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UK Research Collaborative Conference in Newcastle: 13th - 14th October

BurnA

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I am not sure that Mark Edwards has a particular hypothesis for PEM. His hypothesis was about movement disorders. But even so I see no conflict. At any one time there may be immune loops or neural loops or both.

I really don't think you need to worry too much about the functional terminology. As Mark Edwards indicate sin his presentation he is really only interested in biochemical and neural mechanism. In this sense functional means working abnormally without any evident structural change. One could call autoimmunity functional in the same sense - there is no structural change in the bone marrow or lymph nodes and the cells are quite normal in the way they go about things. It is just that the functional outcome is disastrous.

I cannot see why people are being so negative about choosing people with PEM. Edwards is a neurologist. Harrison knows all about ME classification and PEM - he is not new to the field. Why would they want to do a study on PEM without making sure they had appropriate patients?
On a practical level what could this study reveal for patients, and how could it lead to treatments ?
 

Snowdrop

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Don't know to whom you are speaking but I didn't suggest anything else. The point of the 2 day CPET IS to measure the abnormality from the 1st day exercise.
 

Bob

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@Research 1st, thanks for your clarifications, but I'm not sure what I'm supposed to have said wrong, as you seem to have confirmed what I said, or what I meant; i.e. that a two-day CPET test involves two tests separated by 24 hours. I think most of us know that. The question I was answering was whether the tests have ever been, or should be, separated by 48 hours.

Dr Beth Unger is doing a single exercise test, and is following it with 48 hour post-exercise cognitive tests and subjective measures of symptoms. So this isn't a repeat exercise test, but it's an exercise challenge followed by post-exercise measures of cognitive impairment, etc.

BTW, your post is the first time I've ever seen anyone dissing the Lights' research. That was unexpected.
 
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nandixon

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Last point:
To my knowledge the 'Lights' are just that, light. They appear to be looking at CFS and not ME. ME is a neurological disease with signs of neurological involvement such as autonomic dysfunction (POTS), seizures, balance disorders and neuropathic pain, heart failure and cancer. CFS does not require this, and so CFS (Light's research CFS criteria is perhaps the more weak Fukuda CFS criteria Vs ME-ICC or Ramsay). I don't know. This is not the Light Teams fault, it's the CDC's fault, for creating CFS in the first place.
I disagree. The Lights seem well aware of the PEM distinction/requirement in ME/CFS and the associated comorbidities, and at least some of their most important work is on patients meeting stricter criteria.

For example, in their 2011/2012 paper:
Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia Syndrome

the authors go into detail in the Introduction section contrasting Fukuda criteria with Canadian Clinical Criteria. And they also state that for that study:
All CFS patients met the CDC criteria for CFS [1], and 46 (96%) met the Canadian Criteria for ME/CFS as well [2].
 

Sea

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To clarify who my response was to
Bob you appear to have it backwards my friend.

First point:
The American studies on VO2 max that show a big drop not seen in any other disease, are termed 2 days. not 1 day, or 'repeat' VO2 max studies. (On this issue of number of days relating to CFS, Dr Beth Unger @ CDC only agrees to 1 day, because they know this only shows de conditioning, a finding not unique to CFS organic disease). Dr Unger refused to accept 2 day. :grumpy:
Actually if you're going to argue semantics it's probably @Large Donner who has it backwards. Unger did not agree to a 24 hour CPET. She agreed to one test and to compiling the results of that one test (which as you said shows the same information as those who are deconditioned). I don't remember her being interested in looking at anything 24 hours later.

The second test of the 2 day CPET (which I really don't think is helpful to call either a 24 or 48 hour test) is designed to capture the PEM produced by the first CPET 24 hours earlier. In this regard a fMRI is attempting to do the same thing - capture PEM 24 hours after exertion.
 

Bob

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Unger did not agree to a 24 hour CPET. She agreed to one test and to compiling the results of that one test (which as you said shows the same information as those who are deconditioned). I don't remember her being interested in looking at anything 24 hours later.
She's doing online cognitive tests up to 48 hours after the exercise challenge, and subjective measures of fatigue and function etc.
 

