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Does existing science sufficiently demonstrate that exertion is the correct focus concept?

Discussion in 'Post-Exertional malaise and fatigue' started by Samuel, Oct 7, 2018.

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  1. alex3619

    alex3619 Senior Member (Voting Rights)

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    I have lamented elsewhere that really really need not just a diagnostic biomarker for ME but also for PEM. Its so easy to get into blurred arguments simply because we do not really understand what ME and PEM are. We do however have a good understanding of aspects of the pathophysiology.

    To me the current focus of the debate is more about energy deficit, and how that happens, than PEM. PEM is associated with energy deficit, but you can be a severe patient, not engaging in activity, and be in a very bad way. No PEM required. I have put forward the hypothesis quite a few times now, though slightly differently to here, that very severe patients do not make enough energy via the aerobic system for their body to properly manage the basic housekeeping functions. In theory you could run a metabolic rate test on severe patients and show major deficits without resorting to CPET.

    We seem to get PEM when there is a demand on our energy system, and we cannot manage it. The body then goes into alternative pathways. In the test tube this can be shown by a salt stress test on blood cells using the nanoneedle. In CPET its repeat exercise testing, looking particularly at power output on day 2 of the test.

    I think this focus on PEM is due to both historical reasons (its what is usually different to other diseases, even MS) and now we have CPET to measure aerobic energy capacity and how it changes after activity. We have the test, we will investigate this angle. Other angles are not investigated I think because we either lack the technology to do it properly, or are not aware of the technology to do it properly.

    I think energy deficit is a core principle. PEM and fatigue are most likely both secondary to that. However in a clinical workup a clinician can ask questions related to both PEM and fatigue and get a better sense of what is going on, even before advanced testing.

    The second issue seems to be that activity causes a crash in energy availability. This is the opposite of what usually happens with healthy people.

    One recent hypothesis about PEM is that its due to ammonia build-up from excessive use of protein for energy in us. This can now be tested for, but so far the Open Medicine group has not done so . . . I think because the pandemic has stuffed up the testing schedule. Similarly they designed a nanoneedle that can test 100 samples instead of one at the same time, but its delayed because the pandemic has caused issues with manufacturing the device.

    I probably have more to say but I need to shut down my computer, lightning is raining down outside.
     
    Last edited: Oct 31, 2020
  2. alex3619

    alex3619 Senior Member (Voting Rights)

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    Lightning is quiet for now, so here goes.

    The finding of the "something in the blood" offers an additional angle. Something is suppressing energy production, and its either a very large molecule or a group of molecules together, such as in a vesicle. While we don't know what triggers that, nor what the substance/s is/are, we can infer that if patients are worse after activity and a crash then there are three more likely options. Its due to a mechanism specific to the crash, such as ammonia. Or its due to a feedback mechanism, possibly involving the "something" we have yet to identify. Or its both. Of course which explanations are in play may not be stable between patients or even in the same patient over time. There might be a range of ways to crash. Sigh. I am of course forced to ignore the possibility that there is something major we have not discovered yet. That is always possible until we have very robust answers.

    This comes down to both basic biochemistry, and how to model the physiology so we understand what is happening. That means we still need to back our scientists.

    PEM is a surrogate for real understanding, but its a label we can use pragmatically to help us manage our illness. Its very hard for us to reason about things if we don't even have names for these things.

    PEM is also useful to understand, however imperfectly, because it assists in comparing experimental findings. A research cohort where PEM is not required versus one where it is mandatory, or as good as required with our limited testing capability, may give very different results.
     
  3. Wonko

    Wonko Senior Member (Voting Rights)

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    Lightning is always quiet, silent in fact.

    If you study lightning in isolation, (not in a vacuum lol) then you would have no idea why seconds to minutes later there would be sound.

    The problem is made more difficult because lightning is hard to study, it's difficult to run experiments on, until you understand what it is. Most of the time it's difficult to even be sure it's occurred unless it keep recurring in a particular area.

    Hence...angry gods make it.

    I suspect we are still at the level where 'angry gods' cause PEM.
     
    Last edited: Oct 31, 2020
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  4. Mij

    Mij Senior Member (Voting Rights)

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    I know this wasn't addressed to me, but my experience is that 'crashes' can be caused by many triggers, such as food sensitivities, allergies, sensory issues (noise, fragrances, light overload), emotional stress, ignorant remarks etc, for me it's an instant reaction.

