What are the necessary conditions and criteria for a theoretical model of ME/CFS?

Something I've been meaning to work out for a while. For any theoretical model explaining the mechanisms of ME/CFS, there are necessary conditions that must be met, without which a model simply cannot account for the data. What are those? Especially with a purpose to falsify flawed models and hypotheses.

Basically it would serve as a checklist for any theoretical model, where if it fails to meet one of those conditions, it can safely be discarded. This isn't about hunches or personal hypotheses, but about making sense of the data. In science, when data contradict a model, the model must be thrown out. We now have more data than ever, thanks to Long Covid.

For example, we know that several pathogens can trigger ME/CFS, thus any model relying on a single pathogen (e.g. HIV -> AIDS) can be ruled out. Similarly, bacteria can also cause ME/CFS, and so it cannot be about a single type or family of viruses or bacteria. The idea that a pathogen never before encountered by humans is also popular, but can also be discarded either way, especially as reinfections with COVID can also cause ME/CFS, as can the very first one.

Another example, a traditional biopsychosocial model is that it's deconditioning. Well, deconditioning cannot fluctuate, and a necessary condition for a theoretical model of ME/CFS is that fluctuations are not just common, but can be very rapid, cumulative and occur even as a result of mild fitness training. Deconditioning simply cannot account for that, and thus can be dismissed as a valid hypothesis.

Similarly, people who have never heard of ME/CFS, or even of chronic illness in general, as well as people who did but did not believe in them, can develop ME/CFS, which discounts any anxiety/fear model with anticipation of possible lifelong illness affecting behavior.

Many very fit people have developed ME/CFS, which discounts any model involving prior sedentary behavior, or inability to understand or work out how to be active, having to be 'coached' into 'learning simple walking' and other things.

Even when obviously triggered by an infectious illness, severity of acute illness does not seem to predict likelihood or severity of the illness, this is overwhelmingly obvious with COVID. Also, even when not obviously triggered by an infectious illness, subsequent infectious illness often makes it worse, including mild ones. However, sometimes mild infections can make the illness better, usually temporarily. Any model has to, if not account for it, at least not contradict it.

ME/CFS affects men and women, children and adults, and so any valid theoretical model cannot require things like hormonal changes happening later in life. Similarly, there have been poor studies showing elevated childhood adversity, but people with perfectly happy childhoods have also developed it, by which this hypothesis can be safely discarded.

Cognitive exertion can be a trigger for PEM/PESE, just as much as physical exertion, and so any valid model cannot depend on physical exertion involving only muscles or locomotion.

Remission and recovery can be spontaneous, even rapid, which discounts many hypotheses that can only unfold over the long term, and vice-versa. Some remissions and recoveries unfold over many months and years, and any valid model must account for it, or at least not make those data impossible.

The heart of the scientific method is falsification. For example, any hypothesis requiring that only women can be affected can be thrown out by finding a single man. Finding false positive evidence is often easy, but isn't the way to do science. Rather, we posit things that are impossible if a model is true, and if found, then we can discard it.

Let's do some effing science!

 

I love the idea. Just as a thought, would a theory be false if it assumed we needed a trigger that encompasses immune activation from viral/bacterial/fungal trigger? A portion of ME/CFS patients report to get the illness from psychological or physical stress. However, could we hypothesise that these people went through the early physiological chnages of the disease during an infection, and were only made aware of the disease once a psychological or physical trigger caused enough PEM to affect their baseline and create new symptoms?

Basically I’m asking if any theory that tries to model ME/CFS would be falsifiable because it assumes an infection (not a specific one but an infection in general) as trigger.

 

Another thing is the model needs to be able to explain how some people within the same disease category, can live a near normal life, while others are bedridden, unable to speak, unable to move etc.

 

Biology being what it is, I'm less sure about that one—but yes, it's a great idea to think it through.

 

Yes, criteria for a plausible model becomes a whole lot more difficult if you consider the fact ME/CFS could be a collection of similar or related diseases, with differing or semi-related mechanisms. It seems that current evidence suggests that the immune abnormalities present differently in women vs men.