Sidereal

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To my knowledge the 'Lights' are just that, light. They appear to be looking at CFS and not ME. ME is a neurological disease with signs of neurological involvement such as autonomic dysfunction (POTS), seizures, balance disorders and neuropathic pain, heart failure and cancer. CFS does not require this, and so CFS (Light's research CFS criteria is perhaps the more weak Fukuda CFS criteria Vs ME-ICC or Ramsay). I don't know. This is not the Light Teams fault, it's the CDC's fault, for creating CFS in the first place.
On the contrary, the Lights' work is some of the strongest biomedical research conducted into CFS and ME to date.
 
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But are they aware that not everyone will experience PEM right on cue at the 24 hour mark.
It's just not that simple. I think some people, especially the very ill can be in constant PEM.
I would feel a lot more comfortable with a researcher who had a good grasp of ME and it's subtleties.
I have almost constant PEM, it is really just a matter of fluctuation severity... but if I were to do any 'significant' exercise it would definitely be exacerbated and I'd have burning muscles, for sure.. But I think pwME experience PEM differently.
 

Dolphin

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(via @Maxwhd on Twitter)

I haven't read all the messages in this thread so apologies if this has been posted. Some of these names will be familiar to some people with ME/CFS e.g. Anthony David, Richard Grunewald (NICE CFS/ME guidelines), etc.

Functional (conversion) neurological symptoms: Research since the millennium
ARTICLE in JOURNAL OF NEUROLOGY, NEUROSURGERY, AND PSYCHIATRY 83(8):842-50 · JUNE 2012with269 READS
Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK. Impact Factor: 6.81 · DOI: 10.1136/jnnp-2011-301860 · Source:PubMed

Alan J Carson,1,2 Richard Brown,3 Anthony S David,4 Roderick Duncan,5 Mark J Edwards,6 Laura H Goldstein,4 Richard Grunewald,7 Stephaine Howlett,8 Richard Kanaan,4 John Mellers,4 Timothy R Nicholson,4 M Reuber,7 Anette-Eleonore Schrag,6 Jon Stone,1 Valerie Voon,9,10 on behalf of UK-FNS*

ABSTRACT
Functional neurological symptoms (FNS) are commonly encountered but have engendered remarkably little academic interest. 'UK-Functional Neurological Symptoms (UK-FNS)' was an informal inaugural meeting of UK based clinicians in March 2011 with a variety of research and clinical interests in the field. This narrative review reflects the content of the meeting, and our opinion of key findings in the field since the turn of the millennium.
Full text:https://www.researchgate.net/profil...millennium/links/02e7e527a72288766c000000.pdf
 

Valentijn

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All of this speculation would mostly cease if they were a bit more open about their protocol and clearly state their hypothesis...
And if they had a habit of saying "psychosomatic" when they mean "psychosomatic", instead of looking for confusing and ambiguous new euphemisms. Why trust researchers who have ever focused on facilitating deceit?
 
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From a theoretical point of view, exercise can stimulate cytokine production (ie IL1, IL6 and TNF) and people with ME/CFS show an exaggerated immune response to exercise:
http://www.medizin.uni-tuebingen.de/transfusionsmedizin/institut/eir/content/2014/94/article.pdf

So, in theory, the answer is yes.....
That reference doesn't support a change in cytokine levels post exercise, so if that's what this study is testing, then, on this evidence, it will draw a blank:
Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. - PubMed - NCBI
Compared to the normal response of the immune system to exercise as seen in healthy subjects, patients with CFS have a more pronounced response in the complement system (i.e. C4a split product levels), oxidative stress system (i.e. enhanced oxidative stress combined with a delayed and reduced anti-oxidant response), and an alteration in the immune cells' gene expression profile (increases in post-exercise interleukin-10 and toll-like receptor 4 gene expression), but not in circulating pro- or anti-inflammatory cytokines. Many of these immune changes relate to post-exertional malaise in CFS, a major characteristic of the illness. The literature review provides level B evidence for an altered immune response to exercise in patients with CFS.
Mark Edwards' hypothesis seems to be that the abnormal reaction to exercise is brought on be some kind of conditioning (probably related to the initial infection) so that the body comes to 'expect' an abnormal reaction to exercise and fires up the interoceptive network accordingly, even in the absence of infection. It would be helpful to have more detail on this. Are they looking to see what then activates the insula, or simply anssuming it is conditioning if it isn't obviously the immune syste? And how would microglia-driven PEM (another hypothesis) be separated from, say, conditioned PEM?

