What do we mean by a diagnosis like ME/CFS?

[Jonathan Edwards]

Physical exertion certainly does. Cognitive exertion involves glial cells, thus the immune system is involved.

Yeah but it doesn't hack it. People love to write review articles on this but the reality is that physical exertion makes no detectable difference to immunity normally. We have no idea if cognitive exertion involves glial cells and so what anyway the glial cels just sit there, they don't go off and talk to lymphocytes and say 'he was thinking too hard'. In ME/CFS it seems that some sort of signal connection is occurring but best not to blame that on 'gut-brain axis' or 'mind-immunity holism' while waving hands in the air I think.

I would keep clear of talking of the immune system at all. Talk of complement factor H or IL-17 or leptin by all means but these broad statements are Popper's non-science - things that can explain whatever you like however you like.

 

[Jonathan Edwards]

Could the mysterious PEM threshold be related to how well those "recovery" pathways are working on any particular day.

I think that may be another example of circular hand waving though. Recovery pathways are what stops you having PEM so PEM is a problem with recovery pathways or something like that. I don't recall any specific pathways that have been talked of but this might be things like Robert Phair's ideas? It might be worth cross-referencing those if anyone can remember. We certainly want to track some pathways but maybe calling a pathway 'recovery' begs more questions than it answers?

 

[Jonathan Edwards]

I have had just one condition.

I think it reasonable to assume that each person disabled in this way has one condition. The question is whether it has anything to do with the next member's condition or just looks like it.

 

[Sasha]

And yes absolutely the biochemical event could trigger other things but don't confuse it with the symptoms it produces - they are further events along an unknown chain. As soon as you use the same word for both you are dead in the water in terms of working out disease mechanisms. You have to invoke psychology if it the actual feeling ill that feeds back on the biochemistry - that is the definition of psychosomatic, a thought or feeling causing a physical change.

I don't think anyone is suggesting that feeling ill that would affect the biochemistry. (Actually, I don't think anyone is necessarily suggesting the biochemistry underlying PEM is having a knock-on effect on more biochemistry, though I may be mistaken, and I'm wondering if I implied that myself in the process of trying to clarify my own thinking).

 

[Jonathan Edwards]

I don't think anyone is suggesting that feeling ill that would affect the biochemistry.

Thank goodness.
I probably misread you.

 

[duncan]

In a roundabout way, I think that what we mean by a diagnosis of ME/CFS is that there are holes in the field of diagnostics, and researchers either don't see them or are willing to pretend there aren't. Diagnoses like ME/CFS ignore that problem by defining a disease with symptom-based criteria, or by denying the sick are sick. Both routes effectively absolve diagnostic entities, and - more importantly - institutions that endorse status quo, of any responsibility.

 

[Kitty]

I'm trying to think about what (if anything) we really know about ME/CFS. The most basic elements.

I'm tripping over words, though.

One of the things I might suggest we know is that muscles fatigue more quickly than would be expected. Skeletal muscles, but maybe also those involved in functions such as focusing the eyes.

But there are other "muscles" we think fatigue more quickly too. Noise and light tolerance, maintaining concentration, holding more than one thought. But they're harder to pin down; they're functions, not parts of the body we can touch and test. I can only talk about them in analogy and half the time I'm not sure I even know what I mean.

Anyways, it might be useful to try and boil down what we think we know. Especially things we might be able to describe as true commonalities.

 

[Eddie]

When I say 'categories of happenings' that usually means what we call 'things' - tables, ospreys, broken legs - but since this is all about inferring and predicting cause and effect we are always dealing with categories of events or happenings. An osprey is what we call a category of events, including hatching from an egg, catching fish, and even lying alongside a ruler in such a way as to appear 39 inches long.

To me it is less about predicting cause and effect and more to do with convenience in conveying meaning. There are very broad labels that don't tell us much at all about an individual but apply to a wide range of the population. There are also very focused labels that tell us a much greater amount about those in that group but apply much more narrowly. Each label can be useful when discussing different ideas but only when the correct level of specification is chosen.

