Michael Sharpe: "Chronic fatigue syndrome: Neurological, mental or both" incl. PACE

[WillowJ]

***Thanks for posting these abstracts. I think that these papers are some of the more interesting studies that have been done in ME/CFS, and I think that they do provide some clues as to what is going on, but they are all looking at downstream effects in the pathophysiology. Until people start asking about earlier events in the cause and effect tree, they will continue to be describing effects rather than causes, and the treatments that result will not be getting at the root of this disorder.

***Sorry for the rant, but I presented this hypothesis to the research community at the IACFS/ME conference over four years ago, and unfortunately, they continue to quibble over whether it is psychological or neurological or immunological or endocrinological, or rheumatological, or infectious, or toxicological, or mitochondrial, or genomic or gastroenterological, or allergic, or ?, and the fact (in my opinion) is that it affects all these specialties, but its origin is not in any of them.

***If you've read this far, thank you for your indulgence! -)

***Best regards,

***Rich

Thanks for your reply, Rich. I thought those studies were very interesting, too. They all described a pathology, but as far as I could see from the abstracts, only one (Pietrangelo) attempted to consider a cause, and it was an alteration in gene expression, which was only a proximal cause. I wondered if the methylation block could produce that alteration in gene expression, and it sounds like you're saying yes, it could.

What's frustrating to me is that, regardless of whether we agree on an ultimate cause, we have all these replicated pathologies--just like in a lot of well-accepted diseases--yet it's still considered to have unexplained symptoms and be controversial whether it's a physiological disease or not (even whether it's a physiological disease in a subset of broadly-defined CFS).

I also agree that this is a cellular disease, and that cellular disease deserves a new category because it spans everything.

 

[Seirios]

ICD-10 [4] places CFS in both mental and neurological conditions and ME under only neurological conditions.

Where has he got this from? WHO only classifies CFS along with M.E and PVFS under neurological. When has WHO ever classed CFS under mental? Plus the fact WHO don't differentiate between the alternatives names of M.E like he's making out anyway.

I can only assume this is yet again a case of confusion between Chronic Fatigue Syndrome and a seperate unrelated illness Fatigue Syndrome (Chronic), the latter WHO classifies under mental health but WHO makes a note right next to FS about how Fatigue Syndrome (Chronic) is not to be confused with 'the Chronic Fatigue Syndrome' (CFS) which is under G93.3 neurological conditions.

I wonder if he knows WHO's classifications can't be currently accessed as WHO is currently sorting through classifications or something along those lines at the moment. Meaning no-one can prove to him right now that CFS isn't under mental classifications.

I'm not sure if i'm just imagining it but hasn't the psych lobbie recently seem to have been almost somewhat taken aback by the response they got when they published the pace trial amongst other things as they seem to be going out of their way to justify it all and on some other cases they even seem to be backtracking. I wonder if there was a much stronger angrier reaction that what they were expecting and that is at least hope that maybe they've underestimated us and with patient groups becoming more and more connected via internet and because word will be getting around we will be becoming stronger and larger in numbers.

 

[In Vitro Infidelium]

I can only assume this is yet again a case of confusion between Chronic Fatigue Syndrome and a seperate unrelated illness Fatigue Syndrome (Chronic), the latter WHO classifies under mental health but WHO makes a note right next to FS about how Fatigue Syndrome (Chronic) is not to be confused with 'the Chronic Fatigue Syndrome' (CFS) which is under G93.3 neurological conditions.

Where is this note ? It doesn't appear under G93, R53 or F48. The equation of CFS with Neurasthenia has been part of the medical literature for some time e.g http://bjp.rcpsych.org/cgi/content/full/181/4/350-a which is probably enough justification for Sharpe to consider it as established as cognate.

One might not like Sharpe's argument but it isn't that easy to fault it because the WHO classification is largely meaningless in the absence of a definitive case description. Reliance on WHO will not enhance validation of M.E/CFS as a 'neurological condition' no matter how often the refrain is repeated, the WHO classification is just a byzantine bureaucratic process and in the end has n more fundamental meaning than arguing how many angels can stand on the head of pin.

