The P2P Draft report is out

[A.B.]

I don't have PEM. Or maybe I do, just a less severe form. If I cook and buy groceries on one day, the next day it will be a little more exhausting to repeat the same, and the next day even more so. This symptom has been present since I first became ill even. I don't generally have weird neurological or immune symptoms or flu in response to activity. Neuroimmune exhaustion makes no sense to me. I generally don't have massive worsening of symptoms following a single day of increased activity either.

I suspect that I would perform worse on the second day of 2-day CPET, if exertion on the first day exceeds the tolerance threshold (which is unpredictable). At the same time I don't seem fulfill the requirements for PEM in the ICC.

If researchers want to study patients with ICC PEM that is well and good, but excluding patients from treatment or because they fulfill or don't fulfill some arbitrary criteria is, excuse the brutal honesty, no better than what Wessely et al have done.

 

[jimells]

But neuroimmune exhaustion? I can understand neuroimmune inflammation but does this term actually make sense to anyone?

Not to me. But then I cringe every time I see the term "adrenal fatigue". I've never heard anyone refer to cardiac disease as "heart fatigue", although I sometimes wonder just how come hearts never seem to get tired. My grandmother had kidney disease, but nobody ever called it "kidney fatigue". How is it that only the adrenal glands get "tired"?

 

[Bob]

@Jonathan Edwards, I'm struggling to interpret the purpose of this discussion re diagnostic criteria. Are we discussing research criteria, as opposed to clinical criteria? And isn't this a decision best left to individual researchers, and doesn't it depend on the type of research being carried out? Or are we discussing a general set of research criteria for ME that may be used by researchers for guidance? Or are you attempting to understand the best way to select cohorts for ME/CFS research, from your own perspective?

I get the feeling that you don't consider PEM to be a precise enough criterion for selecting patients for research? And that's central to your discussion here? i.e. you believe that it wouldn't be helpful for you in research because the idea of PEM is a bit wooly, not precise, and not objectively measurable at the molecular or cellular level, and you would need something precise or reliably objectively measurable, such as a molecular biomarker before you start to narrow-down the selection of patients for a study? You're interested in differences between patients because they can give researchers unexpected answers or clues, and you wouldn't want to prematurely exclude subsets of patterns in case they could provide you with some answers or clues?

If that's the case then we may all be talking somewhat at cross-purposes. From our perspective, a lack of recognition of the realities of our illness has been our enemy over the years. We consider PEM to be a fundamental feature of the illness that separates it from e.g. depression and stress. (Many academics and clinicians attempt to conflate the symptoms of ME with everyday stress, and they attempt to describe ME as a maladaptive psychological reaction to stress. We consider PEM to be one feature of the illness that distinguishes it from stress and deconditioning etc.) We believe that PEM can be defined and that it is measurable, and it has the potential to be precisely and objectively measurable at the molecular/cellular level, but with more research needed to define it reproducibily. (Two day CPET tests have demonstrated some value in distinguishing ME patients from controls, via a PEM reaction, but perhaps you are interested in using or seeking a molecular marker for your research purposes.)

I think we'd all like to see much more research at the cellular/molecular level looking at the mechanism of PEM in ME/CFS, as we think it might provide answers to the illness, because of the unique nature of PEM in ME. Post exertional 'fatigue' isn't unique to ME, but the specific nature of post exertional symptom exacerbation seems to be unique, as far as I've been able to discern. i.e. a delayed reaction to minimal exertion characterised by a disproportionate exacerbation of all symptoms (i.e. the whole range of symptoms that an individual experiences) that can be a relatively mild reaction or can result in a severe relapse lasting for months or years. I've not yet come across any other illness that has the same reaction to exertion.

I understand that you would need to be able to quantify this precisely, at the molecular level, for it to be the most use in research. There has been research that has attempted to define PEM using biological markers, which has shown apparently remarkable differences from controls, but obviously more research is needed. I haven't got the research to hand but others can point you towards it if you are interested in having a quick look. (It's the Light's research papers, and was there a paper by Maureen Hanson?)

