McGregor's Hypothesis of ME/CFS

[Inara]

This cardinal feature is a pathological inability to produce sufficient energy on demand

This is already an interpretation.

I just quoted. Yes, the authors put assumptions in there. (Not I.) This has been critisized numerous times, and not entirely unjustified. But aren't there assumptions in any diagnostic criteria we have right now?
My point was just that I think CCC/ICC require muscle issues.

It's an and/or criteria which accepts mental fatigue as valid without physical fatigue.

That's a good point and I had to re-check.
CCC require muscle and physical fatiguability (just "and").
ICC require points 1-5 fulfilled to have PENE. Point 1 includes "physical and/or cognitive fatigability", point 5 "Low threshold of physical and mental fatigability". Later the authors speak about "weakness". Altogether, muscle issues are a part of PENE. But, in my view, it is not as clear as in case of CCC (in fact I find it confusing, that points 1-5 need to be fulfilled, in point 1 physical fatugability is optional, in point 5 it is mandatory; I can just speculate that's not what the authors intended).

Stating that 'muscle fatigue is common' is also stating that there are exceptions,

True. Still the CCC require "rapid muscular and cognitive fatigability" as mandatory for PEM, and PEM as compulsory for a ME diagnosis.

Well yes, Ramsay-ME uses not the same criteria as CCC/ICC, I just find it interesting. Something to consider.

By the way, for me this is not about excluding anyone. I just don't think it is correct to say "a CCC/ICC-ME diagnosis doesn't necessarily include muscle issues".

 

[percyval577]

I think it´s good to remember that these criteria are still first attempts.
We all start with vague ideas, and we need to narrow down the new meaning (here possibly one illness). This is what goes on here.
So far physiological research has only provided us with some tendencies, still nothing conclusive.
Therefore one should well stay sceptical about all attempts, as they might have forgotten some important thing or might have narrowed down the term rather too much, already clinical.

However,
reading through the ICC I don´t see that they would suggest that there is something wrong with the muscles.
Neither PENE nor the Pain section insist of muscle dysfunction or muscle pain
(neverhteless, the pain section doesn´t look to me already done well enough).

CCC give the option to fullfill

1. and 2. or
1. and 3-4.
and then some additional points

so 2.

There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post-exertional malaise and/or post-exertional fatigue and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. ...

or 4.

There is a significant degree of myalgia. Pain can be experienced in the muscles, and/or joints, and is often widespread and migratory in nature. Often there are significant headaches of new type ...

I don´t want to stick too much on words when also the whole text gives an idea what we are trying to grasp. However, also here - via 4. instead of 2. - muscle issues are not necessarily included.

In my case, I had headaches of new types, limb pain, and some skin "pain".
When I feel weak, it´s a more generalized feeling.

 

[percyval577]

Point 2. of the CCC is BTW confusing.

Point 2.

Post-Exertional-Malaise and/or Post-Exertional-Fatique

is given an explanation where just the same term shows up. In humanity science you would be laughed at.

There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post-exertional malaise and/or post-exertional fatigue and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. ...

This might show that these criteria are attempts to grasp the nature of an illness, which is difficult to grasp.
It must be done better though and of course, without such "intuitive" pitfalls.

More likely might be that they don´t mean ... and ... but ... or ... respectively ... -
explaining Malaise ... and/or ... Fatique.

Instead of

There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, ... and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. ...

the explanation of point 2.

Post-Exertional Malaise and/or Post-Exertional Fatigue

would read:

There is an inappropriate loss of
physical or mental stamina resp,
rapid muscular or cognitive fatigability resp,
and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen.

There is a pathologically slow recovery period – usually 24 hours or longer.

However, via 4. muscle issues are not necssarily included in the CCC.

 

[Wishful]

The one mention of 'physical and mental' looks to me like a simple error (should be and/or) based on the rest of the writing. Nothing clearly says 'if there are no muscle problems, it's not ME'.

If anyone cares really deeply about the issue, they can ask one of the authors of the criteria for clarification.

 

[Wishful]

But how could that explain pacing?

I don't know. I've never noticed that pacing affected me. Maybe pacing works for some symptoms for some people? Maybe pacing limits muscle use to a point where it doesn't trigger immune activation?

My increase in symptoms are a fairly consistent 24 hrs after muscle-straining activities. As far as I know, the rise in IFN-g after human exertion is a fairly consistent 24 hrs, so it fits my observations of my ME. The increase in symptoms after such exertion is, as best as I can tell, the same as when I get a viral infection, which also increases IFN-g. I admit that it's hard to compare the increase in symptoms, especially when I've had so few viral infections since developing ME. Human judgement of such things is very unreliable.

 

[Wishful]

I was thinking more about the 'fatigue-like feeling that isn't real fatigue'. Aren't there drugs that can create feelings like fatigue without creating the 'metabolic fingerprint' of real fatigue? For that matter, is there a way to clinically measure fatigue?

