McGregor's Hypothesis of ME/CFS

Diwi9

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Last week @Cort released a great article on Neil McGregor's (Australian researcher) hypothesis on what is going in ME/CFS. This article was posted by @Rufous McKinney, but it was embedded in another thread and I think this hypothesis warrants its own thread. Simply fascinating stuff and a great write-up by Cort. If you read the article and scroll down through the comments, McGregor addresses some of the comments.

https://www.healthrising.org/blog/2...gregor-metabolism-chronic-fatigue-glycolysis/
 

sb4

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Very interesting, thanks. I will say that when I was experimenting with high carb I took my BG regularly. My BG was elevated 30/60/120 mins out. I was eating a lot of carbs for these meals but it certainly doesn't indicate hypoglycemia.
 

Wishful

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I can't get excited by it. I think he's following a result of ME, rather than the cause. The various metabolic issues he's discussing don't seem to fit my ME. He does point out that there are various subgroups, but I feel that they're all part of the (large) subgroup of ME that has metabolic issues, but there are other subgroups without those issues, so the root cause of ME lies elsewhere.
 
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I think he's following a result of ME, rather than the cause
Still processing here (slow on the uptake!)...however- I think these are symptoms and downstream effects also. I think that continues to be the case with just about everything being studied at the moment.

I just don't get very hung up on that detail. I don't think we need to at the moment. We need to understand what all this is doing to our bodies and then we can start to address it: puzzle piece by puzzle piece.
 

Wishful

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It's a matter of limited resources. Resources spent studying symptoms and downstream effects that affect only part of the ME population are resources that aren't being applied to the part of the disease that affects everyone. Pharmaceutical companies probably like that approach: they could sell palliative treatments for symptoms without treating the disease. I think it would be helpful if the research community kept a clear record of which aspects of ME are core (affects almost all victims) and which only affect a fraction. Then they can ask themselves the question of 'will studying muscles, or blood serum, or whatever, lead to an understanding of the disease, or just an understanding of one set of symptoms?' Yes, this limits the scope of research, but there aren't unlimited resources, so some narrowing down is necessary.
 

Wishful

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It's a matter of limited resources. Resources spent studying symptoms and downstream effects that affect only part of the ME population are resources that aren't being applied to the part of the disease that affects everyone. Pharmaceutical companies probably like that approach: they could sell palliative treatments for symptoms without treating the disease. I think it would be helpful if the research community kept a clear record of which aspects of ME are core (affects almost all victims) and which only affect a fraction. Then they can ask themselves the question of 'will studying muscles, or blood serum, or whatever, lead to an understanding of the disease, or just an understanding of one set of symptoms?' Yes, this limits the scope of research, but there aren't unlimited resources, so some narrowing down is necessary.
 

msf

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I don't think any of the researchers think they have found the cause yet (rather than the trigger), but this line of inquiry is pretty much the only game in town, both in terms of resources and quality of researchers. And I doubt they would all have concentrated on this one area if they weren't pretty confident it is the right path towards developing effective treatments (which may not require an understanding of the cause of the illness).
 

Wishful

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And I doubt they would all have concentrated on this one area if they weren't pretty confident it is the right path towards developing effective treatments (which may not require an understanding of the cause of the illness).
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.
 

Inara

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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.
They are a core part of ME:

- From the CCC:
"A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; [...]
2. Post-Exertional Malaise and/or Fatigue: There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, [...]"
See p. 2 of http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf
p. 4: "Muscle fatigue is common", "Patients experience rapid muscle fatigue and lack endurance."

- From the ICC:
"A. Post-Exertional Neuroimmune Exhaustion (PENE pen׳-e) Compulsory
This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions. Characteristics are:
1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
[...]
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level."
And from p. 18: "
a. PENE is the pronounced summation effects and after–effects of numerous interactive dysfunctions. Effects: physical and mental exhaustion, weakness, symptom flare and a prolonged recovery."
http://www.investinme.org/Documents/Guidelines/Myalgic Encephalomyelitis International Consensus Primer -2012-11-26.pdf

I.e. fast fatiguability includes fast fatiguability of the muscles (which elsewhere was called "muscle weakness") and excludes endurance activities.