 

PEM, brain fog, and non-viral trigger. Most of the theories -- FND, viral persistence, mitochondrial dysfunction, muscular damage, you name it -- are obsessed with fatigue only and don't account for those factors. Only hypothesis that fits the bill is neuroinflammation. It's been discouraging though that nothing concrete has come out on it yet after so many years.

 

I think this is a very good proposal. It might be quite difficult to keep manageable but it ought to be possible to draw up some requirements for a theory. A bit like Koch's postulates but much more comprehensive. Epidemiology, symptom patterns, disease kinetics over time, pathology, or importantly lack of certain types of pathology, would all be important. I will have a go at trying to make a list when I have some time.

 

I'm happy to see this thread.

 

A few random thoughts:

Any model would need to explain the sensory hypersensitivities and food intolerances, though I sometimes wonder if the food intolerances could be some form of chemical hypersensitivity.

Given the more people look the more we find orthostatic issues, we need some way of explaining these be they directly reflecting the presumed disease process or resulting from some down stream consequences. How does orthostatic intolerance contributing to triggering PEM relate to more specific issues such as full blown POTS? Are these a group of issues or a continuum of increasing severity.

Further the cognitive impairments seem to reflect more global issues of processing rather the focal or specific issues you see in such as a stroke. This presumably is a result of something impacting at the bulk of the cerebral cortical functioning though in at least very severe ME it is possible other parts of the brain beyond the cerebral cortex are impacted too.

In relation to the variability, I remember earlier in my condition I had at times periods when I returned to premorbid functioning, but now that does not happen. Is this just with general worsening the variation is about a point that is now to far away from my premorbid state that it no longer encompasses periods of apparent ‘normality’ or is some deterioration permanent/irreversible?

 

> Further the cognitive impairments seem to reflect more global issues of processing rather the focal or specific issues you see in such as a stroke. This presumably is a result of something impacting at the bulk of the cerebral cortical functioning though in at least very severe ME it is possible other parts of the brain beyond the cerebral cortex are impacted too.

where does executive dysfunction fit wrt focal/specific? for me, it is specifically task-oriented [planning, scheduling, organizing, prioritizing, deciding, initiating, executing, logistics].

it is probably also related to my time blindness and possibly at least part of my social reasoning deficits. i also have prosopagnosia, but that might not be an m.e. feature.

i had all of the above before my m.e. became very severe level.


executive dysfunction got worse as my m.e. got worse. to me, it seems likely strongly related to m.e., even though many/most? pwme do not report it.

i venture a model would have to account for it. [edit: i /meant/ must not be inconsistent with it, although even that could be wrong in principle in some models. btw, not apropos of exec dys, for me sleep is dispositive re causing and healing pem.]


executive dysfunction has been life-destroyingly profoundly disabling to an unbelievable degree and extent all my life.

ever since ed yong identified executive dysfunction with brain fog, whether that is correct or not, i have reaized that it -- things like inability to do bureaucracy, "the not able to get things done even if life depends on it disease", life and social planning -- has had profound effects in events and missed opportunities in life many, many times, essentially literally determining the course of my life independently of other parts of m.e.

i have identified those events and non-events as caused specifically by exec dys. idk why, but it was revelatory to learn of the concept, despite already knowing i couldn't plan, schedule, etc.


i experience general cognitive issues also. exec dys, social reasoning, and general cognition become worse when i am vertical. brain disappears.


i have likely had a basically monotonic progressive course all my life, from my earliest memories, in stages, but when moderate, and severely mold exposed, in 1990s [whiile still not knowing what disease i had or what characteristics to expect], i noticed there were fluctuations [edit: in at least m.e. exhaustion and malaise or similar] at the week granularity, and i think i noticed delayed effect.

fluctuations might or might not have been impacts to the system that i did not recognize. incidentally, at least given my knowledge and experience, i consider pem to be post-impact-to-system, not only exertion.

it would be good, if possible, to scientifically disentangle whether progressive course is an accumulation of pem not recovered from, or whether progression occurs independently of pem.