It may be that this is already factored into the study, but fMRI studies - especially as small as this one - can produce erratic results that can give the authors a lot of leeway in interpretation according to their favoured hypotheses. (see, for example, NeuroChambers: Tough love for fMRI: questions and possible solutions). I like to think this will be a rigorous study that will provide illuminating answers, but more information would help.

I'm quietly hopeful amid the understandable scepticism and distrust in which I've shared here that rather than taking the wind out of the researchers' sails our scepticism and distrust will stimulate them all the more to find the sorts of answers that will both vindicate them and help us. If this happens I'll happily be the first to communicate my humble gratitude.
Will be right behind you.
 
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Hi Simon

Re your first snip from my summary

The point I was making is that in general terms there is evidence that acute exercise can increase cytokine production. Here is an abstract from a recent paper looking at immune function in athletes, which refers to Il-1, Il-6 and TNF-alpha:

________________________________________________________

The production of cytokines increases in response to acute exercise.

Proinflammatory cytokines (IL-1, IL-6 and TNF-α) concentrations rise after prolonged exercise (a 20 Km run, for instance); increased IL-1β is found in the muscular tissue; and increased IL-1 activity can be noted (muscular proteolysis?), even if a suppression of their production one hour after exercise has been reported by other authors [6, 13]. Recent cross-sectional data described increased NGF serum levels in top athletes [14].

Additionally, recent findings are leading to interesting new theories on the anti-inflammatory effect of regular, moderate exercise. Lower levels of Th-2 cytokines and enhanced Th-1 and T-reg responses in murine models of asthma performing aerobic exercise versus sedentary mice have been reported in recent studies [4, 15, 16].

____________________________________________________________________________________________

……..and that there is also some evidence to show that there is an exaggerated immune response to exercise in ME/CFS

I'm afraid there was rather limited 'meat on the bone' at Newcastle relating to this research announcement because it was fitted into a series of short reports updating the current MRC funded studies.

And I didn't have an opportunity to talk to Dr Edwards afterwards (but I am going to write to hime next week)

So the hypothesis I have presented is a personal one

And at this point I don't know what hypothesis Edwards et al are following - and it would obviously be interesting to find out!
 

MeSci

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I might be naive here, but I'm not sure if we should get too hung-up about their usual career focus on functional illnesses. Although it's all rather depressing, we need to judge the trial methodology and the trial outcomes rather their previous history. If they believe that ME is a functional illness from the outset then that might mean that the trial methodology is useless, but if they approach ME as an unknown quantity, with an open mind and an honest attitude, it doesn't matter that they usually deal with functional illnesses. There is a suggestion, from his literature, that Dr Mark Edwards is open-minded to the idea that 'functional' illnesses are as-yet-to-be-explained biomedical illnesses, so let's hope his focus is on that.
Once bitten, twice shy. Many times bitten, extremely averse: a trait favoured by natural selection. If this particular suspect proves the sceptics wrong, then we may revise our views of him. Until then, he remains suspect, based on his past behaviour.
 

anniekim

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Post exertional malaise (PEM), or post exertional symptom exacerbation, describes a delayed and significant exacerbation of ME/CFS symptoms that always follows physical activity and often follows cognitive activity
Regarding PEM being described as delayed, I am bedridden 24/7 and I have immediate exacerbation of global symptoms if I go over my very strict activity limits. If I go over them considerably I will then not return to my baseline level of symptoms the next day but risk dipping below my baseline for days, weeks or longer. PEM seems more nuanced than I sometimes see it described.
 
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SOC

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Once bitten, twice shy. Many times bitten, extremely averse: a trait favoured by natural selection. If this particular suspect proves the sceptics wrong, then we may revise our views of him. Until then, he remains suspect, based on his past behaviour.
Agreed. My position is that trust is earned, not automatically given. So is distrust. This particular individual has earned our distrust. If he wants our trust now, he has to earn it. That's only fair. He has a long nasty record to make up for.

