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

Discussion in 'ME/CFS research' started by Jonathan Edwards, Jan 13, 2025.

  1. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Sasha asked me: "I have the feeling that you as a clinician are approaching the question of diagnosis in a way that's based on your training, and that the concepts used are perhaps very different to what we as patients might assume.


    If that's the case, is there an accessible summary article or similar that we could read to get our heads around it?"


    My reply:

    No there isn't. Nobody has written on this, but this is the story.


    What is a Syndrome like ME/CFS and how do we decide how to diagnose it?


    I was discussing this with Professor John Martin at our presentation to UCL Division of Medicine this week. John is about as old as I am and like me thinks he is a wise old bird. I think he often gets things wrong. The best way to score points off him is to quote an even wiser and older bird, Robert Souhami. I pointed out that ME/CFS is a distinct syndrome and why - much as I do in my Qeios piece.


    The art of making diagnoses is based on an intuitive skill we all use every day to seek out categories of happenings that usefully tell us about what causes what and so what is likely to happen next time. That may sound very philosophical (metaphysics to be precise) but it is worth trying to understand if we want to do reliable science and medicine. Moreover, it is important to realise that we all use this skill unconsciously and it works remarkably well, even in terms of having a repeating error-monitoring system built in, but it works by trial and error, so it constantly needs that monitoring.


    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.


    OK, so physicians in ancient times recognised categories of events that got called illnesses or diseases. They were, in effect, trying to pick out causal paths that would allow them to predict outcomes in other cases and maybe ways to change those outcomes. They got things wrong, with ideas about humours and vapours but they could probably predict prognosis quite well and identify simple causes and advise. No doubt they could work out that frostbite was due to cold.


    (I strongly suspect the 'history of medicine' is as bogus as the 'history of navigation'. We now know from an early fifteenth century Turkish map that South American towns were known before Columbus. The Portuguese had been fishing up the North American coast for ages but kept it quiet. They must have known the earth was a sphere even if learned scholars were supposed to think it flat. The value of vaccination and the origin of smallpox in tiny particles in pus was known way back in the Middle East, maybe ancient Egypt. Jenner got to hear of it from an erudite lady traveller I believe.)


    But as we started to understand things clearly, with the circulation of the blood and chemistry and microbiology, it became clear that each person’s illness involved a whole lot of events in both converging and diverging sequences. Person 1's illness might involve A and B interacting to cause P and Q, with P leading on to W and V.


    A.B >> Q + (P >> W+V)


    Person 2 might have an illness in which A and C interacted to produce P and R, with P causing W and X and R causing Z.


    A.C >> (P>>W+X) + (R>>Z)


    This sort of complexity is everywhere in modern illness, now that the main causes of ill health are no longer whooping cough, starvation, war and falling trees.


    Making a diagnosis in this context, means trying to pick out what A is, or maybe what P is, in the context of W. What we mean by 'ME/CFS' is likely to be something like P. A syndrome is a pattern of history of symptoms plus or minus physical signs - a category of happenings - that we call a syndrome because our unconscious seeking out system tells us that it suspects there is some P hidden in the pathways behind it. A syndrome is a ‘real’ syndrome only if eventually we discover there was a P rather than just a spurious similarity between cases.


    John Martin got muddled over this, as most doctors do. I used the example of diabetes, or excessive passing of water, as W. It turns out that it can be caused by both a P and a separate Q. With P, diabetes mellitus, you also get hungry and lose weight. With Q, insipidus, you don't. Polyphagia, polydipsia, weight loss and polyuria is the syndrome of diabetes mellitus. But it is further complicated by there being a quite separate B or C causing P (and no common A). B causes type 1 diabetes mellitus and C type 2.


    This is important because treatment is partly directed at P, which is a raised blood sugar, and partly at C, which is mostly a matter of obesity. One day we should manage to deal with B, which is autoimmune damage to insulin producing cells.


    The long and the short of it is that for syndromes like ME/CFS we are trying to pick out a common element in the causal path P that may indicate directly how to treat both this and that person or may instead point us to some A, B or C that is what we want to treat, maybe different for different people.


