Why so little focus on Functional Disability and so much focus on “Symptoms”?

[Sean]

What is not clear to me is that we know that it is the PEM (exacerbation of symptoms) that causes decline. I thin more in terms of the exertion causing the decline and the long term nature of that decline as part of what we call the effect - PEM.

I also see PEM as a symptom of over-exertion, not the driver of a decline.

I also think PEM is the consequence not the cause. Its nature does offer clues to the underlying mechanism, but it is not the mechanism itself.

In the same way that excessive urination and thirst is a consequence of diabetes and a clue to its underlying mechanism, but is not the cause of it.

 

[wigglethemouse]

Which is why in recent articles I have suggested that not only do we not have any useful information on mechanisms yet, but it looks as if we need to look for an entirely new sort of mechanism, in the way that autoimmunity was once new, viruses were once new, prions were once new etc.

One aspect of PEM is the delay before it appears, with a timeframe roughly 12-48 hours. How many things in the body have a delay like this, and could one of them be a clue to this disease?

 

[Sasha]

All sorts of mechanisms may well have gone under our radar. The mechanism I based treating RA on had gone under the radar of immunologists for decades despite being fairly easy to see if one thought clearly (which one can do with hindsight).

Prions were totally unexpected. Even germs were unexpected until Pasteur came along.

But these things are undiscovered precisely because we have not thought of anything like them.

Is there a useful distinction to be made between things and processes? It sounds as though with RA, you discovered a process that involved molecules that you already knew about (?), whereas prions and germs where things that weren't known about until people looked in the right places with the right kit.

These days, I find it hard to imagine that we don't know about all of the things in the body, even if we don't know about all the processes, because we have electron microscopes and all sorts of high-res scanners. Is that likely to be wrong? With ME/CFS, are we looking for a hidden process but not a hidden thing?

 

[Jonathan Edwards]

Is there a useful distinction to be made between things and processes? It sounds as though with RA, you discovered a process that involved molecules that you already knew about (?), whereas prions and germs where things that weren't known about until people looked in the right places with the right kit.

These days, I find it hard to imagine that we don't know about all of the things in the body, even if we don't know about all the processes, because we have electron microscopes and all sorts of high-res scanners. Is that likely to be wrong? With ME/CFS, are we looking for a hidden process but not a hidden thing?

This all gets quite metaphysical and when I said thing I was being general.

BUT is you want to be purist and metaphysical then the modern scientific view would be that there are no things other than processes or the dispositions or powers that can entail such processes. That may seem a bit too abstract but in terms of your example it probably applies.

In RA we already knew about the molecules in terms of their powers to show up on electron microscopy or to precipitate from a solution in a gel but we had not understood their powers to interact in pathological ways. For prions we knew the same - the proteins were known in terms of the simple powers. What we had no idea of was their power to self-associate in a chain reaction so that single molecules could seed new self-associating clusters when transferred from one organism to another. For bacteria we knew about many of their powers too - the power to turn dead leaves into a dark brown powder called loam for instance.

So we are not going to be looking for something with simple physical powers like absorbing electrons in an electron microscope that have been missed, I agree. But we may have not even thought of sorts of powers that arrangements of molecules might have that can cause disease.

Alzheimers is an interesting one in that all we know of is that molecules in brains change their arrangements. Neurofibril proteins turn from neat fibres into tangles. Amyloid proteins that are supposed to polymerise only under special conditions polymerise all over the brain for no obvious reason. And of course at this level we are identifying new powers through patterns seen under an electron microscope.

 

[Creekside]

These days, I find it hard to imagine that we don't know about all of the things in the body, even if we don't know about all the processes, because we have electron microscopes and all sorts of high-res scanners.

It seems that there are new physical discoveries every few months. Each new advance in scanning technology allows new details to be discovered. A while back an improvement in microscopy allowed imaging of really tiny cilia on brain cells. Those cilia are doing something, but we can't know what if we lack the appropriate technology.