IVI

 

[Angela Kennedy]

Where is this note ? It doesn't appear under G93, R53 or F48. The equation of CFS with Neurasthenia has been part of the medical literature for some time e.g http://bjp.rcpsych.org/cgi/content/full/181/4/350-a which is probably enough justification for Sharpe to consider it as established as cognate.

You mean someone claims it a few times, so his mates do the same, and suddenly it's valid? I mean, I know Wessely and Sharpe and some others believe that, but you are really thinking everyone else has to accept those unsafe notions? Do you know anything about the history of neurasthenia as an archaic waste-basket diagnosis?

One might not like Sharpe's argument but it isn't that easy to fault it because the WHO classification is largely meaningless in the absence of a definitive case description. Reliance on WHO will not enhance validation of M.E/CFS as a 'neurological condition' no matter how often the refrain is repeated, the WHO classification is just a byzantine bureaucratic process and in the end has n more fundamental meaning than arguing how many angels can stand on the head of pin.

IVI

What is your evidence to support your opinion on this one? You do realise angels on pins are based on supernatural notions? That's not the same as medical categorisation now, is it? Are you using byzantine metaphorically or literally?

 

[Angela Kennedy]

While IVI writes beautifully eloquently, sometimes his elegant prose lacks substance, which makes it difficult to understand what he is arguing, especially when his often classical, sometimes Catholic, allusions are faulty.

From what IVI writes, it appears he is attempting to portray the WHO classifcation of ME/CFS as over-complicated, redundant, atavistic even. He portrays the psychs as sophisticatedly cognisant of this alleged common knowledge (and therefore they mustn't be called on it- their arguments are always 'correct' in IVI's constructions here).

But what we have is this notion that the WHO is archaic, atavistic, over complicated, bordering on pseudocscience (or the supernatural!), when the psychs are absolutely desperate to get ME/CFS reclassified in F48! Sadly, the WHO still has the archaic, wastepaper diagnosis 'neurasthenia' in ICD-10, and people like Wessely actually want to regress to this confused, unstable diagnostic category, abandoned before because of its confused, unstable nature and uselessness as a diagnosis (rather like hysteria, which Sharpe is also keen to revive, with his colleague John Stone, a neurologist who really should know better.)

An advocate some years ago called this phenomenon among the psychs a 'gothic revival'. This is where we see how dangerously close to 'pseudoscience' this 'gothic revival' actually is. Locked attics await the women! (That's a feminist literary allusion).

So for IVI to try and claim WHO as dusty, overly complicated, redundant etc. as he has done in the past here, is hilarious, bearing in mind how someone like, say, Peter White calls out 'God willing' in his desperation to wrest ME/CFS from it's G93.3 neurological classification and shove it over in F48 as synonymous with neurasthenia! If the WHO really was that redundant, they would not feel the need to do that. And they do. They really do...

 

[Seirios]

Hi IVI, I agree with you when you say that the equation of CFS with Neurasthenia has been part of the medical literature for some time, i never stated it hadn't.

My problem with Sharpe however is that he quotes WHO as having classed CFS as mental illness which i have never seen any evidence of them having doing so. Whether people agree with WHO's classifications or the usefulness of WHO's classifications isn't the issue. The fact is Sharpe stated that WHO class CFS as mental illness and they don't and so his statement is incorrect and misleading. To clarify i'm not saying that Sharpe has to agree with what WHO states but he cannot state that WHO classify CFS as mental illness when they don't.

I can't show you the WHO classifications because like i pointed out before WHO has currently taken down their classifications at the moment. I looked at the classification of FS either beginning of this year or late last year before the classifications were removed and i definitely read under F48 says Fatigue Syndrome (Chronic) (Not to be confused with 'the Chronic Fatigue Syndrome' see G93.3).

 

[WillowJ]

"ICD-10 [4] places CFS in both mental and neurological conditions and ME under only neurological conditions."

Where has he got this from? WHO only classifies CFS along with M.E and PVFS under neurological. When has WHO ever classed CFS under mental? Plus the fact WHO don't differentiate between the alternatives names of M.E like he's making out anyway.

devastatingly, the USA's ICD-10-CM does something like this, but he's twisting it into his own version of reality.

