Exhaustion in ME/CFS, what is it and what causes it - discussion thread

[Amw66]

But the question is - what is 'exhaustion' in the context of ME/CFS. We have little evidence that it is actually depletion of energy reserves or a 'run down battery'. It certainly seems to feel like that but there is no shortage of oxygen or glucose and almost certainly not of ATP. More likely something is shifting the power usage regulator to the wrong position and that is apparent partly through a completely involuntary block and partly through a sense of intolerability that prevents voluntary effort.

But what is the ATP doing.
It's a key signalling molecule so it may well not be operating in it's " energy" mode.

 

[MrMagoo]

I’d also say we’re not going to agree here on what ME is, there are various theories and it seems that there are differences in how medics interpret words, to how lay people do.

 

[Jonathan Edwards]

So I think what I’m trying to suggest is that there might well be more than one process involved in what limits the exertions of pwme.

Yes, that sounds right. I see at least two aspects to the immediate difficulty of doing something and with Sean there seems to be agreement that there is the third issue of pacing. The 'block' and the 'intolerability' aspects may seem confusing but I think that is how the central nervous system always responds to immune/danger signals. I recall now that even with my relatively trivial 'Long Covid' there was a combination of simply not being able to do something - maybe get up off the floor after trying to sweep a grubby bit of the kitchen, or just going up stairs - and waves of nausea and sweatiness that made doing things unpleasant. And as Kitty emphasised the two seemed to swing in and swing out independently even though they were presumably part of the same signalling system designed to STOP.

But then, yes, there is the feedback loop with downward spiral. The wrong signalling appears to induce even-more-wrong signalling. I am familiar with that from RA, which is a downward spiral into autoantibody formation. In RA both aspects - the bad signals and the loop to more bad signals - are mediated by antibodies but through different pathways. How that might apply in ME/CFS I have no real idea but again, at least it is a model that we are familiar with from diseases we do understand a bit.

 

[Jonathan Edwards]

I’d also say we’re not going to agree here on what ME is, there are various theories and it seems that there are differences in how medical interpret words to how lay people do.

There are lots of theories but I don't see those as ME. I see ME/CFS as a clinical pattern of illness that we want to find the right theory for. I would hope we could agree what that pattern is - focused on PEM at least.

But it may be that there are members with really quite different symptom patterns. If so it would be useful to tease that out. I tend to take the view that if I at least am trying very hard to understand what the disease feels like and without any preconceived theory, then if people with the disease hope to get doctors to understand what it is like then getting me to understand ought to be a reasonable test of that being likely to work!!

 

[Robert 1973]

There is nothing to suggest a significant shortage of oxygen is involved in the vast majority of ME/CFS symptoms.

Is there not some evidence which suggests impaired oxygen extraction? From memory, the CPET studies and studies looking at endothelial cells.

 

[Haveyoutriedyoga]

Might be repeating something already said but...

The energy factor comes into the conversation because when we do stuff, we get the symptoms, and we associate doing stuff with using energy, and the symptoms we get are ones we have traditionally learned are symptoms of low energy.

 

[Jonathan Edwards]

But what is the ATP doing.
It's a key signalling molecule so it may well not be operating in it's " energy" mode.

I don't really follow.

I am suggesting that ATP is not being used because its use is blocked or not switched on probably via the balance of kinases.

If ATP is still involved in some signalling that may be, but is a different matter. ATP may be a signalling mediator but it is not going to be a control factor like a cytokine or a nerve pathway

 

[Hoopoe]

It certainly seems to feel like that but there is no shortage of oxygen or glucose and almost certainly not of ATP.

I suspect that there are multiple kinds of fatigue that the same patient can experience. Or maybe it's better to think of different aspects of fatigue because they overlap to some degree.

I may be in a specific subgroup, but for me, eating can have a marked effect on fatigue in some circumstances. So it must have something to do with glucose, or something like potassium shifts in muscle ion channelopathies, or some response by the body to eating (maybe preparing for digestion changes some nerve and blood flow activity in a way that is fatigue relieving).

Another kind of fatige accompanies PEM.