If I said I got an animal, that is pretty meaningless, but saying I got a osprey conveys much more information. In reality I don't think an "osprey" actually exists. What exists is a collection of matter that has similar features to these other collections of matter which we call ospreys for convenience. I can imagine a world in which we know everything about every organism, at which point we would just refer to each organism individually without the need to refer to a larger group. At the most fundamental level, I think categorizing is all about the tradeoff between information and effort.

I think that labels should only exist if they are useful. And in the case of ME/CFS it does seem like the label is useful in organizing scientific studies and grouping people together for discussion and to pursue the goal of treatment. I think categorizing by symptoms in ME/CFS is just as valid as categorizing by underlying process in any other condition. They both are human inventions telling you information about the individuals in those groups, just different things. It would be better, however, if we could label by underlying process or by which drug will be effective (which are really the same thing), because that would be even more useful in achieving the desired outcome. However, as we don't have that level of resolution, I think categorizing by symptoms is probably the best we can do right now.

I also don't see how you could argue for getting rid of the category of ME/CFS while still having the goal of treating the people with these symptoms. If the label disappeared entirely then it would be more difficult to look for the underlying problem and I think we would be further from the goal of treating these symptoms. Maybe some certain individuals could argue that we already have ways to treat these symptoms and the label is getting in the way. However, to me it is clear these current treatments are not effective because they didn't work for me, seemly didn't work for lots of other people and have very limited data to support their efficacy.

 

[wigglethemouse]

It might be worth cross-referencing those if anyone can remember.

This is some of what I was referring too about a lack of changes observed after exercise possibly leading to PEM.

I seem to remember presentations by the Cornell team looking at Proteomics, Urine, and Extracellular vesicles before and after maximal exercise in ME/CFS and sedentary controls, and mRNA work by the Moreau team. Perhaps it was the NIH roadmap working group seminars a year or so ago?

Here is what I found after a quick look:
Dr Hanson posted this on Twitter regarding the lack of urine changes in ME/CFS vs sedentary healthy controls.

https://twitter.com/user/status/1624786614764425216

This is the paper on Extracellular vesicles.

Paper : Dysregulation of extracellular vesicle protein cargo in female ME/CFS cases and sedentary controls in response to maximal exercise
Thread : https://www.s4me.info/threads/dysre...-maximal-exercise-2023-giloteaux-et-al.35015/
Study protocol


The Discussion section of this paper starting on page 24 talks about the lack of differential change in EV content compared to healthy controls.

Overall, this study characterized changes in the EV proteome of healthy sedentary control females in response to a single bout of exercise, while also demonstrating highly disrupted EV signaling post-exercise in ME/CFS patients. This is evidenced by: 1) fewer differentially abundant proteins (DAPs) in EVs 15 minutes post-exercise in patients compared to controls (Figure 4A); 2) 63 EV proteins increasing due to exercise in ME/CFS patients whereas 178 EV proteins increased in controls (only 45 overlapping) (Figure 6A); 3) a delayed increase in abundance of several EV proteins in response to exercise in ME/CFS patients compared to controls (Figure 8, Supplementary Figure S3). Thus, ME/CFS patients exhibit altered EV signaling dynamics and failure to mount an adequate response to exercise at the molecular level.

Finally, we found strong and significant correlations between the change in EV protein levels post-exercise in ME/CFS patients and clinical metrics (myalgia, arthralgia, post-exertional malaise (PEM), fatigue, % of waking time spent reclined, and SF-36 physical component summary) (Figures 9-11). This suggests that the profound disruption of EV signaling post-exercise may contribute to the inability of ME/CFS patients to recover from exertion.

Maybe others can find more details - I couldn't find the proteomics data for this exercise study.

 

[forestglip]

I seem to remember presentations by the Cornell Hanson team looking at Proteomics, Urine, and Extracellular vesicles before and after maximal exercise in ME/CFS and sedentary controls, and mRNA work by the Moreau team. Perhaps it was the NIH roadmap working group seminars a year or so ago?

Are you looking for these papers:

Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients 2023, Glass, Hanson et al

Plasma metabolomics reveals disrupted response and recovery following maximal exercise in ME/CFS, Arnaud Germain, Maureen R. Hanson et al, 2022

The proteomics data for the EV study you mentioned is in Supplementary File 3 at the published link.