The truth, which is bad enough, is that CFS due to a viral cause will be listed (in the USA's version, which is not binding on any other country) with ME and PVFS under neurological causes...
while CFS, not otherwise specified, remains--not a psych disease with neurasthenia, however--remains under Vague Symptoms, Signs, and Ill-Defined Conditions.

This is against the WHO rules (to classify a disease in two different places, not to mention the global convention of classifying people with ME under CFS under a non-neurology heading is also against WHO rules).

 

[floydguy]

Where is this note ? It doesn't appear under G93, R53 or F48. The equation of CFS with Neurasthenia has been part of the medical literature for some time e.g http://bjp.rcpsych.org/cgi/content/full/181/4/350-a which is probably enough justification for Sharpe to consider it as established as cognate.

One might not like Sharpe's argument but it isn't that easy to fault it because the WHO classification is largely meaningless in the absence of a definitive case description. Reliance on WHO will not enhance validation of M.E/CFS as a 'neurological condition' no matter how often the refrain is repeated, the WHO classification is just a byzantine bureaucratic process and in the end has n more fundamental meaning than arguing how many angels can stand on the head of pin.

IVI

Yeah, neurasthenia has been around since Freud attributed it to excessive masturbation. The only masturbation going on in the CFS world is the verbal masturbation of the likes of Sharpe et al.

 

[Angela Kennedy]

Yeah, neurasthenia has been around since Freud attributed it to excessive masturbation. The only masturbation going on in the CFS world is the verbal masturbation of the likes of Sharpe et al.

One of Wessely's arguments (with Luthra) for equating ME/CFS with 'neurasthenia' is It is impossible to be certain that the neurasthenia of the 19th century and the CFS of the 20th century are the same illness. However, clinical descriptions are persuasive and there has been no scholarship to suggest otherwise. (2004: 2365)

So basically, they make a claim, and because there's no work to say otherwise, and they are persuaded by their own belief, it should be so. So if they wanted to claim demonic possession caused ME/CFS, that would be their logic...!

As seen in Gosling's research (1988), the neurasthenia diagnosis was extremely unstable, often used as a synonym for "we don't know so we're going with "it's psychogenic". John Haller wrote that almost anything could be a symptom of neurasthenia . It's a real dustbin diagnosis which reflected doctor uncertainty in knowledge and the desperation we've become familiar with when psychogenic diagnoses, in all their discrepant and fallacious reasoning, become default diagnoses in the face of that uncertainty in medical knowledge. And contemporary 'neurasthenia' proponents want to reify that fallacy by regressing to a more medically ignorant time! It's amazing really.

 

[Dolphin]

I don't have time to look it up but somebody pointed out to me before that as far as he could make out the definition for Neurasthenia that the WHO uses was written by Ian Hickie. This person's argument, which seemed convincing to me from looking at the definition of Neurasthenia, was that Ian Hickie wrote it in such a way that it sounded quite like ME/CFS. I'm no expert on Neurasthenia but I believe the people who got the diagnosis in the 19th century would now be recognised as having a variety of different conditions as Angela mentions.

 

[Angela Kennedy]

I don't have time to look it up but somebody pointed out to me before that as far as he could make out the definition for Neurasthenia that the WHO uses was written by Ian Hickie. This person's argument, which seemed convincing to me from looking at the definition of Neurasthenia, was that Ian Hickie wrote it in such a way that it sounded quite like ME/CFS. I'm no expert on Neurasthenia but I believe the people who got the diagnosis in the 19th century would now be recognised as having a variety of different conditions as Angela mentions.

That would be interesting to find out about the possible Hickie connection! The WHO can be somewhat lumbering and that is a problem with trying to find out stuff like that. I would like to find out the history of the neurasthenia entry, which is an oddity considering how archaic and discrepant the neurasthenia diagnosis was, and is accepted as such, even by those trying to regress to it!

