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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Chemobrain (& CFS): critical review & causal hypothesis [=somatoform via biomed]

Discussion in 'Latest ME/CFS Research' started by Simon, Feb 21, 2016.

  1. Simon

    Simon

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    A new review by, amongst others, Brian Walitt, the lead clinical investigator of the NIH intramural mecfs study. It argues mecfs is a somatoform illness, though it's arguing it's triggered by cyotokines leading to epigenetic changes.

    Some aspects of this paper concern me, and I think it deserves some close scrutiny by the sharp eyes on this forum.

    Chemobrain: A critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy


    Abstract [mention of mecfs comes later]

    One consequence of modern cancer therapy is chemotherapy related cognitive dysfunction or “chemobrain”, the subjective experience of cognitive deficits at any point during or following chemotherapy. Chemobrain, a well-established clinical syndrome, has become an increasing concern because the number of long-term cancer survivors is growing dramatically.

    There is strong evidence that correlates changes in peripheral cytokines with the development of chemobrain in commonly used chemotherapeutic drugs for different types of cancer. However, the mechanisms by which these cytokines elicit change in the central nervous system are still unclear. In this review, we hypothesize that the administration of chemotherapy agents initiates a cascade of biological changes, with short-lived alterations in the cytokine milieu inducing persistent epigenetic alterations. These epigenetic changes lead to changes in gene expression, alterations in metabolic activity and neuronal transmission that are responsible for generating the subjective experience of cognition.

    This speculative but testable hypothesis should help to gain a comprehensive understanding of the mechanism underlying cognitive dysfunction in cancer patients. Such knowledge is critical to identify pharmaceutical targets with the potential to prevent and treat cancer-treatment related cognitive dysfunction and similar disorders.


    A few nuggets on mecfs

    True up to a point, there are arguments about whether this is the most relevant way to measure problems (as patients are often fine for a while, then crash). A recent study found:


    Obviously the authors are not familiar with the numerous prospective studies (eg Dubbo) that find mecfs develops in a subgroup of people after some infections, notably glandular fever. One large study was by Peter White.

    I've only started looking at this, but so far am not impressed by the authors grasp of mecfs.

     
  2. A.B.

    A.B. Senior Member

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    Alternatively, the discordance between reported symptoms and what doctors are able to measure is due limitations in knowledge and technology.

    It wasn't that long ago that that peptic ulcer was considered psychosomatic, and it was widely believed that bacteria could not survive in the acidic environment of the stomach. Helicobacter pylori was only cultured successfully because a lab worker left the petri dish over the weekend rather than throwing it away. The time it takes to culture these bacteria was underestimated.

    Concluding that something is psychosomatic because no clear cause for symptoms is apparent is magical thinking.

    I'd expect more critical thinking from a "critical review".
     
    Last edited: Feb 21, 2016
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  3. user9876

    user9876 Senior Member

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    It's not really a testable hypothesis because it doesn't cover what is meant by a 'subjective experience of cognition' I think for a testable hypothesis that needs to be tied down to a very tight extent in terms of a model of how signals are processed from the body to the brain. The problem with such a hypothesis is it would he a hypothesized change to a hypothesized model.
     
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  4. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Underwhelming, I fear.
     
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  5. ScottTriGuy

    ScottTriGuy Stop the harm. Start the research and treatment.

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    How many times in its young history does this (the psychologizing of a physical disease and the subsequent harm and neglect of patients) have to happen in the medical / research establishment before they realize they have a systemic problem?

    Sigh.
     
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  6. lansbergen

    lansbergen Senior Member

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    I agree.
     
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  7. sarah darwins

    sarah darwins I told you I was ill

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    Are they saying "It's not the chemo, it's the stress of the chemo"?
     
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  8. Marco

    Marco Grrrrrrr!