Then there's rapid muscle fatigueability where muscles just can't seem to handle more than a very small amount of work. They begin burning very quickly, can't reach their normal level of strength, and using them is unpleasant. Once these muscles are tired they can lead to a general nonlocalizable feeling of fatigue.

 

[Jonathan Edwards]

Is there not some evidence which suggests impaired oxygen extraction? From memory, the CPET studies and studies looking at endothelial cells.

I am not sure there is anything very robust. But impaired oxygen extraction would suggest to me that the cells had received signals that inhibited their use of oxygen, not that oxygen supply was short. Short oxygen supply would show up on blood gas analysis or reduced blood flow.

 

[Kitty]

But it may be that there are members with really quite different symptom patterns. If so it would be useful to tease that out.

Maybe one of the basic points to establish is that people can't make assumptions about managing severe/very severe ME based on a familiarity with mild or moderate ME.

The underlying problem might be the same, and in some respects the approach is similar—clinicians know next to nothing about it, so all they can do is deal with what's in front of them—but the risks for patients and the consequences of small actions can be worlds apart.

 

[Creekside]

More likely something is shifting the power usage regulator to the wrong position

That's one possibility, with the "power regulator" being neurons and glial cells, and possibly various sensors and reactors (endothial function, for example). Making muscles move involves a bidirectional network of components, so it's hard to isolate just which component is malfunctioning.

Are there toxins or other chemicals that produce a similar effect? There are some that prevent muscles from working properly. Are there any that affect the brain's portion of muscles working properly?

It is a block to action at a level below anything voluntary, combined with a voluntary limitation because of the awfulness of how it feels.

That's my feeling about it. On Monday, I drove to town. The next day I felt lethargic and brainfogged (PEM, I think). My body could have done strenuous activities if necessary, but the "awfulness" made me decide to read instead. It's not exhaustion, but it's a similar mental hurdle that affects decision making.


In recent threads about ME and energy, fatigue, and now exhaustion, I haven't seen any mention of central fatigue. I'm not sure whether central fatigue is better defined or understood than normal fatigue, but it does seem a better match for ME's symptom. My initial flare-up of ME felt identical to a flu coming on, including the central fatigue and aches and touch sensitivity. I don't recall any claims that the "fatigue" from colds and flus is due to lack of ATP, or oxygen uptake of cells or most of the other hypotheses made for ME. From what I've read, it's accepted that there's dysfunction of brain cells causing those symptoms.

 

[Amw66]

I don't really follow.

I am suggesting that ATP is not being used because its use is blocked or not switched on probably via the balance of kinases.

If ATP is still involved in some signalling that may be, but is a different matter. ATP may be a signalling mediator but it is not going to be a control factor like a cytokine or a nerve pathway

From memory ( so I could be wrong) ATP is used as a distress signal when cells are under stress .
It becomes an extra cellular regulator.

It may not be the amount of ATP, but what it's doing/ facilitating .

 

[Creekside]

If it is based on a complex inhibitory mechanism it makes perfect sense and restores ME/CFS to the world of real illness where we see that all the time.

Well, since the symptoms are so similar to what we feel from a cold or flu, it should be accepted. Science don't know exactly why/how we feel "lousy" with a cold or flu, but it's accepted that we can't operate as normal.

 

[Kitty]

I may be in a specific subgroup, but for me, eating can have a marked effect on fatigue in some circumstances. So it must have something to do with glucose, or something like potassium shifts in muscle ion channelopathies, or some response by the body to eating

Yes, me too. To all food, but a particularly enervating response to meals containing higher levels of glucose and salt, which leave me with such floppy muscles I struggle to stand or walk. It's even worse if I rest completely after a bout of vigorous (well, vigorous by my standards) activity.

It doesn't seem to be all that typical of ME, so I'm never sure about it. I probably talk about it too often, tbh, but it is one of the more difficult symptoms.

 

[Creekside]

I think any discussion of the physical limitations of ME needs to account for both Fatiguability AND PEM, because in my experience they are very different beasts.

I don't think I had extra "fatiguability" from ME. I had hurdles in the way of pain or "feeling lousy", but I don't think my body's ability to do tasks was reduced. PEM simply increased those hurdles.