    When in PEM, it is a delayed effect of going over/pushing one's energy and stamina boundary, and going over one's limited 'energy window'. Post exertional malaise as all-encompassing with symptoms affecting every part of the body, and requiring complete bedrest to fully or partially recover that can take up to 3 days or more depending on the energy expenditure. Also, if we continue to go over our energy limit, it can also make us permanently worse in the long run.

    And then there are relapses that can occur from viruses, treatments etc, that can make you worse off and permanently change your baseline.
     
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  5. Creekside

    Creekside Senior Member (Voting Rights)

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    Actually, I'm a poor choice for explaining the differences, because my PEM was non-standard in some ways and I never had crashes. I've simply read lots of other people report a wide variety of responses that get labelled "PEM", which I didn't experience myself.

    For me, PEM was simply a worsening of my general ME symptoms. It would flare up fairly abruptly after a delay: a consistent 24 hr delay from physical exertion, and a variable delay from cerebral exertion, sometimes under an hour delay. My PEM would last for quite a few hours, but not days. It certainly can be hard to distinguish PEM from worsening of symptoms from other factors, such as food sensitivities or viral infections. I certainly couldn't tell the difference.

    Not for me. My trigger didn't seem to be an energy boundary; it seemed to be the usage of muscles beyond their normal usage. I could go for a 20 km bike ride without triggering PEM, but climbing a ladder once (stresses the same muscles to different degrees) would trigger PEM. A 40 km ride would trigger mild PEM, but that's probably accumulated muscle cell damage rather than some metabolic limit. The 40 km rides often involved more steep hills too. Likewise, I could dig soil for hours without triggering PEM if I stuck to the standard movements (stomp shovel in, pull, then heave), but digging with different muscle motions (stab blade forward into soil bank), even a minute or two would be enough to trigger PEM 24 hrs later.

    It's no impossible that I experienced an energy deficit in those lesser-used muscle cells, but I think that's an unlikely explanation for my PEM triggering. I noticed this 'feel better, so go for long bike ride, then feel worse the next day' phenomenon before I knew about ME and PEM, so when I read that IFN-g rises 24 hrs after exertion, I took that as the explanation. It fit the consistent 24 hr delay, and getting the same symptoms from type IV food sensitivities and viral infections (both increase IFN-g) and it also fit how my ME symptom severity correlated with tryptophan levels in my brain: increasing IFN-g increases IDO production in glial cells, which converts TRP into nasty neurotoxic kynurenines, which cause the ME symptoms (and for viral infection symptoms too).

    My ME did not affect my stamina or strength, so from my ME experiences, energy limitation is not a core symptom or dysfunction of ME. It may be a common secondary symptom, and might be explained by neurochemical changes (hormones, nerve signalling, whatever). I think ME's core dysfunction involves glial cells. Which parts of the brain are affected determines what primary and downstream symptoms the individual experiences, and also what factors they are sensitive to to what degree.
     
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  6. Mij

    Mij Senior Member (Voting Rights)

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    But that is the definition of PEM (post exertional malaise).
     
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  7. alex3619

    alex3619 Senior Member (Voting Rights)

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    My comment reflects the notion of a low respiratory reserve. Its not that mild patients do not have energy, its that there is a limit, associated with severity, on how much they can ramp up energy production at the mitochondrial level. Mild patients can indeed exercise to a point, I did myself when I was mild, but from my observation as we get worse that capacity goes away. In very severe patients I hypothesize there is insufficient energy production for anything over bare survival, and almost no capacity to increase that. We could test that with metabolic rate testing.

    This is worsened by energy production going down after activity, by as much as 44% decline in CPET results on a repeat test. This is either damage or a feedback mechanism so far as I can see. Healthy people have an increase by as much as 7% the day after exercise. This decline in energy output on day two seems to be closely associated with PEM. The exact relationship is unknown until we have specific mechanisms.

    Many illnesses have exercise intolerance. To date only ME (and hence strictly defined CFS such as with the CCC) has this crash in energy production after activity.

    From what I see PEM is the label we give to clusters of symptoms. We need mechanisms to really understand this.

    Energy deficiency can potentially occur in any active tissue. Not just muscle. Stanford measures it in blood cells.

    Further I am not claiming energy deficit triggers PEM, though I think it possible. I am saying that energy deficit is probably more the core of the problem than what we label PEM. What we call PEM may be secondary.

    What happens with PEM in formerly very fit people may not be identical to what happens with PEM in everyone else. However so far we see that ME prevents successful aerobic conditioning.

    Any glial cell hypothesis has to explain why we can see an energy crash in blood samples. Since we don't currently know what factors are doing this, its possible some or all might be from glial cells, or other cell lines. We just do not know. What we can say is that any hypothesis of a central brain cause of ME is looking much more unlikely over time. That does not mean its not part of a larger mechanism though, with chemical signalling throughout the body.

