Normal muscle strength and fatiguability in patients with effort syndromes, 1988, Stokes at al

I'm a layperson, but there's another thing about this paper that I noticed:

"Briefly, before all experiments, the temperature of the muscle was standardised by warming the hand and forearm in a water bath at 450C for 10 minutes; this temperature was maintained throughout the experiment with a lamp."


If I understand correctly, an important issue of ME is impaired oxygen uptake in the cells, which can be caused by (a combination of) problems with proper vascular constriction and relaxation, and red blood cell deformation. Ron Davis was part of a team that published about red blood cells being stiffer in ME/CFS patients, in 1987 there was already a publication in The Lancet about abnormal red blood cell morphology in myalgic encephalomyelitis. Hillary Johnson talks about it in Osler's web (p214-215), and gives a report that this deformation happened during flare-ups of the disease and normalised when the patient was feeling better, and it is also discussed the MEA Newsletter of fall 1989, where it is said that the paper author hypothesised that this caused problems in microcirculation, theoretically resulting in localized lactic acidosis and so producing muscle fatigue.


Maybe I'm being dumb (my brain is very wonky atm), but if you warm up a hand and forearm before and during your experiment measuring muscle function at that location, you are dilating the capillaries, and those blood vessels will then be wide enough to not impede oxygen distribution to the cells from rigid or deformed red blood cells, which, with narrower blood vessels in a normal, everyday situation, particularly in a day-after-exercise situation, would happen.

Ramsay in for example his book of 1986 says that muscle function deteriorates from exertion/exercise, while Stokes et al did not find that, and I wonder if a key difference might be that Stokes et al, in warming up the muscle they tested, prevented exactly the mechanism that causes these issues.

(Edwards was a firm believer of ME just being a matter of lack of motivation though, and looking at his 1992 response to biomedical evidence of muscle abnormalities I would not be surprised if he would have missed it in his own studies even if it had jumped out and had screamed "I am a muscle abnormality!" in his face, so I think he saw what he wanted and expected to see, but if I am not mistaken about this than this would not have helped in his arrogant assumptions.)
 
Arvo said:
if you warm up a hand and forearm before and during your experiment measuring muscle function at that location, you are dilating the capillaries, and those blood vessels will then be wide enough to not impede oxygen distribution to the cells from rigid or deformed red blood cells, which, with narrower blood vessels in a normal, everyday situation, particularly in a day-after-exercise situation, would happen.
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I doubt capillary diameter is affected by temperature. A capillary more or less by definition, has no muscular layer - it is just an endothelial tube with pericyte and basement membrane support. I don't think temperature is going to alter red cell deformability issues, which do not seem to have been replicated recently anyway.

If warming up solved the problem then PWME would long ago have noticed that they felt fine on a hot day or after a hot bath. So I don't think this is going to work as a theory!

Arvo said:
(Edwards was a firm believer of ME just being a matter of lack of motivation though, and looking at his 1992 response to biomedical evidence of muscle abnormalities I would not be surprised if he would have missed it in his own studies even if it had jumped out and had screamed "I am a muscle abnormality!" in his face, so I think he saw what he wanted and expected to see, but if I am not mistaken about this than this would not have helped in his arrogant assumptions.)
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I worked in Edwards's lab in the mid 1980s and knew these people. They were very keen to find abnormalities - because they would then have something interesting to publish. They were all very critically minded however - people like Joan Round, David Jones, Mike Rennie. Richard Edwards may have had preformed views but again he always came across as a stickler for good methodology. I am not sure what his 1992 response was but from memory I have never seen any convincing evidence for muscle abnormalities.

Everything I have seen indicates that the problem in ME is not in muscle itself and I think Edwards made a useful contribution in showing normal function. His views about other causes may well have been misguided but I think it would be a mistake to think they made him do bad science.
 