I don't know if this helps the discussion at all? I think you might be thinking in very narrow terms, in relation to your specific ideas about your own research practices, that the rest of us can't quite relate to.

Edit: Actually, reading the most recent posts, I'm not sure if I've understood the purpose of the discussion. We now seem to be discussing clinical criteria as well.

Edit 2: As you and others on this thread have said, not everyone with a 'CFS' diagnosis has PEM... But everyone with an 'ME' diagnosis must have PEM. From my (self-interested) point of view, PEM defines my illness and I would like my illness to be investigated and researched. I have absolutely no objection to other types of illnesses (or subgroups) being researched, in addition to, or alongside my illness, but I'd like my illness to be carefully defined and characterized, and researched. I don't mind what illnesses are researched, but I'd like mine not to be ignored. I can't see how it's possible to research this illness if it isn't carefully defined, and if it can't be distinguished from other fatiguing illnesses, unless carrying out very large scale studies that can distinguish subsets in the outcomes. (Perhaps this is what you have in mind for these discussions?) In any case, any answers for any section of our community will surely help the others in our community. For example, if rituximab proves to help 20 or 30% of our community, then at least we know that the others don't have a B cell mediated autoimmune illness, so that helps narrow down the places to look for answers.

 

[Jonathan Edwards]

As we've established I'm a little slow on the uptake, Dr. Edwards, maybe you can do a kindness and explain how PEM could have a cause that could be labeled myalgic (as opposed to a component)?

Much in the way that the cause of rain might be a raincloud I guess. Language labels have this peculiar stepping stone role in pointing to ideas. Wittgenstein was quite good on this. If you take word meanings out of context you lose them.

Also, I'm not sure you are using circular reasoning correctly, but I would be delighted for you to explain how I have made another mistake. I thought my comparison to using the EM to prove a Lyme diagnosis, when Lyme causes the EM was similar. Same as a rash covering ones body might be useful in diagnosing chicken pox, even though the disease causes the rash. Isn't it the same as defining a bachelor as someone who isn't married, and then saying that by virtue of a man not being married he is single - is circular reasoning? Definitional or diagnostic logic does not necessarily fall into that logical fallacy known as circular reasoning.

No, the bachelor case is a case purely of definition - what the philosophers call an analytic statement. The relation of ME to PEM is about a causal or perhaps a deictic relation between two non-equivalent concepts so involves circular reasoning.

Not for nothing, but as in Lyme, I'm pretty sure finding someone who doesn't have a cover to blow in the ME mess may prove to be a rare deed. Not counting patients of course, at least, not counting most patients.

I think you are pessimistic. There are a good range of people in the ME field with no cover to blow. They just tend to slip beneath the radar. I was pleased to see some of the names on some of the documents we have been discussing.

 

[Jonathan Edwards]

If researchers want to study patients with ICC PEM that is well and good, but excluding patients from treatment or because they fulfill or don't fulfill some arbitrary criteria is, excuse the brutal honesty, no better than what Wessely et al have done.

Yes, that was on my mind.

 

[Jonathan Edwards]

@Jonathan Edwards, I'm struggling to interpret the purpose of this discussion re diagnostic criteria.

I have no disagreement with the rest of that post of yours Bob. I think cross-purpose is creeping in. I want to keep as wide angled a view as possible on how you classify and to suit classification to needs in each case. Maybe the key point I am trying to get at is that of Ralph Waldo Emerson - 'A foolish consistency is the hobgoblin of little minds, adored by little statesmen and philosophers and divines.'

 

[duncan]

Re: circular reasoning: You're close, but not quite right. The premise and conclusion would both have to be on shaky grounds, e.g. unproven, for true circular fallacy to occur.

I have read more than my share of Wittgenstein, and neat metaphor, but I'm still not clear on how your usage of myalgic works as causal to PEM. BTW, I'll match you philosopher for philosopher if you want ,as one of my degrees is in that subject, but I grew tired of that intellectual charade 30 years ago because it refused to move forward (much like this conversation) and I still find its inertia intolerable (same as I find inertia in substantive ME and Lyme research intolerable). But if you get your kicks that way...

