Endothelial dysfunction in ME/CFS patients, 2023, Sandvik, Mella, Fluge et al

[Hutan]

Here is the latest data, where my current status is "not too bad, generally house-bound" but not quite the best it's been during this illness.

I've made a thread to talk about gait. It would be good to hear more about your interesting finding on that thread:
Gait in ME/CFS

 

[JemPD]

I’m not sure if the study he was referring to was ever published. Does it ring any bells with anyone?

Yes, i remember that, it was definitely published, I'm pretty sure it was done by Julia Newton.

Contrary to most responses, I find your observations are insightful and not veering towards BPS territory.

Goodness i hope my response wasnt interpreted like that! I would never think JE was veering towards BPS!
I was merely verbally ruminating about movement changes. @Jonathan Edwards insight is really interesting & valuable, I was just trying to understand the difference between ATP movement changes & what happens to me.

 

[Robert 1973]

Yes, i remember that, it was definitely published, I'm pretty sure it was done by Julia Newton.

Thanks I think this may have been the paper he was referring to, although there may be others:

Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case–control study, Newton at al (2011): https://doi.org/10.1111/j.1365-2362.2011.02567.x

From the Abstract:

Results Chronic fatigue syndrome patients undertaking MVC fell into two distinct groups: 8 (45%) showed normal PCr depletion in response to exercise at 35% of MVC (PCr depletion >33%; lower 95% CI for controls); 10 CFS patients had low PCr depletion (generating abnormally low MVC values). The CFS whole group exhibited significantly reduced anaerobic threshold, heart rate, VO2, VO2 peak and peak work compared to controls. Resting muscle pH was similar in controls and both CFS patient groups. However, the CFS group achieving normal PCr depletion values showed increased intramuscular acidosis compared to controls after similar work after each of the three exercise periods with no apparent reduction in acidosis with repeat exercise of the type reported in normal subjects. This CFS group also exhibited significant prolongation (almost 4-fold) of the time taken for pH to recover to baseline.

I also echo comments above. I’ve never interpreted Jonathan’s comments as “veering towards BPS territory” and I hugely value his input as a disinterested expert observer whose only interest appears to be in understanding the truth – wherever that may lead – and helping patients. I also welcome that fact that he says what he thinks, even if it’s not popular, and is willing to listen to counter-arguments and change his mind. I just wish I could persuade him to call me Rob instead of Robert!

 

[Jonathan Edwards]

But there's a cost. If it was just faulty signalling (which sounds rather like the central sensitisation theory) then people should be able to push past the signalling, and suffer no ill effects. That's not what happens. It took a couple of weeks to get back to my baseline level of functioning after those two days.

But to me faulty signalling makes much more sense than lack of ATP. Lack of ATP should last for a minute or two, maybe twenty minutes after a marathon run. If the faulty signalling involves hormonal signals or sleep centre cycles or other systems that audit activity over longer periods then delayed recovery makes a lot of sense to me.

If I exercise more than usual I may well be aware of the effects for several days. Signals bring in macrophages to muscle for several days. Growth hormone effects that mediate bone responses work over an extended period, and so on. And that is the normal situation.

 

[Jonathan Edwards]

Jo, If ME/CFS was a signalling problem would that be something that would be detectable in the blood as with TNF? Or are there other types of signalling problem that could be occurring?

If the signalling is neural, no. If it is cytokine or hormonal maybe but maybe not. We have learnt that a lot of chemical signals act quite locally. If there is a secondary impact on nerve fibres then the effects are all invisible but generalised.

 

[Mij]

I may be wrong but this is a view strongly endorsed by a colleague who works full time with people with mitochondrial disease. He said the picture was quite different.

I would describe my PEM movements similar to ataxia with less power in my arms and legs and balance problems. I walk into people. I slur and have difficulty processing information.

 

[Simon M]

@Jonathan Edwards, how does the inhibitory signal model explains the consequences of overriding that signal?

When we have flu or are ill and press on, we usually feel terrible soon afterwards.

Is that an extra level of inhibitory signal trying to reinforce the message, or is the ill feeling caused by something else?