 

[In Vitro Infidelium]

I can't show you the WHO classifications because like i pointed out before WHO has currently taken down their classifications at the moment. I looked at the classification of FS either beginning of this year or late last year before the classifications were removed and i definitely read under F48 says Fatigue Syndrome (Chronic) (Not to be confused with 'the Chronic Fatigue Syndrome' see G93.3).

http://apps.who.int/classifications/apps/icd/icd10online/

R53 Malaise and fatigue
Asthenia NOS
Debility:
NOS
chronic
nervous
General physical deterioration
Lethargy
Tiredness
Excludes: debility:
congenital ( P96.9 )
senile ( R54 )
exhaustion and fatigue (due to)(in):
combat ( F43.0 )
excessive exertion ( T73.3 )
exposure ( T73.2 )
heat ( T67.- )
neurasthenia ( F48.0 )
pregnancy ( O26.8 )
senile asthenia ( R54 )
fatigue syndrome ( F48.0 )
postviral ( G93.3 )


F48 Other neurotic disorders
F48.0 Neurasthenia
Considerable cultural variations occur in the presentation of this disorder, and two main types occur, with substantial overlap. In one type, the main feature is a complaint of increased fatigue after mental effort, often associated with some decrease in occupational performance or coping efficiency in daily tasks. The mental fatiguability is typically described as an unpleasant intrusion of distracting associations or recollections, difficulty in concentrating, and generally inefficient thinking. In the other type, the emphasis is on feelings of bodily or physical weakness and exhaustion after only minimal effort, accompanied by a feeling of muscular aches and pains and inability to relax. In both types a variety of other unpleasant physical feelings is common, such as dizziness, tension headaches, and feelings of general instability. Worry about decreasing mental and bodily well-being, irritability, anhedonia, and varying minor degrees of both depression and anxiety are all common. Sleep is often disturbed in its initial and middle phases but hypersomnia may also be prominent.
Fatigue syndrome
Use additional code, if desired, to identify previous physical illness.
Excludes:
asthenia NOS ( R53 )
burn-out ( Z73.0 )
malaise and fatigue ( R53 )
postviral fatigue syndrome ( G93.3 )
psychasthenia ( F48.8 )

My problem with Sharpe however is that he quotes WHO as having classed CFS as mental illness which i have never seen any evidence of them having doing so. Whether people agree with WHO's classifications or the usefulness of WHO's classifications isn't the issue. The fact is Sharpe stated that WHO class CFS as mental illness and they don't and so his statement is incorrect and misleading. To clarify i'm not saying that Sharpe has to agree with what WHO states but he cannot state that WHO classify CFS as mental illness when they don't.

It all comes down to whether Fatigue Syndrome as encompassed by Neurasthenia at F48.0 is considered to (not) be Chronic Fatigue Syndrome. Wessely and Sharpe clearly consider the two entries to be equivalent, therefore from his perspective Sharpe is quite correct to say that the WHO classification covers both Neurological and Psychological categories. The question for M.E/CFS affected people is how do we influence a discourse in which an authority (Sharpe) asserts this coequivalence of classification ?

The scale of difficulty in effecting any influence is demonstrate by the Wojcik study that Sharpe quotes basically the Neurological classification that many M.E/CFS affected people adhere to is not widely supported by Neurologists. If Neurologists dont want M.E/CFS on their shelf of the library of diseases who then is going to argue with Sharpe and colleagues that M.E/CFS isnt psychological and doesnt have a place at F48.0 on the ICD ? We can endlessly rehearse the arguments about how and why Sharpe, White and Wessely are dreadful people promulgating specious doctrines, but that is not going to change the professional landscape in which the arguments that affect us, actually take place. Some way forward can maybe be seen via Suzy Chapmans excellent work on the ICD -11 proposals http://dxrevisionwatch.wordpress.com/icd-11-me-cfs/

IVI

 

[In Vitro Infidelium]

I don't have time to look it up but somebody pointed out to me before that as far as he could make out the definition for Neurasthenia that the WHO uses was written by Ian Hickie. This person's argument, which seemed convincing to me from looking at the definition of Neurasthenia, was that Ian Hickie wrote it in such a way that it sounded quite like ME/CFS. I'm no expert on Neurasthenia but I believe the people who got the diagnosis in the 19th century would now be recognised as having a variety of different conditions as Angela mentions.