My guess is that ME involves a communication problem, such as a feedback loop or combination of loops changing parameters beyond "healthy" levels. That's hard to diagnose, because most of the changes might be subtle, and "normal" levels might not be well defined. Worse, the changes might be hidden inside cells or vesicles, or have very short lifespans, so taking a serum sample and processing it hours or days later would be pointless. ME might have a neurological pattern that would qualify as a clinical marker, but I doubt that the technology to identify that exists yet. Identifying such a marker might require subjects who have a reliable trigger for temporary remissions, for before/after comparisons, but all my triggers worked only a couple of times, so it would be hard to get the (very rare) appropriate subjects into an appropriate lab at the appropriate time.

 

[poetinsf]

My guess is that ME involves a communication problem, such as a feedback loop or combination of loops changing parameters beyond "healthy" levels.

Sound vaguely like an allergy. For what it's worth, my working model of ME/CFS has been an allergy to exertion or a byproduct of exertion. The patient gets sick when exposed to the allergen, and the allergy sometimes gets worse/better from repeated exposure to the allergen. If we find out what that allergen molecule is, diagnosing ME/CFS could become as easy as an allergy test. If it turned out to be an allergy to low level of IL-6, for example, we could test by introducing low level IL-6 and observing the response.
Great thing about this model, aside of explaining everything observed, is the simplicity: I don't need to assume some complicated or a novel process.

 

[Snow Leopard]

Delayed PEM is a loss of function and distinctive from immediate PEM symptoms. They are not interchangeable in my experience. It's a surprise 14-16 hrs later that can not be predicted unless you know your own personal limit and from experience. I can not push through, it's full stop. I could not explain this any other way to my GP.

Yes, but I'm finding it has gotten worse as I have gotten older. I used to be able to push through to do something, even if minimal, now not so much.

I have actually tried riding my bike during this time and there is a dire loss of power for a given level of effort too.

 

[Snow Leopard]

A lot of discourse and people talking about the disease focus on symptoms, and their severity, while nearly ignoring an aspect of functional disability. Even studies trying to characterise the disease or outcome measures for trials sometimes seem to forget the “disability” part and focus on the patient’s symptoms, which doctors often frame as “complaints”. It seems to be a form of medical reductionism, which means in a lot of the case the essence of our experiences as patients are missed out on. A doctor might see us and think “tired, belly hurts, can’t sleep, don’t like sports”…

Yes, very much this. The focus of TREATMENT (and treatment studies) is should not be about focusing on lowering or stopping the perception of symptoms, it is to increase the function of patients such that they have a greater ability to satisfy human needs.

Our subjective rating of fatigue (or pain) on a scale IS NOT IMPORTANT. What is important is the impact it has on our lives in a measurable sense.

 

[Trish]

Yes, very much this. The focus of TREATMENT (and treatment studies) is should not be about focusing on lowering or stopping the perception of symptoms, it is to increase the function of patients such that they have a greater ability to satisfy human needs.

Our subjective rating of fatigue (or pain) on a scale IS NOT IMPORTANT. What is important is the impact it has on our lives in a measurable sense.

Totally agree with this. Very well put.

 

[Jonathan Edwards]

Totally agree with this. Very well put.

I agree too but note that the biggest problem has been just this focus on function justifying GET as an answer to ME/CFS to increase function while totally ignoring the fact that function is driven by symptoms and that if you increase muscle function (which one exercise trial does show reasonably convincingly) while doing nothing for symptoms or making people worse you end up with an illusory benefit.

 

[Trish]

I agree too but note that the biggest problem has been just this focus on function justifying GET as an answer to ME/CFS to increase function while totally ignoring the fact that function is driven by symptoms and that if you increase muscle function (which one exercise trial does show reasonably convincingly) while doing nothing for symptoms or making people worse you end up with an illusory benefit.

But surely that's the point. GET suppposedly enabled some people to walk a little further in a 6 minute walk test, but if they crash just as badly the next day, their overall function hasn't improved at all. GET was based on increasing walking in a single short walking task each day. The impression I get is most are only able to do this by cutting back on other activities of daily living. The obsession on focusing on a single artificial task does not necessarily translate into better overall function.

The SF36 physical function scale is inappropriate for this reason. The individual may be a bit more able to climb a flight of stairs as a one off, but that impacts what else they can do. That's why the FUNCAP questionnaire is so much more appropriate for ME/CFS.

We need outcome measures that look at actual objectively measured global functioning in daily living activities.