Jonathan Edwards said:
I doubt capillary diameter is affected by temperature. A capillary more or less by definition, has no muscular layer - it is just an endothelial tube with pericyte and basement membrane support. I don't think temperature is going to alter red cell deformability issues, which do not seem to have been replicated recently anyway.
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There are a couple of studies out there discussing capilary vasodilation and temperature (Thermal control of blood flow through capillaries and arteriovenous anastomoses in skin of sheep - PubMed (nih.gov), Low temperature increases capillary blood refill time following mechanical fingertip compression of healthy volunteers: prospective cohort study - PubMed (nih.gov)The effect of ambient temperature on capillary vascular malformations - PubMed (nih.gov).) They indeed do not confirm my layperson question (except maybe the sheep-in-the-seventies one), but it does show that capillaries might be affected by temperature. In my quick search I also found this advise of arterialization before taking a capilary blood sample: if I understand it ok -again with the emphasis that I have a wonky brain and this is not something I know a lot about- this means warming the area leads to oxygenation of the blood in the capillaries? Capillary blood sampling: national recommendations on behalf of the Croatian Society of Medical Biochemistry and Laboratory Medicine (nih.gov)

Also, the rigidity of red blood cells was not just found in ME patients, but is now also discussed in acute and Long COVID. IJMS | Free Full-Text | Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects (mdpi.com)

And this is a COVID-19 paper. Evidence for structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients | medRxiv, and it discusses changes in the red cell membranes, just as the 1987 ME paper seemed to do according to Osler's Web.


I understand I'm probably being very annoying atm @Jonathan Edwards :laugh:. So let me stress that you are of course better able than me to know what you're talking about with biomedical topics, and that I respect your doubt as indicating that I'm very probably barking up a wrong tree here. It's just that I find it difficult to let my question go when reading things like "capillary flow was increased by warming the ambient air or the hindlegs alone" and that warming an area oxygenates capillary blood samples.
 
Jonathan Edwards said:
I worked in Edwards's lab in the mid 1980s and knew these people. They were very keen to find abnormalities - because they would then have something interesting to publish. They were all very critically minded however - people like Joan Round, David Jones, Mike Rennie. Richard Edwards may have had preformed views but again he always came across as a stickler for good methodology. I am not sure what his 1992 response was but from memory I have never seen any convincing evidence for muscle abnormalities.

Everything I have seen indicates that the problem in ME is not in muscle itself and I think Edwards made a useful contribution in showing normal function. His views about other causes may well have been misguided but I think it would be a mistake to think they made him do bad science.
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First of all let me stress that I did not say that the Stokes team did bad science. There probably were good reasons for the hand-and-arm warming. What I was saying was that I was wondering if with that technique they inadvertently prohibited low oxygenation due to rigid (or malformed) red blood cells in/or constricted capillaries to happen.

If that isn't a problem and the methodology holds up, then yes, genuine finds are always useful.

I can't speak about the personnel at Edwards' lab, or the whole Stokes et al team, so I have no problem in accepting your personal experience that there were good and able scientists trying to do good work. But "critically minded" and "keen to find abnormalities" is not how I would describe Richard Edwards from reading some of his work. The man to me seems arrogant, disableist and biased. He simply didn't accept that ME patients were bedridden after exercise as "no known physicological disturbance or medical condition does this", from that notion he apparently ignored deterioration from his exercise programs (see quotes from Mary Sullivan's letter earlier in this thread), he was convinced ME was just a matter of lack of motivation, as the Stokes at al paper for example says: "The findings clearly point to lack of central drive or motivation." which is an absurd leap from just not finding muscle abnormalities in your own study. Edwards was completely on board with, enthousiastic about and a source provider of the psychiatric narrative.

From what I've seen he seems to have had a certain lack of curiosity about his patients and e.g. the finds of Peter Behan, and instead of accepting what patients told him and work from there, he dismissed what was right in front of him because his own rigid convictions that what they reported could not be real and that they were just not motivated enough to get better, which he believed could easily be achieved if they really wanted to. I won't say if that made him do bad science, but it is what made him a bad scientist IMO and write unjust and prejudiced opinion as fact in his material.
 
Arvo said:
There are a couple of studies out there discussing capilary vasodilation and temperature
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I think the dilatation is in the arterioles, allowing more blood through the capillaries.

Arvo said:
this means warming the area leads to oxygenation of the blood in the capillaries?
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Again, I think that would be increasing capillary flow rate by opening up arterioles.