What you describe is a basic characteristic of cladistic, archival and library systems an essential conservativism that abhors the removal of a category, even when a category has long ceased to have value, and which in turn can lead to the insertion of a poorly characterised entity on the basis of assumed cognatism, so as to fill the void. This is just one of the many insecurities that arise from trying to use the ICD as a defence of the M.E/CFS is neurological and nothing else position.

IVI

 

[Dolphin]

I don't have time to look it up but somebody pointed out to me before that as far as he could make out the definition for Neurasthenia that the WHO uses was written by Ian Hickie. This person's argument, which seemed convincing to me from looking at the definition of Neurasthenia, was that Ian Hickie wrote it in such a way that it sounded quite like ME/CFS. I'm no expert on Neurasthenia but I believe the people who got the diagnosis in the 19th century would now be recognised as having a variety of different conditions as Angela mentions.

That would be interesting to find out about the possible Hickie connection! The WHO can be somewhat lumbering and that is a problem with trying to find out stuff like that. I would like to find out the history of the neurasthenia entry, which is an oddity considering how archaic and discrepant the neurasthenia diagnosis was, and is accepted as such, even by those trying to regress to it!

Unfortunately, searching for either hickie or neurasthenia in the computer folders I thought it might be in didn't show anything. There is a chance that Ian Hickie was part of a panel rather than the sole author. Sorry I can't find any evidence atm.

 

[Dolphin]

The scale of difficulty in effecting any influence is demonstrate by the Wojcik study that Sharpe quotes basically the Neurological classification that many M.E/CFS affected people adhere to is not widely supported by Neurologists. If Neurologists dont want M.E/CFS on their shelf of the library of diseases who then is going to argue with Sharpe and colleagues that M.E/CFS isnt psychological and doesnt have a place at F48.0 on the ICD ? We can endlessly rehearse the arguments about how and why Sharpe, White and Wessely are dreadful people promulgating specious doctrines, but that is not going to change the professional landscape in which the arguments that affect us, actually take place. Some way forward can maybe be seen via Suzy Chapmans excellent work on the ICD -11 proposals http://dxrevisionwatch.wordpress.com/icd-11-me-cfs/

Yes, it's difficult. In the past, the neurologist Peter Behan and people around him e.g. Abhijit Chaudhuri were useful advocates but then Peter Behan was somewhat unethical in a study and as I understand it was pushed to retire. Russell Lane is another neurologist who has been good sometimes - but he sometimes seems quick to say a large chunk have psychiatric problems and don't have neurological problems. And seems a bit all over the place on exercise. These are just impressions - I'm not an expert on his views. But neurologists are used to "hard" evidence and often we don't "provide".

 

[WillowJ]

Regardless of whether ME/CFS is primarily a neurological disorder, there is hard evidence of neurological pathology:

Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. "Altered central nervous system signal during motor performance in chronic fatigue syndrome." Clin Neurophysiol. 2004 Oct;115(10):2372-81. PMID: 15351380

RESULTS:

Major findings include: (i) Motor performance of the CFS patients was poorer than the controls. (ii) Relative power of EEG theta frequency band (4-8 Hz) during performing the NFT and FT tasks was significantly greater in the CFS than control group (P < 0.05). (iii) The amplitude of MRCP negative potential (NP) for the combined NFT and FT tasks was higher in the CFS than control group (P < 0.05) (iv) Within the CFS group, the NP was greater for the FT than NFT task (P<0.01), whereas no such difference between the two tasks was found in the control group.

CONCLUSIONS: These results clearly show that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue.

Jammes Y, Steinberg JG, et al. "Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses," J Intern Med. 2009 Aug;266(2):196-206. PMID: 19457057

RESULTS:Compared with controls, resting CFS patients had low baseline levels of RAA and Hsp70. Their response to maximal exercise associated (i) M-wave alterations indicating reduced muscle membrane excitability,

Pietrangelo T, Mancinelli R, Toniolo L, Montanari G, Fulle S, et al. "Transcription profile analysis of vastus lateralis muscle from patients with chronic fatigue syndrome." Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):795-807. PMID: 19822097

Importantly, the expression of a gene encoding a component of the nicotinic cholinergic receptor binding site was reduced, suggesting impaired neuromuscular transmission.