    PS There is also the issue that when we have an energy demand we can often supply it by other means, including the lactate shunt and using amino acids as fuel. This may have other secondary consequences. If anyone has a good scientific reference on what elevated lactate does to the chemistry of the liver I would like to see it. If the liver is subject to waves of elevated lactic acid on a chronic basis, what happens?
     
    Last edited: Oct 31, 2020
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  8. Kitty

    Kitty Senior Member (Voting Rights)

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    I experience something comparable too. Once I've got used to swimming again during a period of improved and more stable ME, I can swim between 1500 and 2000 metres as long as I rest before and afterwards.

    Last week I moved my old mattress off the bed and replaced it with a new one. It took less than 15 minutes of shoving and manoeuvring, and required much less energy, strength, and endurance than a swim. I didn't have to drive there and back, shower afterwards, dry my hair, or wash my kit, either. I'd had a rest day the day before, and I didn't do much else that day because I was chilled out listening to an audio book.

    Sore throat, swollen glands, flat out for 48 hours.

    I don't have any theories about it, though...doesn't make any bloody sense at all to me! :confused:
     
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  9. Forbin

    Forbin Senior Member (Voting Rights)

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    This study, by Drs. Alan and Kathleen Light, showed significant increases in the expression of certain sensory, adrenergic and immune genes over time in CFS patients vs control following moderate exercise.

    The top line shows the controls. The CFS patient response is at the bottom. Alan Light said the difference was even greater because the normalized baseline was higher in the CFS patients to begin with.

    It's tempting to imagine that this is a visualization of PEM in action - especially with the peak occurring 8 - 24 hrs. later.


    Light study.jpg
     
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  10. Kitty

    Kitty Senior Member (Voting Rights)

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    Thanks, I'd forgotten all about this. I wonder if anyone has tried to replicate it – from the point of view of someone without medical knowledge, it looks interesting!
     
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  11. Mij

    Mij Senior Member (Voting Rights)

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    I find that I'm ok if I only use specific muscles groups at a time. I can power walk, but can't take a shower afterwards because of the warm water, and it would require using my arms. I can lift light weight afterwards as long as I dont' raise my arms above my shoulders.

    I could never swim or use a rowing machine because it requires using my arms and legs. That would be a disaster for me.
     
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  12. Kitty

    Kitty Senior Member (Voting Rights)

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    I don't kick at all. I use a pull buoy when I'm still rebuilding my core muscles after an enforced break from swimming, and once I'm strong enough to hold my position high in the water, I just let my legs float behind me.

    Outside of elite racing, the kick doesn't contributes much forward propulsion to freestyle and backstroke; it's more about maintaining balance and good body position. If the timing or technique of the kick is really poor, it can actually hinder propulsion.
     
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  13. alex3619

    alex3619 Senior Member (Voting Rights)

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    Going back to the question in the thread title, is exertion the correct focus?

    I would like to answer this slightly differently than before. Exertion is what reveals the problems, its a way of highlighting them. Its not the problems themselves. Exertion leads to consequences that might highlight the problems, and often exertion is a good target for many reasons, but its not the underlying problems.

    A similar concept is used in the glucose tolerance test, often used in diabetics and suspected diabetics. You challenge with glucose to find out what happens. Exertion in ME is a similar concept.

    Its in management of symptoms that exertion is important. If you know that exerting specific ways creates problems then you have a management target. This is a practical application.

    In the science exertion is just another way of challenging the body or sample to find out what happens. Its a tool. Examples are CPET and salt loading of blood cells.
     
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  14. Kitty

    Kitty Senior Member (Voting Rights)

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    Been mulling about this too. In my view, the original list of 'intolerances' (which is a very perceptive way of looking at them), all do arguably involve exertion.

    It's not all voluntary effort – there are involuntary types of exertion, such as having to tolerate being stimulated by noises, smells, or the presence of another person – but if a thing consumes energy over and above what is necessary for the maintenance of life, is it not a type of exertion?

    Perhaps it's more accurate* and inclusive if we talk about our problems as arising from challenges with energy production rather than exertion, though. It's easier for other people to understand that less tangible things like sensory stimulation, digestion, emotion, medication reactions, and stress, all consume energy.


    ETA: *Perhaps not more accurate, as I'm not sure this has definitively been proven yet...but it is more inclusive.
     
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  15. Creekside

    Creekside Senior Member (Voting Rights)

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    I suffered malaise after exertion, so that's within the definition. It doesn't say post exertional endurance loss.

