tiny, tiny grasp of what's really going on in there. A virus might cause an autoimmune dysfunction that results in an inflammation that disrupts an enzyme that causes the mitochondria to go all sideways. You might see little bits and pieces of this evidence and draw dramatically different conclusions as you go. And of course, along the way there will be a hundred red herrings and dead ends and simple errors to help confound things even more.

    There are lots of people who think they have a pretty good idea what's happening, but sadly they don't much agree with one another. We just really don't know - we have lots of very interesting leads, but nothing in the bank, not yet.

    If you'd like to see some of what's going on, you can visit here:

    http://www.ncbi.nlm.nih.gov/pubmed?term=chronic fatigue syndrome

    This will list many of the papers being published on the topic. The further you look back, the wider the net grows.
     
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  3. dlap4

    dlap4

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    So do you think that no one has defined any subsets yet? Klimas in 2009 said she thinks it's 3 to seven different illnesses. http://phoenixrising.me/archives/61

    Are you aware if these were ever defined in any way? Did she ever define them even roughly?

    What I'm looking for doesn't have to be a consensus among researchers, I'm just wondering if any researcher even by themselves has made the picture a bit clearer with some classification.


    An example of what I'm looking for is what Julian M. Stewart did for POTS. Him and his team at NYMC defined 3-4 subsets of POTS, while previously there had only been 2 very fuzzy and inaccurate and meaningless ones. He defined them based on an empirical marker (not necessarily an exact biomarker, but still it had some accuracy to it).

    The empirical marker was blood flow. So he defined a High-Flow-POTS, a Normal-Flow-POTS and a Low-Flow-POTS. He gave estimated percentages of their contribution (just estimates, there was no need for exactness, just SOME clarity was required) He also hypothesised the etiology/ultimate cause behind each case.

    High-Flow-POTS was suggested to be long-fibre neuropathy from autoimmunity nerve damage.

    Normal-Flow-POTS was suggested to be connective tissue disease related such as inherited Elher Danlos Syndrome.

    Low-Flow-POTS was suggested to be related to levels of things in the blood. One such thing was Angiotensin-II and ACE2 enzyme. He found that Low-Flow-POTs could be split in two. 50% had high Angiontensin-II and low NO and the other 50% didn't have this.

    Of course these were still fuzzy subsets but there was SOME accuracy to them. The suggested etiology was not scientfically linked by study but still there was some reason to suggest these causes and so it was mentioned. Only one had a real blood biomarker (levels of angiotensin-II) but there was some rough empirical definition for them all.


    So when it comes to ME, I'm wondering if anyone has done this?

    It doesn't have to A) be a consensus opinion, B) be exact to 1% in describing the incidence, C)be based on a firm biomarker, or really have any firm scientific proof at all. Just I'm wondering if anyone has ever attempted a rough (it can be very very rough) classification scheme of fuzzy (even very fuzzy) subsets. Has anyone also ever attempted to tie them to an etiology (it doesn't have to be scientifically proven firmly but just suggested).

    So really I'll take even the most rough and fuzzy classification scheme as long as its comprehensive and summarises what research has shown thus far. It can even be from a layman! Just I'd appreciate someone elses overview of this illness rather than my own echo chamber.

    I heard from someone for instance that 30% report they feel better on Rituximab, so she assumed that 30% of ME must be autoimmune. It could even be higher. But what would the other causes possibly be? Has anyone attempted a comprehensive summary of all these tidbits?

    Thanks. If a researcher like Klimas has ever gone into what these 3-7 conditions could possibly be at all (even just mentioning 3 out of 7 for instance. I'd appreciate it. I'm still making my way through these archives. As you see this was the first one in 2009: http://phoenixrising.me/archives/61 Thanks for the link to pubmed by the way but I assume a highly rough summary was never peer reviewed. I'm not really looking for a peer reviewed summary since as you say the highly fuzzy and "all-over-the-map" nature of ME research is not conducive to an overview that's scientific and exact. But has ANYONE shed any light on potential subsets before even in passing to the layman?
     
  4. MeSci

    MeSci ME/CFS since 1995; activity level 6?

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    Good question, @dlap4, and a fundamental and enormous one!

    There will always be different theories, although the picture is indeed fuzzy for ME. There is a circular problem in that there are different diagnostic criteria so that the patient groups studied will not always be the same types of patients, and because the criteria are rather vague (due to a lack of biological data), the groups will be internally heterogeneous. But the criteria are themselves based on scientific evidence, to a greater or lesser degree.

    Some theories are complementary, for example leaky gut may cause autoimmunity and also nutritional deficiencies, and the autoimmunity may cause mitochondrial dysfunction. It can be an issue of how far you go back in the chain of causation, and also there are likely to be numerous roads to leaky gut in the first place. Leaky gut may allow pathogens to lodge in our cells, and the pathogens may be causing problems when reactivated for any reason.