Whistler T, Jones JF, Unger ER, Vernon SD. "Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects," BMC Physiol. 2005 Mar 24;5(1):5. PMID: 15790422

Differences in ion transport and ion channel activity were evident at baseline and were exaggerated after exercise, as evidenced by greater numbers of differentially expressed genes in these molecular functions.

It is evident that ion transport and ion channel activity segregate cases from controls and that exercise seems to intensify these differences. Several other conditions have been reported in which fluctuating fatigue occurs that are known to be caused by abnormal ion channels. These conditions include genetically determined channelopathies and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis, and polyneuropathies [19,20].

There are other transmembrane functions associated with differences between controls and CFS patients, including signal transducer activity through receptor binding/activity (Figure ?(Figure3a).3a). Signal transduction of transmembrane receptors occurs by a number of mechanisms, including structural changes, ion channels, and changes of transmembrane potentials. The G-protein-coupled receptors play an important role in the membrane trafficking machinery [21].

The most obvious exercise-induced changes in CFS cases pertain to gene regulation at the point of chromatin structure; whether these changes reflect the differences seen in the mRNA transcripts relating to membrane trafficking differences between cases and controls has not yet been determined.

 

[In Vitro Infidelium]

Yes, it's difficult. In the past, the neurologist Peter Behan and people around him e.g. Abhijit Chaudhuri were useful advocates but then Peter Behan was somewhat unethical in a study and as I understand it was pushed to retire.

I think you may be maligning Behan. Certainly he has retired from full time teaching but he is 76 ! He continues to be listed as Honorary Senior Research Fellow at UoG and is part of a team led by Professor Gow that has recently been awarded a research grant from the Ramsay Research fund.

IVI

 

[In Vitro Infidelium]

Regardless of whether ME/CFS is primarily a neurological disorder, there is hard evidence of neurological pathology

But what Sharpe and others are arguing is that with the development of neuropsychiatry as a discipline largely replacing the classic conceptual divisions of 'brain illness' and 'mental illness', then the formerly used classification differentials may no longer apply. That Sharpe is using the argument for self serving purposes isn't an effective counter argument, and while it is true there's a turf war between the neurochemists and the neuropsychiatrists based around the chicken and egg percept of whether mental illness precipitates abnormal brain chemistry, or whether it's chemistry that precipitates illness, that does not provide an adequate rebuttal to Sharpe's (implied) 'conflationist' argument that 'fatigue conditions' are both mental and neurological. A purist postion on classification is no longer feasible - even on this forum we have people arguing for both various and multiple disease causations, there may be pragmatic reasons to seek specific classifications with ICD -11 and the US opt out version but the key thing for long term progress is to require research $//Es going toward aetiology irrespective of where M.E/CFS sits in any classification system or which particular medical discipline wants to claim 'possession'.

IVI

 

[Dolphin]

I think you may be maligning Behan. Certainly he has retired from full time teaching but he is 76 ! He continues to be listed as Honorary Senior Research Fellow at UoG and is part of a team led by Professor Gow that has recently been awarded a research grant from the Ramsay Research fund.

IVI

Do you know of the specific incident I am referring to? It was something to do with using the same controls for two studies
ETA: the details are here http://www.bmj.com/content/315/7103/269.5.full http://www.heraldscotland.com/sport...-sloppy-preparation-for-court-fiasco-1.381921 http://www.bmj.com/content/321/7275/1490.4.full .
Anyway what I heard was the pressure was put on him to stop working as a doctor but perhaps that was incorrect. I bear no ill will towards Prof Behan. And I am pleased to see he is now active again.

 

[Dolphin]

but the key thing for long term progress is to require research $//Es going toward aetiology irrespective of where M.E/CFS sits in any classification system or which particular medical discipline wants to claim 'possession'.

IVI

I agree. Research progress is what will help us most.