    That didn't seem to be part of my PEM either. I felt much worse when the PEM kicked in, but I didn't notice any reduction in endurance. I expect that my legs would have managed the same 40 km ride 24 hrs later; I just would have had to put up with the lack of will to do so, and the neuropathic pain and so forth.

    Since I didn't notice any such energy deficit, I can't consider energy deficit a core problem for PEM or ME. I do agree that PEM is secondary, since I've managed to cure mine, but still have the other ME symptoms.

    Not to me. I've recently come across several papers that support it. Since the brain controls a lot of bodily processes, it might control the 'something in the blood' too, and glial cells are critical for brain functions, so a problem there can show up elsewhere in the body.
     
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  16. Creekside

    Creekside Senior Member (Voting Rights)

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    It makes perfect sense to me. You used muscles beyond their normal limits, which triggered your immune system to clean up the damaged cells, and the resultant cytokines caused your symptoms, directly or indirectly.
     
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  17. alex3619

    alex3619 Senior Member (Voting Rights)

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    Then, based on published research, it looks like your result is an outlier.

    I do know that some who probably have ME who were very fit at the time have been able to maintain a lot of that fitness. Alistair Lynch, a footballer in Australia, managed to keep playing professional football for a while, but had major difficulties.

    A problem with low respiratory reserve is you may not see the deficit, especially if you used to be fit. Alternative pathways kick in to provide energy, leading to (amongst other things) lactic acid building up. One of the hypotheses looking to be tested is that the post exertional issue is due to amino acids being overused for energy, hence resulting in elevated ammonia. We might have this ruled in or out soon, Stanford now has the capacity to test for this.

    There is no question there are post-exertional epigenetic changes, barring further and better studies showing otherwise. Its not been demonstrated that in ME this is due to cytokines so far as I am aware. I am not sure its ruled out either. Cytokine research has a checkered history in ME.

    Cytokine changes in CSF after exercise probably need more evaluation though. This is invasive testing however, drawing CSF has risks.

    I do not rule out glial cell involvement, but its a long stretch to claim its causal at this point. It might be. Or not. It just does not explain how there are persistent changes in cell cultures from ME patients over time. This aspect does need much better studies though. The factor that causes what looks like an energy deficit in our cells, with an apparent inability to pump abnormal quantities of sodium (my current interpretation) is a very large molecule, or a large vesicle, or something of that order. Its not a cytokine from what I can tell. Its in the large protein range, at around 10,000 kda if I recall correctly. Now vesicles can contain many different cytokines, and there is definitely something abnormal about ours, so this does not completely rule out cytokines. This does of course raise the question, if you presume a glial cell source, of how vesicles are crossing the blood brain barrier. You might have to invoke the possibility that the vesicles, and cytokines, are triggered by glial cells but originate elsewhere in the immune system.

    I am also very unsure how cytokines could impede sodium channels in cells. Maybe.

    One thing I do say a lot though is that we need to pursue every angle until we have enough data. We clearly do not yet have enough data.
     
    Last edited: Nov 1, 2020
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  18. Mij

    Mij Senior Member (Voting Rights)

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    True, but PEM is a very poor definition that doesn't even come close to describing how we feel after going over our 'energy window'.
     
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  19. alex3619

    alex3619 Senior Member (Voting Rights)

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    PEM or exercise intolerance, which is similar but has different energetics? Most ME patients seem to have difficulty producing power on demand, and this crashes after overexertion. One probable causal factor is in the blood, but as yet unidentified. There may be many more.

    One issue that remains unanswered though is what happens to all this chemistry to someone who was very fit when getting ME? There is literally no research on this that I am aware of. So an outlier experience might mean the diagnosis is wrong, or the diagnosis is right but ME is a superfamily of diagnoses, or even a spectrum disorder; or that being fit or some other factor changes the presentation of the problem in an ME patient. We literally do not know.
     
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  20. Creekside

    Creekside Senior Member (Voting Rights)

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    I'm definitely an outlier. Others have reported ME with no loss of physical performance, but I also was very effectively treated by cumin and T2, which haven't worked for anyone else. I think that outliers have the potential to reveal otherwise hidden aspects of ME, but as you say, we could also have unique characteristics that don't apply to other PWME.

    I'm not presuming that glial cells are the source of the 'something in the blood'. I'm suggesting that functionally-altered glial cells alter other brain cells, which in turn control hormones and other processes, which could alter cell functions elsewhere in the body, which could result in that 'something'. The brain is the master controller for a lot of body functions.
     
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