I AM a pessimistic. Any patient with ME who isn't should be applauded. And yes, there are some good folk working for both the ME and Lyme causes - but they are outnumbered, and they don't get invited to any of the really good parties, do they?

Bet you'll never see that Emerson gem - one of my favorites as I raised two debaters - over the entrance way of any successful diagnostic lab.

 

[Bob]

I have no disagreement with the rest of that post of yours Bob. I think cross-purpose is creeping in. I want to keep as wide angled a view as possible on how you classify and to suit classification to needs in each case. Maybe the key point I am trying to get at is that of Ralph Waldo Emerson - 'A foolish consistency is the hobgoblin of little minds, adored by little statesmen and philosophers and divines.'

Unfortunately, that doesn't really clarify things for me.

 

[jimells]

For some reason I have been thinking that the idea of one criteria for researchers and one for clinical use was pretty standard.

But then sometimes the research criteria gets hijacked for other purposes. The new "disease" of "pre-hypertension" comes to mind. As I understand it, "pre-hypertension" was a research classification that suddenly became a "diagnosis" that must be "treated". To me, it's just another opportunity for doctors to lecture their patients about how bad their "lifestyle" is, and an opportunity for pharma to expand sales.

I suspect many folks want to discredit and retire the Oxford criteria as a way to discredit PACE, at least in part. That doesn't seem right. PACE is a disaster because it's fraudulent and poorly done, not because of Oxford. (I think Jonathan said this already.) I think each study should stand or be rejected on its own merits.

 

[Wildcat]

.
http://www.investinme.org/Article42...oper to undated letter by White to Horton.htm

Initial response by Professor Malcolm Hooper to an undated letter sent by Professor Peter White to Dr Richard Horton, Editor-in-Chief of The Lancet

18th May 2011


On 17th May 2011 Zoe Mullan, Senior Editor at The Lancet, sent an email to Professor Hooper in response to the complaint he submitted about the PACE Trial article published online by The Lancet on 18th February 2011 and subsequently in the journal on 5th March 2011. In her email, Zoe Mullan wrote: “We asked the authors of the PACE trial to respond to your concerns, which they have duly done. Your complaint and their response were discussed at the highest management level and this group of executive editors was fully satisfied that there were no grounds whatsoever on which to take further action. We attach the response provided to us here. From an editorial perspective, the case is now closed”.

The undated response to Professor Hooper’s complaint by Professors White, Sharpe and Chalder that was sent to Dr Richard Horton (Editor-in-Chief of The Lancet) on behalf of all the co-authors will, in the interests of openness and transparency, be placed in the public domain and will be fully addressed in due course, as will Professor Hooper’s concerns over what he believes is the failure of The Lancet’s editorial process in this instance, but there is one point in Professor White’s letter that is of particular importance, so it is addressed in this initial response.


‘In their letter, Peter White et al state: “The PACE trial paper refers to chronic fatigue syndrome (CFS) which is operationally defined; it does not purport to be studying CFS/ME”.

