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JAMA -"Advances in understanding the Pathophysiology of Chronic Fatigue Syndrome" by Anthony Komaroff

Discussion in 'General ME/CFS news' started by Kalliope, Jul 5, 2019.

  1. Kalliope

    Kalliope Senior Member (Voting Rights)

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    Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome - Anthony L. Komaroff

    Conclusions

    A great deal more is known today than 35 years ago about the underlying biology of ME/CFS. It is clear that many biological measurements clearly distinguish patients with ME/CFS from healthy control individuals.

    At the same time, some areas of ME/CFS research remain a challenge, and research has not yet given practicing physicians 2 important tools. First, there are as yet no US Food and Drug Administration–approved treatments. Second, although various biological measurements distinguish patients with ME/CFS from healthy controls, none yet have demonstrated the high sensitivity and specificity required for a good diagnostic test.

    However, 1 small study (20 cases and 20 controls) described at the NIH conference (and recently published9) reported perfect sensitivity; the specificity of the test in individuals with other fatiguing illnesses remains to be shown.

    With growing international interest in the illness, and increased research support from the NIH, the day is coming when physicians will be able to explain to patients not only that there is something wrong but also that advances in understanding the pathophysiology have led to effective therapy.


     
  2. Kalliope

    Kalliope Senior Member (Voting Rights)

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    - The illness now called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was first described in the mid-1980s.

    I thought it was described already in the 1930s?
     
  3. rvallee

    rvallee Senior Member (Voting Rights)

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    Bit disappointing. I guess he means the current paradigm wrongly focused on fatigue, which is technically correct but needs clarification that it was an invalid reinterpretation from non-experts that only added confusion from the earlier research and was specifically bullied through against strong opposition from the patient community and the few genuine topic experts at the time.

    IIRC Komaroff was involved in the process that created CFS, which he now views as a mistake, so maybe it's personally sensitive to him but it does a disservice to understanding the full picture. At least this review seems good on recent advances, it's really important to consider the full picture of how things got derailed, leading to lost 3 decades and counting, since regardless of recent progress we are still very much in the Upside Down and not much matters as long as we remain there.
     
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  4. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I find this sort of article unhelpful. It is misleading because it implies that the important 'advances' in ME/CFS are demonstration of all sorts of biological abnormalities. In reality we do not know if any of the findings so far will hold up to repeating. Most have not. The most important advances are the negative findings the have excluded some possible causes fairly definitively. That includes the negative findings for efficacy of therapist-delivered treatments directed at 'unhelpful beliefs'.

    Articles like this perpetuate the hype around biomedical studies that plays into the hands of those who see ME/CFS as bad on false beliefs about biomedical abnormalities. Eyes will be rolled when the article is quoted.
     
  5. chrisb

    chrisb Senior Member (Voting Rights)

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    I think it was first described in1955 or 56 and then applied retrospectively to illnesses under different names. There is a caveat in that it was then called benign myalgic encephalomyelitis, but I doubt it there is an intent to make that point.
     
  6. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    As in many areas, I think various groups have claimed ME and "cfs" for their own. That is having discovered it, named it, and described it.

    I would go with the L.A. outbreak in 1934. However, this disease has, as others say, likely been around for hundreds of years. Maybe thousands.

    Eighty-five years, and we still don't know how to diagnose, treat, cure ME. Of course, it's been actively neglected for many decades.
     
  7. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    @Jonathan Edwards, I know the BPS crowd will say there is still no biomedical proof - no replication, small studies etc.

    However, this info and similar articles give hope to pwME and their families. It perhaps casts some doubt that ME is strictly psychological. To the lay person scientific discoveries about this illness may seem more robust than they do to medical professionals who know there is still a long road ahead.

    As well as educating the public that ME or "cfs" is not an imaginary figment, or a ploy by lazy benefit scroungers, articles like this may generate funding interest, and good PR for the ME community, researchers and clinicians.

    We could wait for a long time if research articles were only released after many years of successful replication.

    Maybe I've misunderstood your point, but I like to see the progress as it goes. It does a bit to positively influence some in the public.
     
  8. Forbin

    Forbin Senior Member (Voting Rights)

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    It may depend on one's definition of "described." The Ramsay "definition" lists numerous symptoms that he observed in the 1955 outbreak. The 1988 Holmes criteria attempts to create a threshold of symptoms beyond which a patient is deemed to have "CFS."

    Komaroff has certainly said that choosing the name "Chronic Fatigue Syndrome" was a mistake that he regrets, but I'm not sure that he feels that the entire 1988 definition was a mistake.