Hmmm, a quick check indicates that there is no simple way to measure fatigue. A couple of quotes from a paper:

-- 'The literature revealed no universal definition of fatigue and a confusion exists between fatigue and chronic fatigue.'

-- 'However, whilst assisting with the understanding of the concept and future research, the complexity of this subject is still evident.'

Scanning a few other sites shows that there is no way to determine if a patient is feeling real fatigue or something 'fatigue-like'. More reason to drop the term 'chronic fatigue syndrome'. It also explains why treatments for normal fatigue don't generally work for ME patients: we're not suffering from normal fatigue.

There seems to be the same problem with 'unrefreshing sleep'. I'm pretty sure that sleep reverses my normal fatigue. I still wake up feeling something like fatigue, but it's not quite the same feeling that I get from overworking or lack of sleep. In earlier postings I said that 'unrefreshing sleep' makes it sound like a sleep disorder, which I don't think it is. ME can cause sleep disorders, but it's not those disorders that are responsible for our failure to bound energetically out of bed in the morning.

The confusion about what our symptoms are (not the same as physical fatigue or sleeplessness) isn't helping research or how doctors deal with ME patients. It might help if at some future gathering of researchers, they made an official statement that "this is not normal fatigue and shouldn't be treated that way, and it's not a result of sleep disorders".

 

[msf]

Wasn't that the case regarding the 'four humours' hypothesis for health problems? The majority might have been confident that they were on the right path. Likewise, the members of a herd of bison probably thought they were stampeding in the right direction...until the cliff's edge. No, I can't accept 'the majority must be right because they're the majority'.

I do wonder whether most of the research groups are selecting patients with significant muscle endurance problems. Maybe that's the most common and easiest symptom to clinically measure. What comes to my mind is the old joke about looking for lost keys under the lamppost, because it's easier to look there.

I just checked: neither the Canadian nor International criteria for ME requires muscle problems, so it seem to be agreed that muscle endurance problems are not a core part of ME. That's why I have an issue with research focusing on that. Likewise, studies on blood serum might not reveal problems inside the BBB. I'd like to pose a question to the researchers: what do the present results say about the chances of the core problem being in the brain, or being in the body? The answer might influence where resources should be directed.

I didn't say the majority of uninformed people, though, I said the majority of highly respected researchers. So that's kinda different. The only people who don't seem interested in this area are people who haven't done much (or any) research in this field, or who are not well known for their research achievements.

Pretty sure you have mentioned having muscle problems yourself, I thought we were debating whether they were caused by lactic acid? Of course, there will people who don't who are covered by those definitions, but that's a problem with the definition, not with the research methods. If there is a clearly identifiable group who don't have muscle problems, but who have some other clearly identifiable and distinctive symptoms, then of course money should be spent on researching that illness too.

 

[Wishful]

Nope, wasn't me with muscle problems. Nothing to indicate lactic acid issues either.

With the 'four humours' hypothesis, by majority I was meaning the highly respected researchers of their time. Science has plenty of examples of the majority of highly respected researchers following a false trail.

I think the subgroup of ME without muscle problems aren't suffering a different illness, but rather a different set of downstream effects. If ME is causing a certain chemical imbalance in all victims, some people might have a genetic vulnerability to that imbalance in their muscles, while others are able to be unaffected or correct for it. Likewise, others might have such vulnerabilities in connective tissue, intestinal walls, or whatever. If such symptoms aren't experienced by all (or 92.5% or whatever statistical level is appropriate) victims, then they should be classed as downstream effects, and IMO, given less priority for research resources.

 

[msf]

By the way, talking of CCC: https://www.ncbi.nlm.nih.gov/pubmed/31161646

I don't know a lot about probability, but the p value for the lactate finding looks pretty good.

 

[msf]

Nope, wasn't me with muscle problems. Nothing to indicate lactic acid issues either.

With the 'four humours' hypothesis, by majority I was meaning the highly respected researchers of their time. Science has plenty of examples of the majority of highly respected researchers following a false trail.

I think the subgroup of ME without muscle problems aren't suffering a different illness, but rather a different set of downstream effects. If ME is causing a certain chemical imbalance in all victims, some people might have a genetic vulnerability to that imbalance in their muscles, while others are able to be unaffected or correct for it. Likewise, others might have such vulnerabilities in connective tissue, intestinal walls, or whatever. If such symptoms aren't experienced by all (or 92.5% or whatever statistical level is appropriate) victims, then they should be classed as downstream effects, and IMO, given less priority for research resources.

Sorry, I could have sworn you told me you couldn't wash your windows for more than a few minutes. Anyway, that study is a pretty good finding, in a CCC group, so it seems hard to justify not investigating this.