The sentence continues by stating that the PACE Trial studied: “CFS defined simply as a principal complaint of fatigue that is disabling, having lasted six months, with no alternative medical explanation (Oxford criteria)”…… ‘


~~~~~~~~~~~~~~~~~~~~~~~


I am pretty sure that Peter White stated the same in the Lancet itself, some time after publication of Pace.
.

 

[Ember]

Accumulation of clinical knowledge needs to be backed up by statistical analysis of controlled studies on discriminating features - what for rheumatic disease was called the 'Delphi method'. Otherwise it is just doctors reminiscing coloured by their beliefs - we have a literature on all the pitfalls here. If you muddle hypothesis with data in science you are sunk.

Are you commenting on the development of criteria or on research design? The International Consensus Panel is balanced between clinicians and researchers; it cannot be characterized as “just doctors reminiscing coloured by their beliefs.”

But that is two effects, not a cause and an effect - inability to produce energy is a result and neural and immune symptoms are a result. The idea was that the neuroimmune bit is the cause.

Whose idea was it that “the neuroimmune bit is the cause?” Wasn't that your interpretation of PENE?

The ICC is comprised of four criteria: (1) PENE, (2) neurological impairments, (3) immune, gastro-intestinal and genitourinary impairments, and (4) energy metabolism/ion transportation impairments. PENE (post-exertional neuroimmune exhaustion) describes symptom exacerbation following exertion.

However, I am surprised about the enthusiasm for restricting the definition of ME in the practical clinical setting. Are people not worried that a large number of PWME are going to lose their disability benefits?

The ICC defines ME for both for both clinical and research purposes: “Those who fulfill the criteria have ME; those who do not would remain in the more encompassing CFS classification.”

 

[Scarecrow]

If ME were to always cause PEM, even if subtly, and if PEM was objectively measurable, then could it be validated as a criterion ME?

One of the problems with PEM is that it can mean different things to different people, so who decides what PEM actually is? It has to be something more specific than merely an adverse reaction to physical or mental exertion (or other stresses). I get two different reactions - one which I seems to be OI related the other immune (I'm guessing, obviously) and they typically happen in response to particular types of activity. As a constellation of symptoms, there is some overlap, eg brain fog. Sometimes I get both reactions at the same time, which also tends to confuse the issue.

Will the real PEM please stand up?

To complicate matters still further I read other peoples' descriptions of PEM and I can't always relate to them. Are they experiencing something else again?

How many PEMs are there?

 

[Bob]

One of the problems with PEM is that it can mean different things to different people, so who decides what PEM actually is?

I think that might be what Jonathan Edwards is thinking. I agree that is difficult to pin down, precisely, but that doesn't mean it is impossible to pin down or to measure. e.g. It has been objectively measured in the CPET research papers. And the Light's research papers have demonstrated biological changes compared with controls. (I agree that PEM is probably experienced differently in different patients - So much more research is needed, in large studies looking for molecular pathways.)

I think these are the "Light's" papers that I mentioned earlier:

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.
Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC.
2012
J Intern Med. 2012;271:64-81.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02405.x/abstract

Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome.
White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC.
Psychophysiology. 2010;47:615-24.
http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8986.2010.00978.x/abstract

 

[Scarecrow]

I agree that is difficult to pin down, precisely, but that doesn't make it impossible to pin down or to measure it.

Yes, but presumably the Lights studies are not demonstrating an association with all PEMs, just one or some of them.

 

[duncan]

For me, there are different types of PEM that are predicated on the part of me exerting. And each has its own predictable time frame to kick in. For instance, I know for physical exertion if I do anything longer than 10 minutes, I run the risk of a crash within two or three days, as a rule. Sometimes it can take several days to kick in, but when it does, I know it for what it is. You get used to the feel. The poison in the hands and feet, the weakness in the legs, the pains in the joints...

If I concentrate, as in read something, or write something lengthy that involves thought (as opposed to just flying off my fingers onto the keys), that commands a shorter fuse to PEM - I will notice really bad cognitive issues and headaches and fogginess within a day, certainly no longer. Focusing is a big one for me, and it could involve things like driving, not because of the physical act of driving, but rather the intensity with which I am required to focus because of traffic or weather or speed.

When I lose my temper, or get very happy, or laugh a lot, that evokes the swiftest response of all, and frequently the most disabling.