    It may be a coincidence, but the CDC came up with "Chronic Fatigue Syndrome" just after it had been discovered that nearly every adult has antibodies to the Epstein-Barr virus (EBV). The discovery made the names currently in use in the US at that time, "Chronic Epstein-Barr Virus Syndrome" (CEBVS) and "Chronic Mononucleosis Syndrome," untenable.

    The CDC may have selected "Chronic Fatigue Syndrome" (bad as it is) precisely because it was so vague that future discoveries could not invalidate it.

    Although the term "Myalgic Encephalomyelitis" seems preeminent now, outbreaks recorded from 1950 to the late 1970's were being labeled "Epidemic Neuromyasthenia" just as often.
     
  9. alex3619

    alex3619 Senior Member (Voting Rights)

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    This was the period in which ME was first formally described, if I recall correctly. I have not read this history in a long time though.

    The '34 outbreak followed earlier cases back to '32, but everyone was perplexed at the time about what it was. Every outbreak seemed to get its own label. ME eventually stuck, as benign myalgic encephalomyelitis. It was benign in the sense that people were not rapidly dying.
     
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  10. Yessica

    Yessica Senior Member (Voting Rights)

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    If this doesn't belong here (straying off topic?), please delete.

    Thank you. I was wondering about benign. I saw a doctor recently and they wrote
    benign myalgic encephalomyelitis for my diagnosis. I was pleased to see myalgic encephalomyelitis, instead of diagnosis fatigue or cfs. I wished they left benign off though.

    The affects on my life and health (our lives and health) are more than benign. I think people who see my records and are evaluating my needs for anything will think it isn't too bad seeing the word benign.

    Edit: took out a word
     
    Last edited: Jul 6, 2019
  11. Samuel

    Samuel Senior Member (Voting Rights)

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    this might be significant for jama publishing it. isn't jama the journal that refused to publish on the disease?

    or has the jama (japanese for obstruction) been already lifted?

    [correction: it was nejm i was thinking of. thanks to @Medfeb.]

    ===

    the 1934 outbreak, as described in a 1938 paper, and a couple more early papers, do not feel like meicc to me. a prevailing polio mindset, which has been suggested, does not seem enough to make the profile seem different to that degree.

    i have heard that the profile changed around the iceland outbreak, but have not seen documentation of this precise claim. a paper describing a later outbreak still did not feel like meicc to me.

    anybody else get this impression?

    why is there a seeming paucity of ltfu?

    ===

    i believe it was ramsay who /also/ removed the word benign?

    ===

    i agree that negative work is good. however, i cannot agree that psycho-woo was ever legitimately scientific, or logical, or ontologically sound to a sufficient degree.

    to me, there was never a reasonable hypothesis. we are participating in the unraveling of, at best, non-truth-seeking, non-sensical, non-scientific, non-normativity-attending behavior that is dressed meretriciously as science.
     
    Last edited: Jul 6, 2019
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  12. Medfeb

    Medfeb Senior Member (Voting Rights)

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    Its the New England Journal of Medicine has never published an article AFAIK. JAMA published an article by the IOM chair, Ellen Clayton. But also a number of unhelpful/poor articles - for instance a 2017 article promoting the GETSET study results and the CDC article reporting childhood trauma increased risk of CFS six-fold (IOM discredited that one)

    I totally agree that the psychological studies were never legitimate in any way.
     
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  13. MSEsperanza

    MSEsperanza Senior Member (Voting Rights)

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    Even with somewhat interested and unerstanding doctors, also in clinics, I rather experienced that they didn't find such reviews helpful. And for the less understanding doctors reviews of this sort only reassured them that all 'proof' of biomedical etiology is unsound and exeggerated. In their view my alleged focusing on this research only proved that I have a somatization disorder.

    What gives me hope are reviews of potential pathophysiologies, clearly formulated as hypotheses and also poining out that there haven't been found until now objectivley measurable biomedical abnormalities that can differentiate pwmE from healthy people.

    I think sentences like "A general downregulation of the hypothalamic-pituitary-adrenal axis is seen in patients with ME/CFS" are misleading. Or have I missed something? Is there a proven downregulation in the hypothalamic-pituitary-adrenal axis in a majority of pwME?

    Regarding the diverse brain imaging studies over the last decade, I have the impression that all the findings cannot be integrated into a common picture of abnormalities.

    As to the more recent findings of Ron Davis' teams around "something in the blood" I think it's good to point to these observations as promising research. However it seems to me also important not to exaggerate the evidence.