 

[percyval577]

I don't know. I've never noticed that pacing affected me. Maybe pacing works for some symptoms for some people?

I think if we wanted to stick to the idea that it is one disease, then we would have to take in considerstion that

1. Some effects may occure downstream, and might not be common.
2. Some effects may occure upstream (e.g. different triggers), and might not be common.
3. Some effects may be central, but might not show up in every patient (clearly).

So , in hope that some properties will define our strange illness we may search for these ones.
And my guess would be that with a good probability pacing is one of those, therfore -> 3.

In my case too pacing was not an observation, only now I see that I switched quite regularily every four months my area of interest, from chess to music etc (without being able to improve any skills in a nice enough time frame, to say it optimisticly).

Another example is PEM or PENE, which might not occure clearly in severe patients. Sever patients may look just severly ill, like in other diseases. My question would be, which mechansim could display delayed PEM (and non-delayed one of course), and the state severely ill are in.

And which mechansim would be able to display both, PEM and pacing.

 

[BeADocToGoTo1]

I applaud any researcher or doctor that is willing to delve into the complicated murky waters of ME/CFS. Since most doctors will look at you strangely when you ask for a metabolic test, or ask anything metabolomics related, having research done at the level Dr. Gregor is doing is encouraging. Even if it is looking at just one area of possible cause, that is a great thing.

There seem to be many ways to get to ME/CFS, so it is unlikely there will ever be a simple one-cure-fits-all for it.

How many metabolic pathways are there? How many ways are there to interfere with the functioning of metabolic pathways? Add epigenetics, other diseases and autoimmunity impacts or bodily damages, and different exposure levels to viruses, bacteria, fungi, toxins, herbicides, pesticides, heavy metals metals, air pollution, diet differences and sensitivities, etc. to the mix and there are a tremendous amount of permutations.

The area Dr. Gregor is looking into resonates with my experience, but perhaps will be quite alien to someone else's experience or path to ME/CFS.

 

[boolybooly]

The big question in ME/CFS, then, in McGregor’s mind is what the heck is whacking that very first stage in energy production – glycolysis. That’s where the key to this disease, he believes, will be found. He reported that he’s now searching for the causes of the glycolytic problems in ME/CFS and hopes to have more information on that this fall.

This quote suggests the good doctor does recognise he is dealing with downstream affects. If disturbed glycolysis is the common factor in CFS subtypes, it may still be true that there are more than one causes for disruption of glycolysis as well as different responses to it.

Its good he has made observations on metabolic anomalies in ME/CFS. I hope he can make ground towards identifying subtypes which will stand the test of replication and can help with diagnosis and cohort selection for research.

My personal experience (which is all the evidence I have) leads me to believe that in my own CFIDS at least there is a primary immune dysfunction which involves TH2 shifting and causes metabolic and inflammatory, especially neuroinflammatory, symptoms.

For me TH2 shift is a fact and one does not need much more than chronic TH2 shift to explain most CFIDS symptoms but I think its possible these may include metabolic symptoms due to an undiscovered functional immune response which may have evolved to shut down the primary means of making energy temporarily to starve pathogens which exploit host energy production, which has become chronically active in some CFS i.e. the fluey feeling everyone gets when they are ill.

If this exists there must be a signalling system behind it and I wonder if that is the blood factor which people have been talking about in relation to the nanoneedle experiments etc. If someone could pin down what is communicating to healthy cells that they should behave as if they have CFS I think that would be a step forwards to identifying the mechanism behind the signal.
https://mecfsresearchreview.me/2019/04/25/something-in-the-blood/

 

[Wishful]

Sorry, I could have sworn you told me you couldn't wash your windows for more than a few minutes.

Yes, that was me, but I don't consider that an ME issue. Feeling pain in my arms after a few minutes of overhead work is just 'not using those muscles in those positions often enough'. If I did appropriate arm exercises regularly, I expect window-washing wouldn't be a problem. Using muscles beyond their accustomed movements does trigger PEM, but I attribute that to the fact that such movements damage muscle cells and thus trigger the immune system.

I'm pretty sure that if I didn't have ME, I'd still feel strain after a few minutes of overhead work. I probably have the same issue with leg side movements under load, or other such movements that I don't do regularly. ME doesn't seem to have caused me any new muscle problems.

 

[Wishful]

My question would be, which mechansim could display delayed PEM (and non-delayed one of course), and the state severely ill are in.

I think the immune system would fit both states. It does include mechanisms for quite precise, consistent time delays, such as 48 hrs +/- only a few minutes. The immune system also is known to invoke many of the symptoms we experience (lethargy, flu-like feelings, pain). It's also known to affect metabolic function and hormones. Unfortunately, the immune system (or systems, since there are several separate ones) is very complex, so it's not a very useful answer. We need to figure out which aspects of the immune system are malfunctioning.