    I had to work all this out in order to get to grips with rheumatoid. My life work was to work out that rheumatoid factor antibodies are not P but A. There are alternative antibodies: B, C. We worked out that P is the binding of very small complexes of antibodies to a receptor on a subset of macrophages that only occur in places like joints and pericardium. Having worked that out we were suddenly able to string all the letters together and suggest that rituximab would be useful.


    I think it may help to use the analogy of species because we have now worked out exactly what the problems and mistakes are in identifying species. People started out categorising species for hunting and eating. Presumably whales were fish and barnacles were shellfish then. There was probably a major effort to be more precise when people started breeding varieties of livestock and birds. As Darwin points out, the breeding of pigeons and songbirds is very instructive and I suspect was relevant to the attempts by people like Linnaeus to categorise ‘species’ precisely.


    It turns out that what roughly we mean by species is a group of animals (or plants) whose existence was caused by the same DNA molecules some time in the distant past. Rather neatly what people mean by a disease (with the a in front) is all the cases of illness caused by identical bits of DNA – taking the role of A. Haemophilia is a disease due to a defective factor 8 gene. Tuberculosis is a disease due to Mycobacterium tuberculosis DNA. Things are now complicated because illnesses rarely have a single simple A cause now, so the idea of a disease is less and less helpful.


    Moreover, for species it turns out that what we call species aren’t actually defined by common DNA. This is hugely complicated, but you can have converging and diverging paths here too. If you look hard enough you find that there is no precise, coherent concept of a species. It is, in a sense, not even a real syndrome. But there is a pretty good practical category and that is those individuals that, at this point in history, will tend to interbreed, and not with others, if left to their own devices. They don’t have to look alike, as Dachshunds and Great Danes prove. They can have inherited some DNA from different species in the past. The way they form actually has nothing to do with natural selection, so Darwin was wrong about The Origin of Species even if he was right about how biodiversity evolves.


    The relevance of this to syndromes, though, is that taxonomists have gone through a process of refining species categories very similar to doctor’s refining of syndrome categories and for species much of it has involved replacing body similarities with DNA similarities. If you look at a barnacle carefully you can actually see its many legs. That is the first stage. Birds of prey were put together because they have hooked beaks, even if some are scavengers and some wasps’ nest burglars, not ‘birds of prey’. But recently the DNA has shown that falcons are not closely related to buzzards. They are closer to parrots and both falcons and parrots are the closest thing to songbirds – in terms of the causal pathway of descent. Condors were also classed as hawks because of things like beak shape even though they are not birds of prey. Early DNA studies suggested that in fact they were storks, not vultures. But later studies showed that they are in the hawk family after all but not particularly related to Asian vultures.


    What I see as the quest for understanding ME/CFS is trying to find the commonality in causation of what looks like the same illness for many thousands of people – which is going to be a P, not an A or B. Like rheumatoid, we can then trace back to A and B. The practical question is what is the most reliable clue to P? Is it the end of the beak or the position of the toes or a way of flying? Is it ‘PEM’ or is it something close to that but not quite that. For rheumatoid we had detailed pathology in many organs nicely described by Dougal Gardner and Eric Bywaters. For ME/CFS it is more difficult, but human biology has moved on so we have new methods to draw on like GWAS screening.


    Birdwatches still argue furiously in pubs whether the arctic redpoll is the same species as the lesser redpoll even though they look different, but they pretty much all agree that Caspian gulls are not herring gulls even if it takes an expert to tell them apart. Hopefully, it is now understood that ME/CS is not just chronic fatigue, but until we know what P is, and even if there is a single P, we cannot be sure why we can be sure of that.
     
    Last edited: Jan 13, 2025
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  2. Sasha

    Sasha Senior Member (Voting Rights)

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    Thank you, @Jonathan Edwards! That's fascinating. I've just read it and am going to reread it to try to really get my head around it.

    What about publishing a version of this, if so many doctors struggle with the concept of diagnosis, including the big guns? It would be nice to keep ME/CFS as the interesting problem...