All the pwME I know have muscle issues, but of course that needn't be representative because I know only a very small portion out of millions pwME. If I remember correctly, Ramsay defined ME primarily via muscle weakness.
 

ljimbo423

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Interesting couple of posts here. I get 2 very different types of PEM. One is very fatigue predominant and the other feels just like a flu. I get the feeling that the fatigue predominate PEM is centered in my muscles or more specifically my mitochondria.

The flu-like PEM, I think, has to be centered in my brain, being triggered by the sickness response. I feel like it's possible to have either one of these different aspects of PEM predominate in ones CFS.

Meaning some people with CFS might have mainly symptoms that come from the brain and others have symptoms that come mainly from their mitochondria or body. Then there are people like me that have been blessed to have both.:D

They both have research supporting them. McGregor, Fluge and Mella support the mitochondrial dysfunction aspect. While Jarred Younger supports the brain causing symptoms aspect (low grade brain inflammation from activated microglia). Just a couple of thoughts.:)
 

percyval577

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My underlining:
- From the ICC:
"A. Post-Exertional Neuroimmune Exhaustion (PENE pen׳-e) Compulsory
This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions. Characteristics are: ..."
This is already an interpretation. And as there isn´t so far any mechansism to focus on. So it´s premature and very unwise, it may be misleading. For example, it could also be that a mechanism of "feeling ill" or "feeling weak" is affected -

my underlining and >><<
"...1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
[...]
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level."
And from p. 18: "
a. PENE is the pronounced summation effects and after–effects of >>numerous interactive dysfunctions.<< Effects: physical and mental exhaustion, weakness, symptom flare and a prolonged recovery."
I think this is right. But >>this<< then is once more a premature interpretation. It may hinder to grasp the difficult thing better.
I don´t want to say that there aren´t numerous interactive dysfunctions, but there are so far only tendencies known. Though there might be one core that gathers them.
It would be better to say "numerous possible interactive dysfunctions" anyway, and to let open which ones, and if they are up -or downstream of such a core, which might be the physiological correlative for the stiff exhaustion we suffer with.

I.e. fast fatiguability includes fast fatiguability of the muscles (which elsewhere was called "muscle weakness") and excludes endurance activities.
When I quickly detoriated I had for one week a "muscle weakness", I could not lift things of a certain wight. After a weak it was gone, though I still went detoriating, sadly. Also when I had EBV my movements tended to reach too far, and I was weak too - to me this looks neurological.

All the pwME I know have muscle issues, but of course that needn't be representative because I know only a very small portion out of millions pwME. If I remember correctly, Ramsay defined ME primarily via muscle weakness.
Some ppl can play guitar for six h´s but cannot walk. I can walk but can´t play guitar for longer than 2 min (then I get exhausted). Several times I have read that patients from the EBV subset would suffer from leg pain, and this is true for myself,
but I had muscle pain only under very special circumstances. And then EBV is a prominent trigger for mecfs.


My impression is that the symptoms do vary a lot. So, what is the common thing that could define one illness? I like to put:
- Why do patients feel exhausted but basically never nicely tired? Which mechanisms could be an explanation? Of note is, I think, that our disease is not degenerative, so again, why?
- Why can the exhaustion appear delayed? And even regularily delayed, as 24 or 48h seems to be often the case?
- Why is pacing a common possibilty? (I don´t see at all that pacing is restricted to movements, whilst I see that some movements are sadly part of everydays necessity.)
- Which structure could bundle all the (very) different and often strange experiences together?
- Which structure could be vulnerable (through many possible triggers) to become badly - or (better) wrongly - functioning?
- (And why would the recovery rate in outbreaks differ from that in sporadic or endemic cases, if so?)

If scientists don´t ask the right questions, they will not find out. If the data - here so far only the patient´s reports and behaviour - are not structured adroitly and possibly open (if needed), the sight will be obstructed.

I don´t thing that muscles are of any major interest, the pain is just one concrete symptom that happens to appear very often.
 