I expect that metabolics are involved in ME, but as part of the feedback loop that keeps our immune systems locked in the wrong state. Some symptoms arise from the immune system, and some from the altered metabolism.

 

[Wishful]

For me TH2 shift is a fact and one does not need much more than chronic TH2 shift to explain most CFIDS symptoms but I think its possible these may include metabolic symptoms due to an undiscovered functional immune response which may have evolved to shut down the primary means of making energy temporarily to starve pathogens which exploit host energy production, which has become chronically active in some CFS i.e. the fluey feeling everyone gets when they are ill.

I agree. When my ME started, I developed type IV food sensitivities, which I suppose might indicate a chronic TH2 shift. That went away abruptly after a bout of food poisoning, which would have had a strong effect on my microbiome, which in turn would have altered the inputs to the T-cell immune system. I still retained most of the symptoms, which I later realized were ME, but at least they stopped flaring up every time my T-cells reacted to foods.

 

[percyval577]

I think the immune system would fit both states. It does include mechanisms for quite precise, consistent time delays, such as 48 hrs +/- only a few minutes. The immune system also is known to invoke many of the symptoms we experience (lethargy, flu-like feelings, pain).

But the immuneystem - typically active in diseases - never leads in other diseases to the possibility of Pacing. If you are ill, you simply shouldn´t overdo. Maybe because of IFN-g.

How could a rise of IFN-g or any part of the immunesysten
occure when doing the same amount of effort but (pacing!) in randomly other areas of activity?



And then, I think, IFN-g is not known for concomittantly inducing delayed lethargy etc. I admit that this nevertheless would be thinkable.

In addition, we have the widespread diversity of concrete symptoms, not being able to swallow e.g. Why would IFN-g (genuinely) relate to these symptoms, in such different areas?

 

[gregh286]

But the immuneystem - typically active in diseases - never leads in other diseases to the possibility of Pacing. If you are ill, you simply shouldn´t overdo. Maybe because of IFN-g.

How could a rise of IFN-g or any part of the immunesysten
occure when doing the same amount of effort but (pacing!) in randomly other areas of activity?



And then, I think, IFN-g is not known for concomittantly inducing delayed lethargy etc. I admit that this nevertheless would be thinkable.

In addition, we have the widespread diversity of concrete symptoms, not being able to swallow e.g. Why would IFN-g (genuinely) relate to these symptoms, in such different areas?

Fatigue states exist in many immune disorder.MS...MG....sjorjens etc.

 

[Inara]

Sorry, I could have sworn you told me you couldn't wash your windows for more than a few minutes.

If I did appropriate arm exercises regularly, I expect window-washing wouldn't be a problem.

Before starting resistance training, I had no problems with washing the windows, washing my hair, brushing my teeth or just holding up an arm. When I started resistance training I still had no problems with such things (or many other muscle related activities). I still do a bit - maybe 10% of what I was doing. But I have trouble with washing windows or even with performing "over-the-head-activities", with washing or brushing my hair/teeth or even just holding my arm, because the muscles burn instantly. I can endure the pain for a short while, but at some point (after some seconds) the muscles just don't obey me anymore.

The more I know about ME, the more it confuses me... I do agree with @BeADocToGoTo1, I have respect for researchers who go into that field (and hope that more will do).

 

[percyval577]

Fatigue states exist in many immune disorder.MS...MG....sjorjens etc.

1. It´s supposed that Fatique does not equal MECFS. And I would say this is indicated by possibly delayed PEM and the possibility of pacing (or if you want, by the attemps of ICC or CCC).
If there is a relationship, e.g. if MECFS is somehow an exaggeration of a normal fatique mechanism in illnesses, is an open question.

2 a. There might be some autoimmunity common in MECFS, maybe for homeostatic reasons.

2 b. More interesting might be the question, if an autoimmune-disease which often does not display MECFS-like symptoms can sometimes induce it, and then why.


If you ask me, the appearance of symptoms in MCFS, and the linkage to fatique in generel, point to an feeling-ill mechanism (which one is of course completely common, probabaly therefore my doctors say, "Your symptoms are not specific." thanks).
If you ask me, I would say this supposed very mechanism is ill in MECFS, but not automaticly - or not necessarily - in MS or in Sjorgrens. (In Sjogrens I think it was 70% of patients who display a severe fatique.)

Then the question is, where could a feeling-ill mechanism be located (in higher organisms)? I think a good candiate is basal ganglia and thalamus together. I bet this would make the complete chaos of symptoms here and there understandable,
a)... it could also explain an exaggeration, including delayed PEM and pacing (conditioning is not possible)
b)... it could explain the strange diversity of symptoms that you can read about eg on this forum, and
c)... it would explain the non-specificy of concrete symptoms and the linkage to (more) normal illness-fatiques.