    For anyone else who struggles to read long things on-screen, I attach a Word version I created for myself to print off (please don't share it, I'm not sure if this is a private subforum).

    Back to pondering, and thanks so much again for putting all this work and thought into answering my question.
     

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  3. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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    I would argue that the causal path is valuable for researchers, and an indication of what treatment to use is useful for doctors, but for patients it can simply be enough to have a description of what you're going through.

    Even if the pathology or treatment for many us turns out to be very different, it is still valuable to find other people who are going through a similar experience in terms of symptoms and disability. People with chronic fatigue differ too much and the category is too broad to be useful in that respect compared to ME/CFS.
     
    Last edited: Jan 13, 2025
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  4. Kitty

    Kitty Senior Member (Voting Rights)

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    Is it useful to think of things it might be?

    Like the gap, which seems to be necessary for what we call PEM to develop?
    Or the undetectability of the threshold, the crossing of which leads to worsening?
    Or the difficulty of defining what events are enough to lead to worsening and what aren't, because it's so changeable?
    Or the dynamics of it—how it compounds, and why sometimes it compounds and at other times merely aggregates?

    Or does that just leave us with all the same problems? :D
     
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  5. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Absolutely. That is the task. To think of something it might be that predicts findings from research.
     
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  6. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    From a social perspective, yes. And for ME/CFS, because many doctors do not even recognise its existence, it is crucially important for patients to know that at least there are thousands of other people with similar illness who recognise what they feel.



    But if it turns out that there is no single P and that there is a P and an R and they have completely different implications and are only related to the extent that they just happen to produce closely overlapping patterns of illness in different people, then patients joining together and sharing experiences may simply worsen the confusion.

    My impression is that patients want to share with others because they too like the idea that there is some unique common causal pathway to their illness that validates it as a specific illness, or even disease, that becomes part of the way they negotiate their lives. That validation depends on all the arguments I have been discussing above I think.


    I am not very sure about what 'people with chronic fatigue' experience. Is there even such a thing? I don't know. I have not encountered anyone significantly disabled by 'chronic fatigue'. Is it an imaginary category constructed by the psychiatrists to suit their agenda?

    My impression is that there may be two groups of people, one of which are capable of suddenly spontaneously getting better, often following some arbitrary treatment that may well be irrelevant, and another group that doesn't have that feature. But it does not seem to track to whether you have specific diagnostic features of ME/CFS. I am quite sure that ME/CFS is not chronic fatigue but I am much less clear exactly what the most useful discriminating features of ME/CFS are.
     
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  7. Sasha

    Sasha Senior Member (Voting Rights)

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    I'm still processing this but I raised the issue of how diagnosis works on another thread where we had got into a discussion about PEM. In your diabetes scenario, diabetes (the excessive passing of urine) is the endpoint of earlier processes, which is why you give it a letter at the end of the alphabet. It results from earlier steps (which are therefore given earlier letters in the alphabet). Would PEM similarly be at the end of the alphabet, as an endpoint of earlier processes? Do we know that it doesn't itself lead to further processes and maybe belong in the middle of the alphabet?

    I'm still wondering why PEM has been chosen by many as the cardinal symptom for ME/CFS, and how well the analogy with diabetes holds up from that point of view.
     
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  8. Sasha

    Sasha Senior Member (Voting Rights)

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    My experience has been mostly of chronic fatiguability rather than chronic fatigue - that is, I'm not tired all the time but can easily become exhausted through trivial effort.
     
  9. forestglip

    forestglip Senior Member (Voting Rights)

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    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".
     
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  10. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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    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).
     
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  11. Kitty

    Kitty Senior Member (Voting Rights)

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    Maybe it's worth asking questions of those people, though, to see if there's anything else.

    I've had lasting spontaneous remissions. They happened before I even knew what ME/CFS was, let alone that I had it, so they weren't related to treatment or expectations.

    PEM symptoms always start with the immune-type features: sore throat, swollen glands, generally flu-ish. I feel much better in the early stages of developing a viral illness, and the first AZ Covid jab put me into near-remission for a week. (Second also worked, but for a shorter time.)

