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

[Yann04]

I'm not totally sure about this - certainly it would be good to be sure. It's very hard to separate cognitive exertion from physical exertion. Often cognitive exertion can involve periods upright, travel, missed rest periods, writing or typing, speaking... I wonder if periods of immobility that can also be associated with prolonged cognitive exertion such as sitting at a desk, might cause PEM, due to decreased blood perfusion.

Atleast in my personal illness experience, when completely bedridden, no sound or light input, only liquid food etc. No confounding factors. Sometimes simply thinking about a stressful thought, or thinking about something that takes a lotta energy (like solving a math problem in my head) could cause visible delayed PEM which presents in the exact same way physical PEM did. Since I did absolutely nothing all day except swallowing pills and nutritional drinks, I can’t think of a confounding factor that would explain that except that cognitive PEM must exist.

 

[duncan]

As far as I can tell, any theory would have to account for:

A myriad of fluctuating symptoms that can be broadly inconsistent among the patient community;
Diminished acuity;
Inability to register a meaningful and persistent antibody response with conventional metrics to typical pathogens;
PEM;
A failure to demonstrate a common trigger/cause of ME/CFS.

I'm not clear the severity has to be explained. I'm not sure that PEM has to be explained by a new mechanism, although that may prove to be the case (it can be explained, for instance, hypothetically by acquired channelopathies I think).

I keep stumbling across a somewhat fringe definition of immune tolerance/suppression resulting in the activation of latent virus/HERVs, that suggests this reactivation cannot be captured with usual diagnostics because our antibody production is compromised. So for instance, a pwME might be suffering from reactivated EBV - activated from any number of potential antigens - but only show elevated IgGs ad not IgMs.

It's interesting to read about, but not clear about any number of things. Like, if our immune response is abrogated, why do we feel symptoms to the degree we do? If PEM is an acquired channelopathy (I think that university in Australia suggested something along those lines?), is this a result of the original insult or the aberrant immune response - and how do you demonstrate either?

Sorry, just coincidentally been reading a lot in this area, with less clarity than I'd prefer.

ETA: Added diminished acuity. Case in point.

 

[Kitty]

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.

Yes, I remember a relative being prescribed benzodiazepines for about a month, and it struck me how much her cognitive function resembled mine. She couldn't make connections, describe things, or hold onto more than the simplest thought at once.

Interestingly, she also acquired some of the reduced co-ordination that I get in PEM—colliding with door frames, for instance, or dropping a plate of food by not gripping it hard enough to counter the weight. That general subduing of mental processes does seem to be what's happening in ME.

 

[Jonathan Edwards]

I keep stumbling across a somewhat fringe definition of immune tolerance/suppression resulting in the activation of latent virus/HERVs, that suggests this reactivation cannot be captured with usual diagnostics because our antibody production is compromised.

That seems implausible in that if the immune response is poor it should make it easier for reactivated pathogens to be found in terms of RNA or DNA. The studies so far show neither any extra antibodies nor more viruses.

What I think may get forgotten is that we are hosts to vast numbers of micro-organisms all the time. Our guts are full of bacteria and there are quite a lot in the lung and we probably more or less tolerate a whole range of viruses at low level. If you have no neutrophils you are likely to die of infection within weeks if not days. The immune system is silently busy all the time.

That being the case I am not sure that there is a need to postulate any reactivation - just an overenthusiastic response to the junk always present. Which would be much the same for PWME/CFS and others so nothing would show and antibody levels would be the same.

 

[duncan]

That seems implausible in that if the immune response is poor it should make it easier for reactivated pathogens to be found in terms of RNA or DNA. The studies so far show neither any extra antibodies nor more viruses.

Could it be the quality of the diagnostics?

That being the case I am not sure that there is a need to postulate any reactivation - just an overenthusiastic response to the junk always present. Which would be much the same for PWME/CFS and others so nothing would show and antibody levels would be the same.

Ok, yes, I can see that. That makes sense. But this is where I need help. So our symptoms attributable to immune responses are irrespective of our immune response vis a vis antibodies? I apologize. I've struggled with the symptom component vs antibody component. How can our bodies be so contradictingly capable/incapable, simultaneously, when it comes to immune responses?

That general subduing of mental processes does seem to be what's happening in ME.

Yes, I'd like to go back and add "diminished acuity" to my list.

 

[Kitty]

I'd like it to account for the fact that some people feel better with an infection—and for a minority, very much better for a short time after some vaccines.

 

[Trish]

Yes, I remember a relative being prescribed benzodiazepines for about a month, and it struck me how much her cognitive function resembled mine. She couldn't make connections, describe things, or hold onto more than the simplest thought at once.

Interestingly, she also acquired some of the reduced co-ordination that I get in PEM—colliding with door frames, for instance, or dropping a plate of food by not gripping it hard enough to counter the weight. That general subduing of mental processes does seem to be what's happening in ME.

I think a model or set of models also has to account for those of us whose problems are more with physical rather than cognitive symptoms, or whose cognitive symptoms are noticeable mainly when the effects of cognitive fatiguability kick in, or when in PEM.