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    I admit that I haven't read the paper as yet but that summary didn't alarm me that much. Somatoform is such a non-explanation that an argument that induced abnormal signal processing may result in symptoms for which there are no apparent detectable physical abnormalities seems like an improvement to me.

    But they then apparently go on to hypothesise that chemo induced cytokine release causes neurologic injury and then dismiss their own hypothesis as the cause of 'chemobrain' by suggesting that its may be a somatoform (i.e. psychological) because that's the case (sic) in ME/CFS and fibro where there is a similar disconnect between subjective symptoms and objective measures.

    No doubt chemo induced peripheral neuropathy is also psychosomatic and nothing to do with the chemo drugs' effects on neural mitochondria :

    http://www.painresearchforum.org/news/41532-painful-chemotherapy-induced-neuropathy-tk

    which of course would be unlikely to effect the functioning of the brain anyway?

    As for the disconnect between subjective symptoms and objective measure you would have thought that the NIH's own commissioned IOD report would be essential reading for any NIH employee about to launch a major study into ME/CFS. Especially when that report had already carried out a substantial review of neurocognitive dysfunction and concluded that it was real enough to be considered as one of the two additional symptoms after fatigue, PEM and unrefreshing sleep necessary for a SEID diagnosis.

    At least with Brian leading the intramural study, any physiological abnormalities found are unlikely to be attributed to confirmation bias :rolleyes:

    ETA - I've just skimmed the paper - I'll read it later but it's not as bad as I thought. They seem to be suggesting that chemobrain may not be due to the direct (destructive) actions of the chemo agents but that the chemo agents cause a cytokine chain reaction that causes cognitive subjective symptoms and that similar mechanisms may underlie similar symptoms in other disorders often considered 'somatoform'. Fair enough. Still wish they'd referenced the IOM report though.
     
    Last edited: Feb 21, 2016
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  9. Denise

    Denise Senior Member

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    It could be that the article in its final format had already been submitted for publication before the release of the IOM report (10 Feb 2015).
     
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  10. Snowdrop

    Snowdrop Rebel without a biscuit

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    I'm not overly comforted by that possibility.

    I find this kind of thinking lazy.
     
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  11. Denise

    Denise Senior Member

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    I am not excusing the article by any means.
    I am only pointing out that the timeline may have precluded mention of the IOM report.
     
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  12. Snowdrop

    Snowdrop Rebel without a biscuit

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    I know you would not excuse the article because of this. :)

    I just find this man so frustrating, I've probably got a few more posts in me on the subject.

    Also, I have just twittered my ire re Walitt to NIH
     
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  13. Denise

    Denise Senior Member

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    I was concerned that I sounded as though I was excusing them.
    Phew! I am glad you understood that I was not.

    I understand the frustration with this guy's views.

    I think it is also worth noting that Leorey Saligan is a co-author on this article and he presented at the P2P meeting in Dec 2014. He studies fatigue (of all sorts).
    I don't know if he has any idea how different PEM is from fatigue.... (For that matter I am not sure any of the investigators on this study understand the difference between PEM and fatigue.)
     
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  14. Old Bones

    Old Bones Senior Member

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    The segment of @Simon 's original post that jumped out at me is the following quote in the report abstract: "Like chemobrain, patients with these illnesses experience subjective and clinically distressing dyscognition, with attention, concentration, forgetfulness, word-finding, multi-tasking, and organization being the most common complaints."

    No doubt I'm not the only ME patient whose professionally-administered cognitive testing confirmed problems with "attention, concentration, forgetfulness, word-finding, multi-tasking, and organization", Not only were my results poor, the psychologist asked afterwards if I'd noticed my significantly "raised voice" while responding -- an indication, in his opinion, that I was working exceptionally hard to answer the questions.