Spoiler: personal anecdote

When I had to give up my teaching job, I was still able to teach a single lesson some days, but no longer had the overall capacity to teach for up to 5 hours a day and to do the same the next and the next day without crashing. My overall symptoms and 'fatigue' hadn't worsened, but my PEM threshold had dropped significantly. My scores on the CFQ and SF36 were no different, but my ME/CFS was much worse.

 

[Mij]

Yes, but I'm finding it has gotten worse as I have gotten older. I used to be able to push through to do something, even if minimal, now not so much.

I have actually tried riding my bike during this time and there is a dire loss of power for a given level of effort too.

Menopause has changed my stamina both physically and cognitively. The loss of power in my legs occurs abruptly out of nowhere. I feel like I should do less because I'm not sure if I'm making myself worse off.

 

[Creekside]

Sound vaguely like an allergy.

No, feedback problems are completely different. An allergy is more like an error in an adblocker: it misidentifies a bit of code as malicious rather than safe. A feedback problem is a change in parameters in a mathematical function. In a mechanical system, think of wear or build-up of gunk. For electronics, component parameters do change over time or due to damage. For biology, molecules can build up, structures can change, DNA can be modified, or telomeres can get too short. Change multiple parameters even slightly, and you can get a completely different mathematical response.

 

[Yann04]

GET suppposedly enabled some people to walk a little further in a 6 minute walk test, but if they crash just as badly the next day, their overall function hasn't improved at all

Yes. Ignoring the fact most those studies are using diagnostic criteria where many of the patients probably don’t have what we consider ME.

All GET/CBT did is teach patients to ignore limits and push themselves further. In the short term, they might have been able to do a tiny bit more, but as we see with most of the long term surveys, this improvment did not last, and a majority actually say that it made them worse in the long run. So GET doesn’t really change anything except trying to get people to push their limits, which as many of us can attest too, tends not to be the greatest idea long term.

 

[Snow Leopard]

I agree too but note that the biggest problem has been just this focus on function justifying GET as an answer to ME/CFS to increase function while totally ignoring the fact that function is driven by symptoms and that if you increase muscle function (which one exercise trial does show reasonably convincingly) while doing nothing for symptoms or making people worse you end up with an illusory benefit.

That is why function needs to be linked to human needs and not just say 'do more exercise' if being able to do exercise itself doesn't improve quality of life.

 

[Ravn]

Why are we focused on the symptoms, and not the disability? (and the phenomenon of PEM, which seems to be the driving factor behind the disability)…

The reason may be as mundane as availability bias. When researchers do their literature reviews they see symptom questionnaires - however inappropriately applied - used in other studies over and over and over and over... When those researchers then design their own study banal familiarity means those symptom questionnaires are the first thing that comes to mind and hey, there must be a reason everyone else is using them so I better do to

It's anyone's guess why the standard loss of function questionnaires have been used less often in ME, quite possibly because the authors of some influential early papers couldn't conceive of ME causing any 'real' loss of function. Whatever the case, that may have accidentally been a good thing as those standard questionnaires don't account for PEM and therefore are inappropriate for use in ME anyway. This left a gap to be filled by the much better FUNCAP

As for symptoms versus loss of function, to me they are two aspects of same thing, just viewed from a different angle. An analogy would be looking at a mountain from different directions. One side has steep rock faces, the other has a snow field, they don't look alike at all - but it's still all the same mountain. Which side you direct your attention to depends on whether you want to climb or to ski. Our ME 'mountain' in that analogy is our abnormal response to exertion and you can look at it from the angle of increased symptoms or the angle of loss of function. Which angle is more helpful in any specific case depends on what you're trying to do

Generally speaking in treatment trials improvement in overall function matters much more than improvements in some individual symptoms, welcome though the latter are. It can still be informative to measure both (with appropriate questionnaires and where possible with objective measures) because when one improves but the other one doesn't it's important to figure out why

For generating hypotheses and for mechanistic research, on the other hand, it often makes sense to search for explanations for specific symptoms and especially specific symptom patterns

 

[Yann04]

I’ve been thinking about this more, and perhaps this is pushed by pharmaceuticals.

It’s much more profitable to have to “treat” every single symptom a chronic illness patient has with drugs, than to find a single drug which gets down to the root cause and treats the illness.