    Stephen Holgate looks at the possibility of "twelve to fifteen different 'causal pathways'" in this thread.
     
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  5. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Thats a good question and something even the researchers dont know. I think at the moment putting people into sub groups is very rough as even testing for viruses and which ones are active or not is still very up in the air.

    My short answer is its a cross between an immune defiency, chronic infection/s and autoimmune disease with varying levels between each of them per individual.

    I think things like oxidative stress, adrenal dysfunction, mito dysfunction maybe all secondary flow on effects??

    If u have a good doctor they will find abnormalitiies in tests its just that they might not be unique to just cfs. I think the saying that all your tests comeback normal is sort of wrong as ones doctor probably isnt looking deep enough.

    I think go after these abnormalities and try and treat them, the secondary issues needed to be treated but one might not see any positive results until the infection/immune/autoimmune stuff is treated?? Then to complicate things add in the pots/oi stuff.

    Sometimes the only way to know your in a sub group is to be in one that can be treated and if you respond then your in one of the lucky sub groups. EBV is a common one, maybe lucky if thats the only issue and then get a good response from say valtrex. But i think if one doesnt respond after something like that, dont forget say antivirals but leave it on the back burner and search for something else that may be going on.

    Its search, trial and error with treatments, mix, stir and do it all again. Until a definite cure comes along and even currently if you respond well to a certain treatment, we always seem to be chasing our tails.

    Also its been mentioned before but maybe its like cancer in that it can effect different parts, organs etc, eg prostate cancer, breast cancer, bowel cancer, they all have different biomarkers and treatments. Maybe cfs/me is like this in that we all have this immune dysfunction it just depends on where we get hit??
     
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  6. DanME

    DanME Senior Member

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    Hi,

    the short answer is no. As far as I am aware of, nobody came up with a conclusive (or even speculative) definition of different subsets. A lot of doctors and researchers have speculated about the possibility of different diseases or subsets, but nobody came up with anything specific.

    The reason for this is quite simple. Until now, nobody knows for sure, what triggers ME/CFS or what the underlying pathology is. There are a lot of theories around (some more compelling, some less, some are just nonsense). Be aware, that the last thirty years research was mostly driven by ambitious doctors, who worked alone or in a small team. This led to a lot of different theories, which all sound quite compelling, but often conflict which each other. Only recently more and more universities got involved and collaboration began between the different departments and physicians.

    The last couple of years more and more serious and well made research papers have been published about different aspects of the disease.

    What we know for certain from all the patient stories, they are at least two different subsets. A sudden and a slow onset type. Usually the sudden type starts with a heavy flu-like disease. The slow onset type can start with flu like symptoms, too, but sometimes comes just out of nowhere and usually progresses over time.
     
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  7. MikeJackmin

    MikeJackmin Senior Member

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    Well, this layman can share his opinion, FWIW.

    Scientists sometimes have a pretty good handle on things. Sometimes they have a fuzzy grasp, but at least they have something. And sometimes they have nothing.

    When they have nothing, they don't say "sorry, we got nothin'", especially if it's an important thing, and a thing that have been working on for decades. What they say instead is that the problem is complex and multidimensional, and they have a half-dozen different approaches that might be promising, and that might even tie together in interesting ways. They are speaking the truth, too, but that's what it's like when they just don't know. "Not knowing" does mean a lack of good ideas and interesting clues and hard work. It just means the hopeful things don't really pan out, because the prescriptive and predictive power that comes from knowing things isn't there yet.

    If you want, I'm sure you could a few examples of people who have tried to classify this disease, and you might find that one of these classifications is more popular than the others. And you will find these things, regardless of how much value there is to any of the classifications at hand. Clsssifications and consensus are equally frequent in places where some of the truth is known, and in places where everything is still a mystery. If you don't agree, ask a room full of toddlers where rainbows come from. You'll hear no shortage of ideas, and some will be quite popular.

    If this sounds hopeless and defeatist, it's not. It means we have a blue sky in front of us and the truth might lead in any direction. There's no reason to narrow the focus too soon, to put too much faith in ideas that aren't yet worthy of it.
     
  8. dlap4

    dlap4

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    Hmmm. I guess Daniel is right. Research was so fragmented into individual silos until recently. I hope someday soon some worthy ideas come about now that there is renewed interest (due to the XMRV I heard there is renewed interest).

    By the way I am partial to the autoimmunity theory, but if there is indeed a huge cohort with hypoimmunity causing chronic viral reactivation then can anyone tell me if any immune defects have been found in these people? An immunological workup is hard to get I know but it's not impossible. Here is a list of the immunodeficiencies you can have that wikipedia compiles: http://en.wikipedia.org/wiki/Immunodeficiency

    I am up to speed on other autoimmune conditions and are aware of many people with them getting an immunological workup and the tests finding for instance complement system deficiencies. They are then put on IVIG and are feeling much better.