Similarly, in the case of overdoing things with ME would the model put PEM, or even relapses, down to more inhibitory signals or some other mechanism?

Comparison with the central sensitisation theory

@Hutan noted some similarity with the idea of central sensitisation. This proposes that due to problems in the brain (thalamus/insula), people with ME are oversensitive to normal signals and so experience excessive fatigue/pain/symptoms. It's a biological veneer for a psychosocial theory.

It's logical conclusion is that we can safely override the warning signs from our body ("hurt does not mean harm"). The idea fails because when we do the consequences are awful.

The hypothesis assumes faulty interpretation of normal signals, rather than an inhibitory signal.

 

[josepdelafuente]

@Jonathan Edwards, how does the inhibitory signal model explains the consequences of overriding that signal?

When we have flu or are ill and press on, we usually feel terrible soon afterwards.

Is that an extra level of inhibitory signal trying to reinforce the message, or is the ill feeling caused by something else?

Similarly, in the case of overdoing things with ME would the model put PEM, or even relapses, down to more inhibitory signals or some other mechanism?

I think I was also wondering this, though not sure how to articulate it. Thanks for articulating it so clearly @Simon M !

 

[Jonathan Edwards]

Is that an extra level of inhibitory signal trying to reinforce the message, or is the ill feeling caused by something else?

Similarly, in the case of overdoing things with ME would the model put PEM, or even relapses, down to more inhibitory signals or some other mechanism?

I don't think anyone knows.

I think discussion in terms of 'faulty interpretation of normal signals' ends up meaning whatever you like unless one is specific. All signals will have a normal function at the right time. Interpretation may just mean the way another sort of signal follows the first and then you go round in circles asking which is the first one to be inappropriate.

My post-Covid fatigue feels like peripheral sensitisation in that I have no doubt that I am getting sensory signals that would normally indicate I am ill. In ME light sensitivity suggests a more central problem but still not necessarily thalamic.

I suspect that there is maybe some abnormal dialogue between peripheral sensory structures and hypothalamus in ME. Certainly the 'central sensitisation' story I hear from the BPS crowd seem to me to be disingenuous pseudo models that justify a psychodynamic narrative that is conveniently hidden.

There is a world of difference between hypothalamus and thalamus/insula/cingulate, limbic structures etc.

 

[Hutan]

My post-Covid fatigue feels like peripheral sensitisation in that I have no doubt that I am getting sensory signals that would normally indicate I am ill. In ME light sensitivity suggests a more central problem but still not necessarily thalamic.

I don't have light sensitivity. I don't have a sensitivity to foods that I have noticed. I don't have sound sensitivity, except when in PEM, when any stimulation can feel like too much, a bit like when you have a headache, you really don't want the neighbour mowing the lawn with their petrol mower.

Maybe what I have is only a post-viral syndrome, but it's been 10 years now and I do get PEM, and it's quite awful enough. I don't know how to explain the presence or absence of sensitivities within the one syndrome - perhaps the pieces don't fit. However, I think it might be partly to do with severity; perhaps when severe there is less capacity to process stimuli, just as there is less capacity to do anything.

Just as some of the mitochondrial diseases can have quite a spectrum of presentations, maybe depending on the impact of other genes, maybe that is also true of ME/CFS. For what I have, I don't believe that sensitivities are a necessary part, a core part, of the illness.

 

[Jonathan Edwards]

Yes, I raised light sensitivity because it might seem central but it is still not central in the central sensitisation sense. So case unproven.

Tipping into PEM where any stimulus is too much seems to me to distinguish the valid concept of ME from what I have (and had fifty years ago). My symptoms are frustrating but not more than that. If you have to go to work to pay the rent then what I have had would be a big problem but not ME. I suspect that the problems I am left with are old age even if I never had tingling in my hands before, or pains at night in my shins.