    One of EUROMENE's recent papers seems to me a good and realistic approach to review the biomedical research on ME:
    Scheibenbogen, Carmen; Freitag, Helma; Blanco, Julià; Capelli, Enrica; Lacerda, Eliana; Authier, Jerome; Meeus, Mira; Castro Marrero, Jesus; Nora-Krukle, Zaiga; Oltra, Elisa; Bolle Strand, Elin; Shikova, Evelina; Sekulic, Slobodan; Murovska, Modra (2017), "The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE", Journal of Translational Medicine, 15: 162, doi:10.1186/s12967-017-1263-z

    And a publication that gives me some hope is this paper from 2016:
    Jonathan C.W. Edwards, Simon McGrath, Adrian Baldwin, Mark Livingstone, Andrew Kewley. (2016) The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem. Fatigue: Biomedicine, Health & Behavior 4:2, pages 63-69,
    https://www.tandfonline.com/doi/full/10.1080/21641846.2016.1160598

    I realize that regularly updating such reviews might be exremely strenous and less interesting work. I think it could be very helpful as a basis for decisions regarding further research, though. Maybe it could also convince outsiders that scientifically sound biomedical research on ME does exist.

    [Edit: 'scientifically sound' meaning reporting what was investigated, found and not found in a clear and reasonable manner an not exeggerating the evidence.]
     
    Last edited: Jul 6, 2019
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  14. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    But false hope is not a good idea. Especially if it encourages parents to take their children to physicians who dabble in untested treatments that may do a lot of harm. And especially if it increases the division between patients who believe in certain explanations about their illness and doctors who do not share them. I don't think medical journals should be hyping weak evidence on the basis that the lay public may swallow it even if professionals do not.

    As I have mentioned before, I review grants for funding. I sit on special advisory boards and write personal testimonials for researchers. I write a lot of positive reviews but this article would make me say 'no thanks, this is an amateur cobbling together, it doesn't look as if there is anything here of interest'. My colleagues, who are less interested than I am in ME biomedical research, are likely to say 'well yes, this is why there is no point in funding ME research'.

    Replication does not delay release of articles. A research group publishes their observations and if they look solid the science community takes that on board, even if it wants to replicate and refine the findings. The problem with most of the biomedical findings in ME are that they do not look very solid to start with. Most that people have tried to replicate have not stood up. The recent findings do not look particularly likely to d o better. We are still scratching around for the sort of study that makes the medical science community sit up and take notice.
     
  15. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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    I also think that Komaroff's summaries tend to overplay what is known about ME/CFS. He seems to count the number of studies that reported a biological finding instead of the ones that can be replicated by multiple teams.

    In his summarizing talks at conferences, he seems to make the argument that if team 1 reported abnormality x in the immune system and team 2 reported another abnormality Y in the immune system and team 3 does the same for abnormality z in the immune system, that this is clear evidence that there must be something wrong in the immune system. I don't really think this is how it works. You need to focus on a particular abnormality and see whether it can be replicated in large, well-designed studies by independent teams.
    The small, inadequate studies about different abnormalities do not add up to something IMHO. They are most likely to be artifacts of statistics, selection bias etc.

    I think it would have been better if he used the studies and NIH conference as a sign that biomedical research into ME/CFS is accelerating and an exciting area to be in, instead of evidence that we know things about the pathology of ME/CFS.
     
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  16. Mithriel

    Mithriel Senior Member (Voting Rights)

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    Epidemic neurasthenia was used in the US. In the UK the "benign" part was added because it did not lead to death and paralysis the way that polio did. It is an example of the way medicine uses words to mean something specific when the term means something else to the public. Also things change in meaning. Malaise was a specific term used for flu like symptoms, what we would now consider a release of interferon but the word has been diluted. (When I was in hospital having my first child 40 years ago one woman was very upset by having 9 abortions listed on the chart on the end of her bed. She was not reassured by a doctor saying that abortion was just the lay term for termination not miscarriage)

    The link with polio epidemics was strong and the initial infections were similar. In polio you had to wait to see what the outcome would be. When patients developed what we would call ME instead of paralysis or death it was called abortive poliomyelitis.

    The introduction of widespread polio vaccination probably changed the face of enteroviral infections (all the viruses are very closely related) so epidemics are not so extreme with sporadic cases and smaller outbreaks more usual today.

    The epidemics marked an initial infection whereas nowadays that infection is well over by the time anyone sees a doctor. What the patients experienced after the initial epidemics match the ICC.

    I became ill in 1968 after a Coxsackie B infection (often referred to as summer flu) I have followed ME research since before CFS and have seen nothing to make me think that basic ME is different now.

    There was debate at the time as to whether chronic EBV was the same as ME. EBV research was always dominant in the US whereas the UK experts dealt with enteroviruses. I read that the Holmes definition was simply the definition for chronic EBV changed when they discovered some of the patients in the Lake Tahoe outbreak were EBV negative. Nothing else explains why they developed the definition of an outbreak disease as 6 months of unexplained fatigue.