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Which structure could bundle all the ((very) different and often strange experiences together
Squeeze (inflammation) or collapse (collagen decline) of the lower brain stem: just seems massively capable of producing much of this mess. The collagen decline probably explains this blood return failure. My left vein in my leg is clearly- in big trouble. ( My weight is quite low/normal).

I've made major dietary corrections...so why does stabilizing insulin and basically eliminating sugar not resulted in a noticeable reduction in this BRAIN INFLAMMATION? (cause it doesn't seem to have fixed that at all).
 
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The collagen decline probably explains this blood return failure
Ok: explains part,.....in this N=1, I show no measurable Nitrous Oxide, compared to my husband who turns the strips bright red. So: thats contributing as well.....

Ok- add ten more reasons.

And I am one of the: high blood pressure, yet low blood volume types (altho I don't have POtS, mostly).
 

Wishful

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@Inara , the bits you quoted prove my point: the criteria doesn't require muscle fatigue. It's an and/or criteria which accepts mental fatigue as valid without physical fatigue. Stating that 'muscle fatigue is common' is also stating that there are exceptions, and thus it isn't an essential part of ME.

Same with PEM: I get mental fatigue and the perception of physical pain (which doesn't seem to have a physical cause) but I don't have muscle fatigue. I describe it as: 'my legs feel up to a 40 km ride, but my brain wants to flop down on a fluffy pillow'. I could probably do that on a stationary bike.

If I remember correctly, Ramsay defined ME primarily via muscle weakness.
If so, that's wrong according to the criteria. Just because it is common doesn't mean that it's a core part of ME.
 

Wishful

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Why do patients feel exhausted but basically never nicely tired?
There have been times when I've felt up to some strenuous activity (long hikes or bike rides, sawing firewood, digging, etc) and have felt 'healthy fatigue'. It's hard to describe the difference, but there definitely is a difference between healthy physical fatigue and my ME symptoms. I don't even want to call my ME symptoms 'fatigue', because it isn't fatigue; it's an impediment to moving and thinking, and it might be due to some chemical or physical changes different from fatigue.

Why can the exhaustion appear delayed? And even regularily delayed, as 24 or 48h seems to be often the case?
My theory on that, before I even knew about ME, was that physical activity triggers an increase in IFN-g 24 hrs later (lost the reference to that, but it was a journal paper), which in turn triggers an increase in indole oxidase, which converts more TRP to kynurenines in the brain, and some of those kynurenines are neurotoxic and cause the symptoms we feel.
 

Wishful

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I've made major dietary corrections...so why does stabilizing insulin and basically eliminating sugar not resulted in a noticeable reduction in this BRAIN INFLAMMATION? (cause it doesn't seem to have fixed that at all).
I don't know. For me, there was a definite, abrupt increase in my ME symptoms 20 minutes after ingesting significant amounts of starch or some other quickly-digested carbs, and that effect was blocked by taking BCAAs. I assume the carbs triggered an increase in insulin, which increased tryptophan transport into the brain, and thus increased the production of neurotoxic kynurenines.

I'd question whether you are really feeling brain inflammation, or just feeling the symptoms normally associated with brain inflammation, which might actually be due to those nasty kynurenines (or possibly some other mechanism). If it is kynurenines, and you for some reason already have high levels of TRP in your brain, then the insulin response might not make a difference.
 

percyval577

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There have been times when I've felt up to some strenuous activity (long hikes or bike rides, sawing firewood, digging, etc) and have felt 'healthy fatigue'. It's hard to describe the difference, but there definitely is a difference between healthy physical fatigue and my ME symptoms. I don't even want to call my ME symptoms 'fatigue', ...
If this isn´t key I am an aircraft.

My theory on that, before I even knew about ME, was that physical activity triggers an increase in IFN-g 24 hrs later (lost the reference to that, but it was a journal paper), which ...
But how could that explain pacing?

Any illness where you need to rest for healing would take any (relevant) effort as the same hindering.

Any "normal" illness where you are specifically damaged here or there doesn´t allow for pacing in itself.