Arvo said:
Also, the rigidity of red blood cells was not just found in ME patients, but is now also discussed in acute and Long COVID.
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Discussed maybe, but that looks pretty much a ragbag review mostly of other things.


Nothing annoying about raising these things. It is useful to discuss mechanisms - and I think everyone, including me, ends up with a clearer understanding.
 
Arvo said:
From what I've seen he seems to have had a certain lack of curiosity about his patients and e.g. the finds of Peter Behan, and instead of accepting what patients told him and work from there, he dismissed what was right in front of him
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I think that may be unfair. He had enough curiosity to test muscle function - which hardly anybody else did. I have looked at Behan's papers and to be honest there isn't much there one would make much of. Edwards's group would have been well aware of what Behan was proposing. Their analysis techniques were a lot more sophisticated.

And I think it is right not to accept patients' accounts in terms of what is causing what because that needs to be established from controlled studies. People attribute cause very unreliably.

I think Richard had a puritanical streak that may have been associated with an inappropriate interpretation of what he found. But for me the key point is that it is very unlikely that his views meant that he missed findings he should have found.
 
Jonathan Edwards said:
Everything I have seen indicates that the problem in ME is not in muscle itself and I think Edwards made a useful contribution in showing normal function.
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I don't think they made a useful contribution with this study because their methodology is not useful for demarcating muscle diseases from healthy subjects, hence the conclusions are inappropriate.

Did you know that conditions which do have problems in the muscle such as muscular dystrophies also show "normal" (or even less) fatigubility with this methodology (supramaximal twitch interpolation or stimulation)?

https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.880100104 (a study of duchenne muscular dystrophy, also by RHT Edwards)
Dystrophic muscle was slower to relax and less fatiguable than normal.
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But both ME patients and those with muscular dystrophies show the same pattern when it comes to central fatigue - the reason for this is very simple, central fatigue arises from stimulation of peripheral afferents that sense metabolic products and in turn inhibit the excitability of the motor cortex. The main purpose of this is to increase the ratio of ventilation to force output - central fatigue should not be confused with motivational concerns, nor task failure. Central fatigue is coupled to metabolism, whereas Edwards notion of "peripheral fatigue" only relates to the functioning of the peripheral nerve itself. So increased "peripheral fatigue" is observed in myasthenic patients - but such myasthenic patients also demonstrate abnormal "central fatigue" as well - of a similar level as ME patients.

Also notably, RHT Edwards also demonstrated in another study (presented at Ciba Foundation Symposium 82 published in a book) that a patient with mitochondrial abnormality did not demonstrate unusual fatigubility, whereas only patients with glycogen storage diseases and (myophosphorylas or phosphofructokinase deficiency) demonstrated rapid fatigubility.

RHT edwards said:
We have studied a patient who presented with muscle pains and fatigue on mild exertion, a low maximal oxygen uptake (C1.0 l/min) and profound lactic acidosis, and who also showed impaired oxidation of NAD-linked substrates by skeletal muscle mitochondria.
The energy economy appeared normal, since the rate of metabolic heat production in a maximal contraction was normal (dT/dt, 0.74 "C min-I),
the relaxation rate was normal and the average ATP turnover rate, holding a standard submaximal force to fatigue under ischaemic conditions, was
19.8 p o l ATP s-1 mmol-l total creatine (normal; see p 267). As expected, therefore, endurance in the latter test and the ability to sustain force during electrical stimulation (Fig. 2) was well within normal limits.
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It wasn't until they utilised a different "experimental system designed to place demands on oxidative metabolism", or specifically repeated contractions of the quadriceps at 60% (or higher) of MVC with very short rest periods that the patient complained of excess pain and fatigue and was unable to complete the test.

Hence testing the effects of occlusion on the finger or thumb muscle is not generalisable to major muscles in the legs or arms which have orders of magnitude higher energetic demands (and hence circulatory demands). The energy demands for short twitches can easily be driven by anerobic metabolism, so all this methodology tells us is whether there is sufficient glycogen in the muscle, or whether the nerves themselves are being inhibited or not (they are not). Or to put it more clearly, their methodology is not capable of ruling out problems that arise from an inability to sustain aerobic energetic output in the muscle.