I think the severity thing is relevant. I sort of see this a bit like what laptops do when software screws up. First of all there is a pink dotted box with red words saying 'error, username or password incorrect'. Then there is a new page saying 'three incorrect entries have been made, the site is no longer accessible'. Then there is the page and you cursor freezing so that you have to reboot. And so on. I suspect that our neuroimmune apparatus has a complex repertoire of such inhibitory signals. The irony is, of course, the the origin of the problem might be you having your password written wrong in your diary or it might be somebody has devised some lousy software or there has been an update not recognised by your system or all sorts of other things. The battery might be nearly run down and the connection need a certain voltage (what happens with my hearing aids).

 

[Simon M]

Me: how does the inhibitory signal model explains the consequences of overriding that signal?

I don't think anyone knows.

I was hoping that, at least in the case of illness, we would know what causes the reaction to overexertion – because that would good be a clue to what is going wrong in ME.

Do you see a way to investigate the idea of an inhibitory signal being at the heart of the illness?

 

[Jonathan Edwards]

I was hoping that, at least in the case of illness, we would know what causes the reaction to overexertion – because that would good be a clue to what is going wrong in ME.

Do you see a way to investigate the idea of an inhibitory signal being at the heart of the illness?

Good points @Simon M.

Feeling terrible when trying to move with flu is attributed to cytokines like TNF and Interferon sensitising nerves. The precise mechanism may not be clear but release of prostanoids (potent neural sensitisers, as indicated by the effect of ibuprofen) would be an obvious intermediary.

But I think we recognise more than that. We soldier on with flu for a bit and then suddenly go to pieces with sweating, nausea, and weakness, all of which are likely to be mediated by autonomic discharge. Something similar happens in cold exposure - you can go on coping for a good while feeling very cold and then suddenly you are overcome with uncontrollable shivering and inability to even walk (in my experience).

The best way to investigate the idea of an inhibitory signal would be to find some blocking mediator. But where to find it who knows. It might be that guanoabana juice is rich in such an inhibitor but unlikely because someone would have discovered that it cured ME in Ecuador a while ago!

 

[Simon M]

Feeling terrible when trying to move with flu is attributed to cytokines like TNF and Interferon sensitising nerves. The precise mechanism may not be clear but release of prostanoids (potent neural sensitisers, as indicated by the effect of ibuprofen) would be an obvious intermediary.

But I think we recognise more than that. We soldier on with flu for a bit and then suddenly go to pieces with sweating, nausea, and weakness, all of which are likely to be mediated by autonomic discharge. S

Thanks. Could you explain a bit more about autonomic discharge, and also if that ties into the point you made earlier about a key role for the hypothalamus?

 

[Jonathan Edwards]

Thanks. Could you explain a bit more about autonomic discharge, and also if that ties into the point you made earlier about a key role for the hypothalamus?

I probably cannot give much more detail of any reliability. The hypothalamus is where temperature is regulated and where the central nausea centre is. It almost certainly controls shivering as well as fever.

Autonomic discharges are features of various adverse states and I am not good on the classification. Fear produces tachycardia but fainting at the sight of blood involves bradycardia. It all depends on whether it is sympathetic or parasympathetic I thin but somebody else might know a lot more.

 

[Robert 1973]

Thanks again to Simon for asking the questions that I was struggling to formulate.

If the signalling is neural, no. If it is cytokine or hormonal maybe but maybe not. We have learnt that a lot of chemical signals act quite locally. If there is a secondary impact on nerve fibres then the effects are all invisible but generalised.

The best way to investigate the idea of an inhibitory signal would be to find some blocking mediator. But where to find it who knows. It might be that guanoabana juice is rich in such an inhibitor but unlikely because someone would have discovered that it cured ME in Ecuador a while ago!

If I’m understanding correctly, it seems like it would be bad news for patients if the primary cause was faulty neural signalling, as it would be hard to test or treat unless one happened to stumble on a drug that helps.

If it was a neural signalling problem, would you expect there to be abnormal physiological effects of those faulty signals which could be objectively identified?

Apologies if this is a dumb question (as you know, I’m not a scientist) but do you think it’s plausible there may be something as yet unidentified which is interfering with the signals – ie that there is a signalling problem but it’s not primary?