 

[AliceLily]

Perhaps a tangent, but part of why I think that, despite the variation between people, ME/CFS is a single condition is that in the course of the 30 years of my ME with variation in severity and variation in specific symptoms including a number of years in a darkened room and a period of near complete remission all along it subjectively felt I have had just one condition.

This is important for those of us who have had ME a very long time. Over a 30 year period I went from mild to very severe then severe to moderate and now I think I am a mild-moderate ME. The variations are interesting along the levels.

I really need to write each level down and how the ME was expressed in each.

I was thinking of an example of PEM and how different it can be expressed through the levels and for me at very severe ME, PEM was like hitting a wall in a car crash and the symptoms were as many as all the broken bones that can occur in such a crash. Whereas at moderate level the injuries were not as many. The very severe example is getting life-threatening where secondary complications can occur. A pretty logical example.

 

[AliceLily]

For me, while I've certainly had times where I was clearly hit by a crash two days later, most of the time it's very gradual and ambiguous how much of a delay there is. (Though that may be because it's almost all cognitive crashes now, as I am much better able to control physical overexertion.)

What is constant though is that I can not do a normal person's level of activity, physical or mental, not because I physically can't do them in the moment, but because my body will make it harder for me to do those things if I try to keep it up, whether through continually worsening physical/mental exhaustion, anxiety, or low motivation, and this lasts at least four or five days usually. Like maybe that is the common denominator: the feeling of your body doing whatever it can to keep you resting - to win a tug of war with any parts of you that want to move.

I'm not sure the delay of onset is as important as how long this worsening lasts. Maybe a cutoff of something like "normal amounts of activity will usually have me feeling consequences, including it being harder to do those same activities, at least four days later".

This is another good example of level variation that I have experienced.

 

[Sean]

To me, PEM is a worsening of existing symptoms due to some causative factor. Exertion is only one of many causative factors that can trigger worsening.

I think this is important. Exertion, of any form, certainly is a consistent trigger/exacerbator of PEM for me. But it can also happen without any exertion in the previous few days (beyond minimal self-care and life admin stuff).

The so called 'baseline' for me, to the extent it exists, is nothing more than whatever degree of PEM that unavoidable minimal level of necessary exertion produces. But it is still highly variable, often opaquely and unpredictably.

 

[Obermann]

@Jonathan Edwards. Previously, I have used the following definition of a syndrome like ME/CFS. Do you think it agrees with your position?

A syndrome is a set of symptoms and/or signs that occur in combination much more often than expected by chance. If you have a malfunction of a complex system, it will potentially lead to many consequences (i.e. symptoms and/or signs in this context). It is likely that different malfunctions of a complex system lead to different sets of consequences. A syndrome is therefore suggestive of a common underlying cause. However, you categorize sets of symptoms and/or signs as a syndrome only when the underlying cause is not known, and you cannot rule out that there may be different pathways that cause the same set of symptoms and/or signs. There is a grey zone how unique and how well defined sets of symptoms and/or signs must be to constitute a syndrome, and it is complicated by the fact that all patients do not necessarily have all symptoms and/or signs. Usually, it is expert committees that define syndromes, and the constructs are often subject to controversy.

 

[Jonathan Edwards]

Do you think it agrees with your position?

Yes, very much the same idea.
There is subtlety that John Martin missed though. A syndrome is justified by some underlying commonality in causal paths. It does not need to have a common cause and usually doesn't. It remains valid if some component of the causation is common to all cases.

So haemophilia is a useful syndrome that picks out a genetic defect in the extrinsic arm of the clotting cascade that activates Factor Ten. The defect can be in Factor 8 or Factor 9. That does not matter. What makes it a syndrome is the lifelong aspect and the dynamics of the extrinsic pathway.

This is of course relevant to a GWAS study of ME/CFS. There may be no single gene association. One current study is deliberately looking for gene combinations. But if various combinations all trigger a particular pathway then the syndrome concept is valid.

Lupus is a syndrome of a particular type of failure of complement activation but it has a number of causes feeding in to that. And so on.