Anyway, the last two types of PEM might be measured using conventional cognitive eval tools. Perhaps they would have to be refined to be used quarterly or monthly, but other than that, I don't see why they couldn't at least be trialed as metrics for neuro PEM. (The problem with a lot of these neuro evalvs is that there isn't really a lot of them, if I understand correctly. So individuals who take them remember them. That mitigates their utility.)

 

[Large Donner]

I suspect many folks want to discredit and retire the Oxford criteria as a way to discredit PACE, at least in part. That doesn't seem right. PACE is a disaster because it's fraudulent and poorly done, not because of Oxford. (I think Jonathan said this already.) I think each study should stand or be rejected on its own merits.

This statement is problematic for me. Peter white himself said the PACE trial was not a study on people with "CFS/ME" but a study on the operational definition of fatigue. He only admitted this under duress via questioning from Malcolm Hooper.

The whole point is the Oxford criteria is fatigue and nothing else. However this didn't get the paper retracted and it is now spun out to other journals and the mainstream press as well as featuring in "toolkits" for the likes of the CDC.

The reason I don't agree with Dr Edwards statement.....

I think the P2P idea that variable criteria has wasted research is wrong, its a failure to adress biological questions

....is that this is it allows the notion that the issue in many studies is a “failure of imagination” in the way government often use that type of excuse for failure when they actually new about issues and just carried on.

Infact PACE is purely a document of pure imagination precisely because of the variable criteria wasting research. In this case the Oxford criteria.

 

[daisybell]

Yes, but presumably the Lights studies are not demonstrating an association with all PEMs, just one or some of them.

This issue is what I have been worrying at in this thread http://forums.phoenixrising.me/index.php?threads/what-causes-pem-symptoms.34555/

Sorry if that link hasn't come out right. I struggle with understanding how to insert links (and multi quote etc etc)!

 

[Nielk]

From the International Consensus Primer:

Post- Exertional Neuroimmune Exhaustion (PENE pen׳-e)

Normal fatigue is proportional to the intensity and duration of activity, followed by a quick restoration of
energy. PENE is characterized by a pathological low threshold of physical and mental fatigability,
exhaustion, pain, and an abnormal exacerbation of symptoms in response to exertion. It is followed by a
prolonged recovery period. Fatigue and pain are part of the body’s global protection response and are
indispensable bioalarms that alert patients to modify their activities in order to prevent further damage.

The underlying pathophysiology of PENE involves a profound dysfunction of the regulatory control network
within and between the nervous systems (36, 37) This interacts with the immune and endocrine systems
affecting virtually all body systems, cellular metabolism and ion transport.(38 )The dysfunctional activity/rest
control system and loss of homeostasis result in impaired aerobic energy production and an inability to
produce sufficient energy on demand. A test-retest cardiopulmonary exercise study revealed a drop of 22%
in peak VO2 and 27% in VO2 at AT on the second day evaluation.(39) Both submaximal and self-paced exercise
resulted in PENE.(40) These impairments and the loss of invigorating effects distinguish ME from depression.

References:

36. Tirelli U, Chierichetti F, Tavio M, Simonelli C, Bianchin G, Zanco P, Ferlin G. Brain positron emission tomography (PET) in chronic fatigue syndrome:
preliminary data. Am J Med 1998; 105(3A): 54S-58S. [PMID: 9790483]
37. De Lange F, Kalkman J, et al. Gray matter volume reduction in the chronic fatigue syndrome. Neuroimage 2005; 26: 777-81. [PMID: 15955487]
38. Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med 2009; 2:1-16. [PMID: 19436827]
39. VanNess JM, Snell CR, Stevens SR. Diminished cardiopulmonary capacity during post-exertional malaise. J Chronic Fatigue Syndr 2007; 14: 77-85.
40. Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, et al. Pain inhibition and postexertional malaise in myalgic
encephalomyelitis/chronic fatigue syndrome; an experimental study. J Intern Med 2010; 268: 265-78. [PMID: 20412374]

 

[Sean]

I suspect many folks want to discredit and retire the Oxford criteria as a way to discredit PACE, at least in part. That doesn't seem right. PACE is a disaster because it's fraudulent and poorly done, not because of Oxford. (I think Jonathan said this already.) I think each study should stand or be rejected on its own merits.

PACE is a disaster in part because of the criteria used, in part because of sloppy and even dishonest methodology, and in part because it is being grotesquely misrepresented by its authors and their fans.

 

[jimells]

In their letter, Peter White et al state: “The PACE trial paper refers to chronic fatigue syndrome (CFS) which is operationally defined; it does not purport to be studying CFS/ME”.

The sentence continues by stating that the PACE Trial studied: “CFS defined simply as a principal complaint of fatigue that is disabling, having lasted six months, with no alternative medical explanation (Oxford criteria)”……

So the psychobabblers have been beating us on the head with a poorly-designed and fraudulently executed study that isn't even about our illness or patient population?

If the paper's authors state that the study is not about us, why is it part of the evidence review, and why is the NIH trying to apply it to us?