 

ME might be a single disorder, multiple disorders, multiple overlapping disorders, or a spectrum disorder. Models may look different in each case.

Most of what I saw here I would class as either desirable or highly desirable features of a model of ME. Its less clear as to which are essential.

To me the real test of a model is not at the beginning, in which many of these features are highly desirable (and I have my own list) but what happens next. A useful model must lead to treatment predictions, clinical trials, and real measurable beneficial outcomes. Any model that fails here is trash. Yes, I am thinking of psychogenic models here.

A model does not have to be complete or explain everything. If a model leads to working treatments it has value. Measurable beneficial outcomes, not just claims based on unreliable data. Such a model might be expanded or even replaced as things progress. The expanded model or replacement model must lead to better outcomes.

You might have models that explain most things but do not lead to falsifiable predictions or clinical treatments. How useful would that really be? Incomplete models can be used to design experiments and maybe lead to breakthroughs, but its still clinical outcomes that matter the most.

If a model predicts outcomes that only apply to patients with symptom A and biomarker B then its still useful if that can be tested and lead to clinical results. The model is clearly inadequate for all of ME, but its still useful on that subgroup. If it randomly leads to good clinical outcomes in some patients then its much less useful as a model.

Weird stuff I regard as desirable to explain or produce hypotheses about include spontaneous temporary remissions, the delayed nature of PEM, and why many have so many metabolic and other abnormalities but none is central to ME. Even if the repeat CPET results are used as an aspect of PEM they only seem to apply to 86% of us.

So I think in considering any ME model, and how to advance the research on such a model, we need a long list of pertinent questions. This thread contains many of these. If we can formalize such a list it would be useful. If we can formalize the selection and outcome requirements of good studies than its progress.

 

I think this is an excellent idea and it should be possible to come up with some "basic checklist".

Something that could still be relevant is that we cannot be certain to be working under the assumption that ME/CFS is indeed one "thing". That doesn't mean one should now be open to 10 simultaneous and different models for all kinds of different things leading to a Fukuda type dilution but rather that there for example might be 2 different models driven by sex differences or something similar (gradual onset vs sudden onset following viral infection).

So whilst this could be a "checklist" for any unifying hypothesis for ME/CFS, which are anyways to date the only hypotheses that have existed, one might not want to discount hypotheses that could be applicable to a larger subset of people (if someone were to come up with such a hypothesis).

Even if there are different subsets or models, I think for all of these there would still be 3 necessary conditions that would always have to be met:

• The model has to be consistent with no abnormalities being detectable using current (or already used) assessments (psychological assessments, biomedical examinations etc)
• The model has to explain the delayed nature of PEM
• The model has to explain cognitive problems in ME/CFS

(I didn't want to get into the debate of cognitive problems vs cognitive PEM, because to my knowledge the cognitive difficulties in ME/CFS haven't been studied and characterised well enough).

 

I think that is a very important point. I used to be sure that cognitive exertion itself could drive symptoms. However, I have realized that I am often sitting upright and have an increased heart rate when exerting in this way. It is also hard for a study to separate these forms of exertion as travel, being upright, some nervousness about being studied and many other factors could all impact PEM.

I would want any theory of ME/CFS to explain why orthostatic issues are much more common in this patient population. While it does not seem every person with ME/CFS has this problem, I think it is common enough and unique enough to deserve to be included as part of any explanation (even if it ends up being a secondary issue).

 

This might be correct, or not. Its not just POTS. Its also NMH, which induces bradycardia not tachycardia, or at least it did with me. Then there is the sudden drop of blood pressure in the brain without peripheral blood pressure loss which was discovered several years ago, and is not detected by a tilt table challenge. Combined I think these probably approach 100% but we lack a large study to find the exact percentage. I am also unsure if the new problem has a name yet. Does anyone know?

 

I think any model that explains cognitive PEM could explain sensory hypersensitivity through that same framework.