Yet I also wonder do we need another PEM category? PEM+D

I think that's not a separate form of PEM, but rather a different response to PEM. Imagine that PEM was caused by an excess of a waste product, and some people have waste removal mechanisms that are less or more effective.

 

[cassava7]

Is exhaustion in ME/CFS not some specific kind of sickness behaviour similar to that which kicks in when someone is down with an infection or other illness (which as far as I’m aware doesn’t have to do with ATP / energy production)?

Then the question is not so much what it is but what triggers it.

We had discussed a neuroscience paper on sickness behaviour two years ago: https://www.s4me.info/threads/brain...-sickness-behaviour-2022-ilanges-et-al.29401/

 

[Mij]

Sickness behaviour has never negatively affected my cognitive energy, balance or speech. Not during viral-onset M.E for 6 years or when I contracted Covid and couldn't stand or walk for weeks. It feels very different from what I experience with delayed PEM and M.E.

 

[Jonathan Edwards]

Is exhaustion in ME/CFS not some specific kind of sickness behaviour similar to that which kicks in when someone is down with an infection or other illness

It might be, but then it might be something of the same sort but importantly different. When I had Covid I had 'sickness behaviour' as for flu. I knew when that had gone but it was replaced by something a bit different. The same happened for EBV for me. People have talked of a hibernation response and maybe that is not unreasonable. You are out of jail but still on probation with a ball and chain round your ankle.

 

[cassava7]

It might be, but then it might be something of the same sort but importantly different. When I had Covid I had 'sickness behaviour' as for flu. I knew when that had gone but it was replaced by something a bit different. The same happened for EBV for me. People have talked of a hibernation response and maybe that is not unreasonable. You are out of jail but still on probation with a ball and chain round your ankle.

Fair point, this is indeed what it does feel like — at least for mild to moderate ME/CFS.

 

[JemPD]

Maybe one of the basic points to establish is that people can't make assumptions about managing severe/very severe ME based on a familiarity with mild or moderate ME.

indeed. Particularly with it being called CFS, and with so called mild/moderate being the majority, the assumption that the mild/mod experience is the same as severe but with severe just being a bit worse, is misleading i think.

I suspect this is part of what gives rise to the 'how can feeling exhausted possibly cause ____?' thing.
Particulary among drs, who will have worked to the point of utter exhaustion, and through it, during training & in their professional lives all the time, i image ED drs especially.

My initial flare-up of ME felt identical to a flu coming on, including the central fatigue and aches and touch sensitivity.

mine too and continues to, i feel all the time as if i have some degree of flu/virus/bacterial infection - which all feel the same to me and from which ME is only distinguishable by the lack of actual fever & sinus symptoms. When i'm well rested & at my best, i feel (whilever i remain supine) like i am coming down with something, as soon as i do anything it gets a little worse, and PEM is the full blown influenza Plus other symptoms on top.

The only way i can distinguish my ME from an actual infection is when i realise the symptoms arent fluctuating - if i go a few days without fluctuation i think 'oh, perhaps i have actually got something' & i take my temperature... & viola! Last time that happened i also looked in my throat which was sore (but its often sore as part of PEM- glands up etc) & there were big yellow pustules all over it & my temp was 39, at which point i thought wow it took me 4 days to realise that it was an actual virus/infection/whatever. I had chills/was sweating, but then i often a. Its indistinguishable apart from the lack of fluctuation.

Obviously have other symptoms too but the underlying thing is always essentially having the flu. Which is why i struggle so much with it being called 'fatigue' - not raising that here - i accept that we're calling it that, but being exhausted & having flu (ie being ill) are just such different bodily sensations for me, that i struggle with calling it that for myself. It just feels so inaccurate.

Well, since the symptoms are so similar to what we feel from a cold or flu, it should be accepted. Science don't know exactly why/how we feel "lousy" with a cold or flu, but it's accepted that we can't operate as normal.

Yes wasnt there some research, back by but not necessarily funded by the MEA in around 2010/2011 that tested interferon (i think thats the name of the drug - one thats used in MS & causes flu-like symptoms???) to see whether that would tell us anything - dont know what became of that.