    Ramsay described a disease where exertion made symptoms worse, fatigue was common but not universal. When CFS was invented the link with exercise was dropped for decades. The link with enteroviruses is still ignored in many places (One recent paper, otherwise quite good said ME developed after flu, not common, never mentioned enteroviruses).
     
  17. Hopeful1976

    Hopeful1976 Established Member

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    Sometimes, I'm totally flattened by responses on here too.
    So, there's nothing in dr Davis' research to hope for? All research so far is insignificant, giving false hope somehow? So I'll just go pop my clogs now huh.
    I agree, we NEED hope, it's what keeps us going in dark times.
     
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  18. MSEsperanza

    MSEsperanza Senior Member (Voting Rights)

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    If I understood this correctly and it means funding for ME research, I find this encouraging:
     
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  19. Forbin

    Forbin Senior Member (Voting Rights)

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    I think you may mean "epidemic neuromyasthenia," not "epidemic neurasthenia."

    "Neurasthenia" was a 19th century diagnosis of people who were deemed to have been afflicted with the stresses of modern life in a post-industrial, urbanized world. Its popularity as a diagnosis had dwindled to almost nothing by the 1920's.

    "Epidemic Neuromyasthenia" is just a synonym for myalgic encephalomyelitis / chronic fatigue syndrome used by certain researchers, such as U.S. Drs. Alexis Shelokov and Donald Henderson*, between 1950 and 1980. I assume the term pretty much just translates to something like "a neurologically involved muscle weakness that can break out in clusters."

    In 1978, Melvin Ramsay himself used the term to describe the 1955 Royal Free outbreak in an article entitled 'Epidemic neuromyasthenia' 1955-1978

    [*At one time, Shelokov and Henderson seem to have been epidemiologists for the CDC and NIH, respectively. In 1959, they wrote a paper in the New England Journal of Medicine called "Epidemic neuromyasthenia; clinical syndrome." I guess this was before the NEJM forbade articles on the illness.]
     
    Last edited: Jul 11, 2019
  20. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    I agree, @Jonathan Edwards, false hope is not good. I've been there many expensive, and sometimes harmful times. However, I don't see how this article is a bad idea and creates false hope. If we are going to say that about this article, which references several important biomedical studies, as well as the NIH conference this last April, we may have to say any announcement to the public, or the medical and scientific community that is not fully formed with a biomarker and effective treatment in place is creating false hope.

    It is my understanding those who support the BPS model of ME, dismiss biomedical findings using reasons such as these are small studies, not replicated etc. Hence the eye-rolling when articles, and any biomedical study about ME are published. But research starts small. For a long time governments and those based in the BPS model who advise funding bodies, have not given biomedical researchers a chance to do larger studies, or even small studies. Generally, it's the ME community itself that has done a large portion of the funding. The MO for governments' and others with influence seems to be - choke off the biomedical funding, then deride or ignore any science based studies that do manage to get done.

    All we have are small studies, largely funded by the ME community which is impoverished by illness, and disability arms of the very same governments that deny funding for biomedical research.

    This article, and I would say all other biomedical research on ME may create a division between persons with ME, and their medical providers who see ME as purely psychological, or just a complete bother. This very unfortunate divide continues to grow, as more pwME see that CBT and GET for ME are harmful and non-evidence based. This division and conflict also hampers treatment for co-morbidities, with the potential for tragic outcomes. Medical professionals need appropriate training about ME. The entire health system supports the potential harm of pwME, not only for putting them through GET and CBT programs, but for allowing an attitude of neglect and derision to be the order of the day in many circumstances.

    On the other hand, this article and publications of biomedical findings in this field, just may bring more physicians on board, who may thus become more supportive of their ME patients. This may even lead to treatments documented in manuals such as the one by the IACFSME: https://iacfsme.org/portals/0/pdf/Primer_Post_2014_conference.pdf

    I agree, medical journals shouldn't hype weak evidence. They have certainly done that with the GET/CBT model. However, to a lay person such as myself reading this article with multiple references to the recent NIH presentations, and other studies appears relevant, and important.

    I understand that replication does not delay release of articles. I could have misunderstood, but my reading of your comments on this JAMA article are that it is saying nothing of import.
    I also understand, and perhaps again mistakenly, that you see the studies referenced in this article as not meaningful, nor having any potential. Again, I say we have to start somewhere.
    So far the community has not funded large, earth-shattering research that proves a biomarker and treatments. Neither have foot-dragging governments.

    I see your point that research is still scratching around, and some studies have not been replicated. Funding is an enormous hurdle in this field. I still think that articles such as this, and new discoveries chip away at the false belief that ME is caused by psychological problems. It gives us hope, and something to show those around us who dismiss us out of hand, as lesser human beings.
     

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