    Is that a pattern that's consistent in others, or just some random items from a list of possibilities?
     
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  12. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    This is where I think it is crucial to be rigorous about word usage and that isn't easy because the medical profession never is.

    PEM is a category of symptom happenings. It isn't quite a symptom but it is a feature of the symptomatology. So by your rule it should probably be XIM (Xertion-induced malaise) or WAE (worsening after exertion). But you cannot then use the same word to mean a category of happenings that cause XIM. You have to call that PCXIM (putative cause of XIM). It is just conceivable that feeling rotten causes other bits of the illness but no-o-o-o way do you want to go there because that is the psychological cycle of the BPS model.

    Doctors don't get this. If you ask what causes your painful lumps on your fingers you may be told primary osteoarthritis. But if you ask what is primary osteoarthritis you will be told that it is painful lumps on fingers. Doctors come out with this without any idea it makes no sense.

    The problem is important because researchers do not necessarily pick up on just how sloppy the literature is. Chris Ponting's group gave us a paper recently with the first author being Beentjes. It is a useful and interesting paper. But the analysis is based on a diagram of causation that includes something called 'ME/CFS status'. And I cannot work out quite where that is supposed to be in the chain of happenings. To me ME/CFS status is the end result. But you might also think of it as a category of happenings that give rise to the end result. I am not at all sure which direction the arrows should go in. If the arrows do go the way they say then the analysis looks very reasonable, but what if the arrows don't quite go like that? I am not sure you can conclude so much about the role of inactivity then.
     
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  13. Sasha

    Sasha Senior Member (Voting Rights)

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    PEM, XIM and WAE sound identical. If the malaise is the subjective experience associated with a particular biochemical event that has been triggered by exertion, couldn't that biochemical event trigger other biochemical events and hence other bits of the illness? I don't see any need to invoke psychology.
     
    Last edited: Jan 13, 2025
  14. Kitty

    Kitty Senior Member (Voting Rights)

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    Perhaps because it appears to be distinctive, and most of the other symptoms are common?

    Some people argue PEM is ME/CFS, but that's another case of both cause and effect.
     
  15. Creekside

    Creekside Senior Member (Voting Rights)

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    What jumps to my mind is whether the commonality involves the immune system (s). Are there any causes of worsening that doesn't have some sort of effect on the immune system? Physical exertion certainly does. Cognitive exertion involves glial cells, thus the immune system is involved. Hypersensitivities would involve glial cells too. Microbial infection, obviously qualify. This might not be all that useful of a commonality, since maybe there aren't many factors that don't involve the immune system(s) in some way, but maybe it could be narrowed down to specific aspects of the immune system(s).
     
  16. Creekside

    Creekside Senior Member (Voting Rights)

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    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.

    Symptoms that only appear during PEM might simply exist at an unnoticeable level during non-PEM, but increase a lot more than other symptoms during PEM.
     
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  17. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    This thread is interesting and makes you think about ME/CFS in a different way.

    Would it be helpful to revisit the few PEM induction studies that have been carried out? I was left with the impression from those studies that during & after exercise there is a failure of the body's "recovery" pathways and that leads to a worsening of symptoms over time. If true, another way to look at the PEM question could be - what is causing that lack of "recovery" pathway activation? Could the mysterious PEM threshold be related to how well those "recovery" pathways are working on any particular day.
     
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  18. EndME

    EndME Senior Member (Voting Rights)

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    Does such a thing exist? There have been exercise studies like 2-day CPET studies or the study by Rob Wüst, but not PEM induction studies as far as I'm aware. They simply look at different metrics on how pwME/CFS respond to exercise, rather than whether or whether not PEM was induced. It may be that some studies would have induced PEM or it may be that people were already experiencing PEM when going into the experiment. I think the suggestion of "recovery" pathways not functioning correctly has largely been interpretation without evidence to try to find a vague explanation for PEM without even having studied it.
     
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  19. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    They were supposed to be. I was just trying to find some end of alphabet letters.

    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.nAs 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.
     
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  20. Peter Trewhitt

    Peter Trewhitt Senior Member (Voting Rights)

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    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.
     
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