One doesn't automatically trust an abuser just because s/he says s/he's changed. Similarly, I don't trust a researcher with a strong background in psychogenic theories just because the new research proposal looks superficially okay (which it doesn't entirely). Given that he has said nothing about rejecting psychogenic theories, we aren't even in the position of someone saying, "Yes, I was abusive previously, but I see the error of my ways so you can trust me now." All we have is a parallel to an abuser saying, "Just trust me!" No thank you. I will trust you if and when you prove beyond question that you have permanently changed direction. That takes time and hard work on your part.

If this research proves solid and without false psychogenic interpretations I will accept it. Good research is good research, whoever does it. However, based on this researcher's background and the fact that he has not rejected psychogenic theories, are think it's safe to go with history and assume he is going to continue in that direction until proved otherwise.

Let's not fall into the same trap that some abuse victims do. They want so very, very badly for things to be different that they get sucked in by any lie that fits their wishful thinking. "Honest, honey, I've changed! Really! I'll never hit you and the kids again." The victim ignores all the history, the lack of proof of any honest change, and clings desperately to the only thing (the lie) that suggests reality is not as rotten as it is. Let's not be that victim.

This man has the opportunity to prove himself. If he does, great. We should all value good research, whoever does it. But the proving comes before the trusting. I'm watching. Time will tell. Until then, I'm not getting my hopes up.
 

Woolie

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I'm so disappointed, but maybe I'm misunderstanding something
No, you don't misunderstand, Simon. I've just reviewed Dr. Edwards' work for another project, and his views on FNDs, as he calls them, as very much psychological.

Functional movement disorders are the result of the patient's distorted expectations about their movement capabilties. They are fully capable, from an anatomical and physiological point of view, of normal movement, but are convinced otherwise.

He argues that individuals are highly averse the having these kinds of strongly-held expectations disconfirmed. So they "adjust" their movements - at pre-conscious level - to ensure the movements actually do align with expectation.

Edwards also believes that strongly held false expectations are more likely to develop in those with certain psychological characteristics (anxiety, depression, a tendency to somatize, all the usual suspects)

I haven't seen any published work of his on seizures, though.

Having said that, Edwards is certainly not alone in his view on these conditions. In fact, there are no dissenting voices at all in the literature to the "psychogenic" view of these disorders. And Edwards' work is a little more theoretically sophisticated than most out there.

But what really concerns me is how different his story is when he talks to the patients themselves. He doesn't tell them up-front what he believes about their condition, but first tries to establish what they themselves believe, and then bases his explanation around that. Some patients posting on FND forums have absolutely no idea of his real views on their illness.

From his article for practitioners in Neurology now, he advises doctors to:
Ask what the patient thinks is wrong. Does he or she have any thoughts about why they have these symptoms? If not, what do family or friends think? If they (or their family) are convinced they have multiple sclerosis or Lyme disease or ‘‘crumbling bones’’ in the spine you need to know this, so you can tailor your later explanation".
EDIT: Sorry, my mistake. The Neurology Now article is by Jon Stone. So not fair to put those words in Edwards' mouth. I do get the impression, however, that his view is much the same.

His patients do love him, and he does seem to be one of those rare doctors who really cares about them. Some of his treatments may even be effective (I'm not sure). But I do worry about the ethics of this type of misrepresentation.
 
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Woolie

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Tagging @Woolie because I know she "enjoys" stuff like this.
Yep @Sidereal, in a bizarre sadistic way... have just posted a plain English summary of Edwards' current views on functional neurological disorders (above in this thread).

@Cheshire, you are right on it with the ambiguity thing, its quite deliberate.

Would like to hear people's views on this misrepresentation thing. Even if these disorders are "psychological" (and I very much doubt they are, not in the way Edwards thinks), and even if your objective is to try not to scare people off so you can help them, is it okay to lie about your true beliefs?
 

Valentijn

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Even if these disorders are "psychological" (and I very much doubt they are, not in the way Edwards thinks), and even if your objective is to try not to scare people off so you can help them, is it okay to lie about your true beliefs?
No. Even if psychosomatic disorders are ever proven to exist, the doctor does not have the right to take away the informed self-determination of the patient and replace it with what the doctor thinks is best.

The one possible exception is when someone has been found to have a psychiatric disorder which is severe enough that they have legally been assigned someone to make medical choices for them. Albeit with a lot more checks and balances than the current systems seem to have, where one psychobabbler makes an accusation of hysteria and all rights suddenly evaporate.