Symptomatic treatment is like best case scenario for pharmaceutical profits. You have drugs that don’t fix the illness (so lifetime customers) and your drugs are generic and treat only symptoms, you you have a large and diverse market.

 

[EndME]

I’ve been thinking about this more, and perhaps this is pushed by pharmaceuticals.

It’s much more profitable to have to “treat” every single symptom a chronic illness patient has with drugs, than to find a single drug which gets down to the root cause and treats the illness.

Symptomatic treatment is like best case scenario for pharmaceutical profits. You have drugs that don’t fix the illness (so lifetime customers) and your drugs are generic and treat only symptoms, you you have a large and diverse market.

In reference to ME/CFS that however seems to make little sense to me as there's no drugs to treat anything and as such also no customers.

I've never found the "lifetime customers" a strong argument in the general situation, because adressing a root cause could equally produce a lifetime customer if the root cause can't be fixed with definite treatment but requires prolonged treatment or even requires a more expensive treatment or in the many situations where there simply is no treatment whatsoever. If one were to only look at the financial aspects only, one would then probably have to see which one is more profitable to everyone in a given situation (pharmaceutical companies, doctors, hospitals, insurances, patients etc). There's possibly even situations where hospitals like to adress "root causes" via expensive operations where the better approach might actually be something else.

I think it'll be hard to speak of the general situation because in certain situations very different reasons could apply and in others, others will apply and I guess it's usually a very complex environment of different interests on all sides (medical, political and financial) which can all influence the outcome.

There's certainly many situations where treatment of symptoms occurs via cheap drugs which nobody profits of anymore whilst root causes are left unaddressed. Why one doesn't address root causes could depend on the situation at hand, in some cases there is probably laziness on the pharmaceutical side who are content with what their already existing product yields financially, whilst in other cases the laziness to actually figure out the root cause will dominate the problem and perhaps in other cases it is such a complex problem that nobody even has a concept of root cause yet.

If someone is smart enough to come close to figuring out a root cause and can prove to treat it via a RCT, I don't see anybody actively preventing him from doing so, but that doesn't mean he'll get a helping hand on his route or that big stones won't be lying in his path that could have easily been moved. Said differently perhaps the current environment isn't the best to produce such scenarios or the incentive structure is messed up and not dominated by what would be better for the "greater good".

 

[Yann04]

as there's no drugs to treat anything and as such also no customers.

Technically there isn’t but patients will end up stocking up on loads of drugs in most cases.

Drugs for pain, sleeping, nausea/stomach problems, diziness/OI etc, and a subset also “fatigue” drugs like adderall. And that’s not counting those who try all soets of experimental stuff and expensive supplements often spending hundreds to thousands per year.

This whole thing is probably more profitable than a single drug that “treats” the root cause. Unless that drug is ridiculously expensive.

 

[EndME]

Technically there isn’t but patients will end up stocking up on loads of drugs in most cases.

Drugs for pain, sleeping, nausea/stomach problems, diziness/OI etc, and a subset also “fatigue” drugs like adderall. And that’s not counting those who try all soets of experimental stuff and expensive supplements often spending hundreds to thousands per year.

This whole thing is probably more profitable than a single drug that “treats” the root cause. Unless that drug is ridiculously expensive.

I'm not too sure on that. Those drugs are very inexpensive and hardly profitable. And some patients probably often spend a similar amount on supplements, where pharmaceuticals loose out on profit. I think an expensive biologic (like Efgartigimod which also requires regular use) would be much more profitable (the income for those can be tens of thousands per patient per year).

Think of Efgartigimod and BC007, two companies who launched trials in the hope of addressing a "root cause" (before even launching trials into conditions where there is more evidence of their drug being promising) with the hope of bringing a new product into a market where no treatments exist. The problem here was probably that they didn't do good enough research beforehand rather than anything else.

If you were a pharmaceutical company would you launch a drug trial into ME/CFS? The market may be large but on the basis of which evidence would you even conduct a trial? (I think the problem is more so that if a drug is already on the market even though it isn't very effective but which is profitable the incentive structure is messed up, but that doesn't apply to ME/CFS).

I doubt that drug companies have had a large influence on focus areas seen in ME/CFS (at least not directly).