    I also question this claim in the abstract: "Chemotherapy, or the psychological ramifications of cancer treatment, may simply be one of a variety of “triggers” that ultimately lead to dyscognition." I have been taking a chemo drug weekly for more than five years (Rheumatoid Arthritis). And rather than having negative "psychological ramifications", I am delighted that it has given me back the use of my hands, and has prevented visible joint damage. Regardless, my dyscognition started decades before the chemo. Whether or not the worsening, in some respects, can be attributed to the drug, I don't know. It's not something I waste time thinking about. Perhaps cancer patients are similar, since the medication wasn't really an option for them either. Unless, of course, they would have preferred death to cognitive problems. It's a bit insulting, actually -- implying that cognitive problems associated with chemo are triggered by emotions rather than the physical effect of the drug.
     
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  15. Marco

    Marco Grrrrrrr!

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    Having read the paper in full I don't really have a problem with the general thrust of it (it's hardly novel and could have been better written) and giving the benefit of the doubt, the following paragraph could be easily interpreted as a determination to undermine the notion of 'somatoform' meaning no biological basis :

     
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  16. Bob

    Bob

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    Note (mainly to self) that "physiologic" specifically means "normal physiology" or normal physiological processes. So when the paper says: "Rather, accepting the possibility that chemobrain is related to that seen in somatoform illness provides a unique opportunity in examining the physiologic underpinnings of these illnesses", it is not suggesting that the illness has an abnormal physiological underpinning, but it is stating that there is no abnormal physiology.
     
    Last edited: Feb 22, 2016
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  17. Bob

    Bob

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    If there are epigenetic changes, I struggle to understand how they can conclude that it's a somatoform disorder. It baffles me.

    But isn't that a contradiction? If there are (epigenetic or cytokinetic) changes then isn't that a detectable physical abnormality?

    What am I missing here? I don't understand how they are defining "somatoform". Have they redefined it to mean "subjective experience"? Or are they trying to assert that measurable physiological changes in the brain or (what they describe as) "neurologic injury" must be observed for symptoms to be accepted as biological/organic in origin? I think perhaps it's the latter, or similar; They are neurologists and want to detect "neurologic injury" of some sort. If no neurologic injury is observable then it's a somatoform disorder. So perhaps they consider epigenetic or immunological changes to be irrelevant because they only consider brain injury to be relevant. Epigenetic or immunological changes can't directly cause neurological-type symptoms, in their view? In short, if there's no neurologic injury then it's a somatoform disorder? It's very narrow minded.
     
    Last edited: Feb 21, 2016
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  18. Simon

    Simon

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    Good news and bad news, now that I've read the full text.

    The Good News

    I've now read the paper and basically agree with @Marco. This is simply a new twist on an old idea: cytokines linked to chemotherapy trigger long-term changes in the brain that cause cognitive dysfunction.

    The new twist is simply to suggest that those long-term changes are caused by epigenetic mechanisms, but since many long-term changes are the result of epigenetics, that doesn't add very much.

    The authors then suggest that because of similarities with fibro and mecfs, these illnesses too might be caused by cytokine triggered events. But that since the initial trigger has passed by the time patients get diagnosed, chemotherapy for cancer patients could provide a model for understanding these illnesses too, because you can track problems developing in patients as they get chemo.

    Researchers including Andrew Lloyd, Jarred Younger (for fibro too) and Hugh Perry have all suggested a similar cytokine-triggered model for mecfs.

    And this all fits with the immune-event triggered illness hypothesis that the NIH is explicitly testing in its intramural mecfs study.

    So far so good. Don't have the energy for the bad stuff yet but will post later.
     
    Last edited: Feb 21, 2016
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  19. Bob

    Bob

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    Choice quotes:
     
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  20. Bob

    Bob

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    They state that ME/CFS is a somatoform disorder, and use a purported lack of abnormalities in cognitive tests as their evidence. But they cite only selective evidence in relation to cognitive testing. ME/CFS patients do demonstrate impaired cognition in tests, but only for specific types of cognitive processing. So the authors have outdated partial knowledge about the subject, leading to false conclusions.
     
    Last edited: Feb 21, 2016
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