    So the question is, if ME has a hypoimmunity/immunodeficiency aspect why don't we ever hear of people being diagnosed with a primary immunodeficiency? Is it a different type of immune deficiency other than the ones listed on wikipedia? Because if it was a simple primary immunodeficiency I would have thought it could easily be found in an immunological workup in this day and age and treated with IVIG like is usually prescribed.

    So hypoimmunity and chronic viral reactivation theory doesn't really make sense to me at the moment, because why can't it be detected. And if it is detected do these people get IVIG and feel better? I haven't hung around these boards much to hear many stories but surely I would have heard if immunodefiency diagnoses and IVIG treatment were been given to people with ME. It's hard for me to accept other subsets of ME than a basic autoimmunity cause when I never hear of any actual diagnoses of things like immunodeficiency and treatment of it. Hopefully you guys can tell me if indeed there does appear to be a subset with http://en.wikipedia.org/wiki/Primary_immunodeficiency.
     
  9. MeSci

    MeSci ME/CFS since 1995; activity level 6?

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    ME doesn't appear to be a classic immune deficiency/hypoimmunity issue but an immune dysfunction, i.e. our immune system is disordered, with some elements in excess and some in deficit.

    Have you looked at the threads on the drug Rituximab? The posts by Professor Jonathan Edwards are particularly good.
     
  10. MeSci

    MeSci ME/CFS since 1995; activity level 6?

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    My advice, based on experience, is that if a doctor says that all test results are normal, you should challenge him/her, perhaps on tests that you expected to be abnormal.

    The reason I say this is, as I have said elsewhere on PR, that my current GP once told me that all my results were normal, and I was surprised, as one test I had specifically asked to be done should have been abnormal by my reckoning.

    He then confessed that he didn't know if that result was normal or not, and proceeded to Google it.

    Amid continuing bafflement, I went away and did some more research of my own, and it was indeed hard to tell anything concrete from that test unless it was done in tandem with a few others. However, the result was consistent with my theory - that I was losing a substantial amount of sodium in urine despite being hyponatraemic which, if my body was controlling levels properly, would surely not happen.

    This was crucial to diagnosis and treatment.

    But the main point is that the GP was not telling the whole truth and did not actually understand all the results.

    I had another GP tell me over the phone that he didn't know what units my results were in. Much later I got a copy of them, and the units were shown clearly next to the figures. :rolleyes:
     
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  11. WillowJ

    WillowJ คภภเє ɠรค๓թєl

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    There are some speculative subsets.

    Kerr has done some work in this, as has Jason (can't find a link to his subsets paper). Montoya and Lerner with treatment relevancy. Klimas and Hokama and Behan and Natleson with possible lab & imaging tests. I think Baraniuk was talking about looking for this.
     
    Last edited: Aug 11, 2014
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  12. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I guess it depends how one puts them in sub sets. Do we put people in acute vs slow onset. Maybe different infections or different immune tests, elevated lymphocyte subsets or low lymphocytes. Nk dysfunction with normal nk numbers or lower numbers. Those with low or high neutrophils. Elevated B cells. Inflammatory markers like crp and or esr. Than combinations of these. Oh different cytokines too.

    Symptoms I think need to be limited to a few that can separate some as in tired but wired with insomnia and then those that sleep 20hrs a day. Pots/ oi. Those with different pain levels.

    Maybe as testing improves groups can be narrowed down. Getting to this stage has to help docs tailure the appropriate treatment with less educated guesses? ??

    It's an interesting subject
     
  13. xchocoholic

    xchocoholic Senior Member

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    Apologies if this was mentioned, celiac disease is known for causing auto immune diseases. The NIH states that celiac is being misdiagnosed as cfs, ibs, etc.

    Most of my diagnosises that I've googled have been found in other celiacs. There is an abundance of studies on celiac too. I just recently found a study on hypoperfusion and celiac.

    The NIH also states that 97% of celiacs are undiagnosed. I suspect that percentage has lessened since info about gluten and the problems with celiac testing are on the web.

    Tc .. x
     
  14. MeSci

    MeSci ME/CFS since 1995; activity level 6?

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    An additional problem is that there appear commonly to be different biochemical findings (and symptoms) at different stages of our illness. So we might have hypersomnia to start with and hyposomnia later; high cortisol to start with, low cortisol later, etc. 3 years seems to be an important timepoint where parameters change.
     
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  15. dlap4

    dlap4

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    Thanks for the input guys. Never thought about how the biomarkers may change over time and such. Seems very complicated. I hope Steven Holgate gets his 5000 patient study funded and done soon. Wish we could help somehow.
     
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  16. JalapenoLuv

    JalapenoLuv

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    I think they're just documenting common symptoms and missing the causes. You can put band aids on things but unless you attack the causes you'll never cure them.
     

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