 

[yME]

I might suggest we know is that muscles fatigue more quickly than would be expected.

But are we guilty of looking at the negative side only in Jonathan’s equation? We all have varying levels and duration of pem - muscular failure being but one part. But do we not have a complimenting recovery mechanism leading to those very rare ‘good days’ or even run for England hours which overshoot our baseline? Assuming others experience the same, what is the C that may trigger this meteoric change which for me can occur just a quick as pem arrives. This behaviour has rarely been mentioned in discussion apart from vague good days statements.

Muscles free and energy returns and most importantly both can deliver immediately way above peer performance. As Jonathan suggested in the recent pem discussion as yet no irreversible damage has been found so recovery is a possibility if a dose D is discovered.


Apologies if this is the wrong place but yesterday I was in the run for england mode as an oap after 18 months and wanted to share this as a thought provoking exercise.

 

[Jonathan Edwards]

Assuming others experience the same, what is the C that may trigger this meteoric change which for me can occur just a quick as pem arrives. This behaviour has rarely been mentioned in discussion apart from vague good days statements.

I also think this is important - what I call the ladders of the snakes and ladders. Not everyone seems to have this but it is equally perplexing and perhaps characteristic of at least some ME/CFS.

 

[obeat]

I do love those rare " ladder " days when one's body and brain feels light instead of cloaked in lead.

 

[Trish]

I haven't dived in with my usual half baked rapid response on this thread as I needed time to think about it and I'm not sure I have anything useful to add. I confess I read @Jonathan Edwards introduction and thought simply, well, yes, that's what I thought a syndrome was all along.

So have I got this right, or is this an oversimplification to the point of being wrong?

I think ME/CFS is a syndrome because it has been recognised that there is a particular set of symptoms and disabilities that differentiate a recognisable group of people from people with other syndromes and diseases and from healthy people.

I think the central set of symptoms has largely come down to abnormally rapid and disabling fatiguabilty (cognitive and/or muscular) with slow recovery, and a pattern of sudden onset deterioration lasting usually days or longer that sometimes follows increased exertion (PEM) and sometimes follows other stressors such as sensory challenges, infections, sleep dysfunction or for unknown reasons. These core features are accompanied by a variety of other symptoms that differ between individuals and in any individual may fluctuate, including pain and OI.

The recognisable pattern of youth and young adulthood onset of disability accompanied by symptoms we associate with disease, but without known disease cause, and with unknown biology, is so odd and has such a drastic effect on their lives that it requires explanation and a search for treatment.

The search for a psychosomatic explanation and treatment is a busted flush. So we are left with biology.

The biology is unknown and, given the wide range of symptoms experienced by different people, is quite likely to involve subgroups with at least partly different biological pathways.

Research can start from looking at the end of the path - what happens when specific parts of the pattern are induced deliberately, as in exercise challenges.

Or it can try to work backwards from the effects of experiments with drugs that some people seem to find have major or minor effects on their symptoms or severity.

Or it can look at what might be the beginning of the path, with genetics and infectious triggers of onset.

Or it can look at different subgroups of patients according to their description of their symptoms, or it can do long term monitoring of patients regularly over months with biological samples taken along the way and correlated with symptoms and functional capacity at each sampling.

Or it can do complicated maths on vast sets of data from omics analysis. Or it can think sideways theoretically at possible metabolic traps, and test them. Or it can attempt to create and analyse animal models.

I suspect all of these and more are needed.

But the point of calling it a syndrome to me is simply that it's a pattern of symptoms and disability that is sufficiently distinctive to separate it from other diseases and syndromes, and without understood biology.

Edit to add: And probably most of all we need a Jonathan Edwards type of scientist or group of scientists who can sort the dross from the gold in all these research findings and piece it together into coherent pathways.

 

[Haveyoutriedyoga]

From a lot of the descriptions from various people, this seems to me to be more to do with the 'feeling sleepy' kind of fatigue as opposed to the ME 'lack of energy'.

(I recently was hit with 'fatigue' of that ilk when I was put on BP medication, CCBs, which went once the medication was stopped).

Me too, and it's not the same as the fatigue that hits disproportionately quickly, or as part of PEM, and/or upon waking.