So I hope it is now clearer what RHT Edwards did and did not directly rule out in this case - the study ruled out glycogen storage diseases and myasthenic syndromes but did not rule out muscular dystrophies nor all forms of impairments of oxidative metabolism.
 
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Arvo said:
Maybe I'm being dumb (my brain is very wonky atm), but if you warm up a hand and forearm before and during your experiment measuring muscle function at that location, you are dilating the capillaries, and those blood vessels will then be wide enough to not impede oxygen distribution to the cells from rigid or deformed red blood cells, which, with narrower blood vessels in a normal, everyday situation, particularly in a day-after-exercise situation, would happen.
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Another RHT Edwards study shows that cooling the muscle helps with metabolism.

https://pubmed.ncbi.nlm.nih.gov/5014103/

Warm temperatures (such as 45 degrees C) actually reduces the rate of glycolysis in the muscle. The reduced endurance at hotter temperatures was not associated with depletion of local energy resources in muscle (which would in turn be effected by circulation issues). The optimum temperature in terms of endurance was about 26 degrees C.
 
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Snow Leopard said:
I don't think they made a useful contribution with this study because their methodology is not useful for demarcating muscle diseases from healthy subjects, hence the conclusions are inappropriate.
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I was referring to the UCL body of work in general. I presume the negative result in this particular study adds one more useful piece of information. (It had been claimed that the cardinal feature of ME was fatiguability.)
 
The negative result could have been useful if it had been left at that but he then went far out of his area of expertise by assuming a psychological or behavioural cause with no thought to what the consequences would be.

The arrogance choked me at the time.

This paper was used as strong evidence that we were just imagining we were ill.

chrisb said:

Discussion

...Patients are often told simply to rest, but resting may aggravate the symptoms by causing cardiovascular unfitness. The patients with effort syndromes in this study had muscle that responded normally to exercise even though they experienced fatigue prematurely. This evidence can be used to reassure patients that it is safe to exercise, even though exercising may make them feel worse. Anxiety about tachycardia and breathlessness can therefore be allayed, and the vicious cycle of unfitness and fatigue4 can be broken by carefully and gradually increasing the amount of activity.

For patients who either do not respond to or are unwilling to try this approach to treatment further consideration of psychological influences may be necessary. Psychological factors often complicate effort syndromes, particularly if the patient has suffered from lack of understanding from family, friends, and medical practitioners. Such psychological problems should be identified by careful assessment and treated. Whatever the causes of effort syndromes, a coping strategy is required while there is no specific treatment. Behavioural therapy using the principles for managing chronic pain may prove useful for increasing tolerance to exercise. An integrated approach giving advice on exercise as well as psychological support" seems most helpful in returning these patients to normal functioning.
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What makes me sad is to see how much (already in 1992) the voice of the patients is not really taken into account (I am not talking here about the supposed causes) but about the lived, real experience of these patients in connection with physical exertion (anormal worsening of symptoms). The authors quickly speculate as possible causes, a simple lack of motivation, fear of exercise and psychological problems.

Conclusion: no one, however brilliant and scientific, is immune to bias, prejudice and the influence of the spirit of the times. It's a bit cliché but the important thing is to be aware of your own biases so that they interfere as little as possible with your judgment. We all make mistakes, and the positive aspect is that with a dose of humility, we can learn a lot from them. Ok, sometimes easier said than done, I admit...
 
Jonathan Edwards said:
I was referring to the UCL body of work in general. I presume the negative result in this particular study adds one more useful piece of information. (It had been claimed that the cardinal feature of ME was fatiguability.)
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My point was the conclusion that there isn't any excess fatigubility is not justified given their body of work - fatiguability due to a decline in aerobic capacity was not tested for. That is why I pointed out that patients with muscular dystrophies, which are associated with a patient experience of elevated fatiguability have the same results on their tests as ME patients - they did not test for all causes of fatiguability.
 
My immediate reaction, having glanced through some of the comments above, is that presumably there would be clues in the GWAS (Chris Ponting) - thank you to those who proposed the GWAS study via their participation on the MRC expert review panel.
 
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