[edited formatting]

 

[Amw66]

You may well be right about the inhibitory signal. But, I'm not sure why the ability of people with mild ME/CFS to perform normally on a single CPET when well-rested indicates that there is no problem with the ability to sustainably produce ATP. Why do you think that?

I think we have seen a bit of evidence that there are problems with the production of ATP, although admittedly the literature is very messy, with small samples and focused on cells that are normally quiescent.

Could there not be an ability to produce enough ATP for a short burst of exercise, maybe assisted by adrenalin or something, but an inability to sustain that production for longer and without substantial consequences? If that itaconate shunt evolved to help a sick animal starve out a pathogen, there would be an evolutionary advantage for the animal to be able to override that mechanism when necessary to attempt to evade a predator.

We tend to focus on uses that are the most usual but compounds/ molecules multi task, and signalling is a key other aspect for many.

ATP is also a signalling molecule .
If there's a problem, signalling may be prioritised over energy use

If the set points for part of a system are wrong then it may be in some form of feedback loop and not switch back fully ? ( Or knock onto other areas)

Relationships and ratios with other compounds / molecules may offer insights rather than simple high / low individual statuses.
Machine learning plus genetics / epigenetics may be a game changer - I just hope we don't have to wait a lifetime to unlock some answers and treatment .

 

[Amw66]

Jo, If ME/CFS was a signalling problem would that be something that would be detectable in the blood as with TNF? Or are there other types of signalling problem that could be occurring?


Some more thoughts on comments above:

– I don’t think this is what Jo was referring to but his comment reminded me that a medic and a scientist in my family have both suggested that I have a distinctive gate that they have observed in at least one other moderate/severe ME patient. The first time they met the other patient they said they instantly recognised the gate. I don’t know if anyone has ever studied this. As a severe patient, I think I am probably in a PEM-type state all or most the time, although it gets worse if I try to do more.

– Again, I’m not sure if this is the type of movement that Jo was referring to but my leg frequently flaps about quite violently when I am trying to rest. I can usually stop it if I try hard enough but it is less effort to let it happen. It is very unpleasant and distressing. I also get a lot of rapid involuntary hand flapping when I am in a half-conscious state.

– Re. lactate: I recall a private conversation a few years ago with an ME researcher who told me there was a study that showed lactate production was not abnormal but that lactate clearance was abnormally slow in ME/CFS patients (which would tie in with the recent urine metabolite study). I’m not sure if the study he was referring to was ever published. Does it ring any bells with anyone?

Gate / gait (?) Is one thing that noticeably changes for my daughter in PEM.
It's as if the body is trying to minimise energy expenditure ( plus increased pain) .

Perhaps this is a case of if you don't look you don't find..has anyone been asked about this by a medical professional ?

 

[Mithriel]

Lack of ATP should last for a minute or two, maybe twenty minutes after a marathon run.

This is as accurate a description of my ME as I have ever seen. Stop completely, wait a couple of minutes then start again. It has been like that right from the start when I was still able to go to school and live a fairly normal life. It has never been a fluey feeling or general fatigue that has characterised my symptoms. They happen but only in episodes while the stop and start is constantly with me.

I would describe my PEM movements similar to ataxia with less power in my arms and legs and balance problems. I walk into people. I slur and have difficulty processing information.

I get that too Mij. When people talk about ME, a lot of the time it does not
match what I get.

It is interesting discussing symptoms with medical professionals. If we do not accumulate lactate acid what causes the deep burning, acid in the muscles and bones feeling you get with ME?

 

[Robert 1973]

If I’m understanding correctly, it seems like it would be bad news for patients if the primary cause was faulty neural signalling, as it would be hard to test or treat unless one happened to stumble on a drug that helps.

If it was a neural signalling problem, would you expect there to be abnormal physiological effects of those faulty signals which could be objectively identified?

Apologies if this is a dumb question (as you know, I’m not a scientist) but do you think it’s plausible there may be something as yet unidentified which is interfering with the signals – ie that there is a signalling problem but it’s not primary?

@Jonathan Edwards Just giving you a nudge in case you didn’t see these questions.