 

[JemPD]

Atleast in my personal illness experience, when completely bedridden, no sound or light input, only liquid food etc. No confounding factors. Sometimes simply thinking about a stressful thought, or thinking about something that takes a lotta energy (like solving a math problem in my head) could cause visible delayed PEM which presents in the exact same way physical PEM did. Since I did absolutely nothing all day except swallowing pills and nutritional drinks, I can’t think of a confounding factor that would explain that except that cognitive PEM must exist.

This has been my experience also. So i for one am certain that cognitive exertion alone can induce PEM, as can sensory stimulation alone (or possibly in conjunction with cognitive). For example lying in dark room listening to music can be too much & trigger PEM if i do it for too long, the 'too long' is reduced in length if i am not in darkness - ie light + sound triggers PEM faster than sound or light alone.

I dont see any scientific research being done to the impact of sensory stimulus. It usually gets mentioned only as an afterthought, but for me, any model would need to account for it. Even if only as a form of cognitive exertion. IT is my most life limiting symptom, as it prevents & limits my interaction with the world. If i could fix the sound "sensitivity" alone it would transform my life.

I think, as i've said before i know, but i think the word "sensitivity" misleads people, as it makes people think of not liking something or being upset by it. But processing sensory input on its own can trigger a nasty bout of PEM, & once i am in PEM its like sound in particular, has it's 'fingers' on a dial somewhere in my body (brain?), that turns the volume/intensity up on ALL my symptoms, so when someone makes a sound it doesnt simply hurt the eyes, it ramps up the intensity on EVERY symptom i'm experiencing.

That is such a bizarre phenomenon, that i cant understand why it isnt studied. How can a sound i enjoy, at very low volume, turn up the severity of all pain i'm experiencing, nausea, dizziness, faulty proprioception, malaise, all of it, gets worse while its being made, its like the person who is making the sound has their hand on the dial of the volume of my suffering. I mean i can see how it might be able to increse dizziness & nausea through a vestibular response in the ear... but once i in PEM how can the slightest sound make pain in legs or hands worse? What's that about??!

Why cant i control my gait when the birds are singing (a favourite sound of mine, that makes me happy)? it seems to scramble all the signals in my brain like a rotary wisk.

It makes no sense & i do wish someone would study it.

So i hope any model could, at least theoretically account for it

 

[Kitty]

Why cant i control my gait when the birds are singing (a favourite sound of mine, that makes me happy)? it seems to scramble all the signals in my brain like a rotary wisk.

That's really interesting. Is it because the sound forces you to shift attention to it, and you can't deprioritise it? (I ask because I have trouble like that due to autism, and wondered if it might be a shared trait.)

 

[rvallee]

Given that several studies have found between sex biological differences in ME/CFS, I think it's possible we may need two separate models.

We may be lucky if it's only two

There may be a root with many smaller branches. Or there may be more than one root branch, possibly by factors such as location. And they may not be exclusive, as we saw with attempts to create subsets of Long Covid, they are never exclusionary, some people overlap more than one, and that can change over time.

So if there is an overarching explanation, it must allow for this to be possible, for symptoms to develop later, cease, improve, resume, and so on.

 

[Creekside]

The key for me is it must provide a biological explanation of delayed PEM.

For physically-induced PEM, immune response delay might explain it. Muscle activity triggers an immune response, which has certain delays, which might trigger neuroimmune response after further delays, resulting in symptoms. One question is whether physical exertion triggers PEM without those delays in some people. That's a bit tricky, since some people might have their PEM triggered by the cognitive exertion of that physical activity. Maybe in some people, activity can trigger PEM via the autonomic system, with less delay than from immune response delays. So, a few subjects who don't fit the model don't really negate it.

My cognitive-induced PEM has a much shorter (<1 hr) and more variable delay, but that could be explained by local neurological activity and changes. Since the symptoms seem similar, I think it's likely that PEM is generated in the brain, and the signals from the rest of the body can also trigger that mechanism, just with a delay in the communication channel (immune delays).

 

[rvallee]

The model has to be consistent with no abnormalities being detectable using current (or already used) assessments (psychological assessments, biomedical examinations etc)

On that I'd say it's rather no specific, consistent abnormalities. There are many abnormalities, and it's impossible to say whether they are downstream or play any causative role, in triggering or perpetuating, but there definitely are many. And they vary between people, and within people, but are frustratingly inconsistent.

So a valid model has to account for those, to be able to explain why such abnormalities don't just occur, but appear chaotic and change a lot. It's not a smoking gun, it's a hundred tiny pistols, some of which smoke some of the time.

 

[Creekside]

Given that several studies have found between sex biological differences in ME/CFS, I think it's possible we may need two separate models.

No, just awareness that males and females have some different biological pathways to accomplish the same tasks. That means different sensitivities to various factors. If ME was fully understood, you could point to some part of it and say "this difference is why females are more likely to have this symptom more severe". The differences in symptoms might be useful for identifying which biological function is involved with which symptom.

 

[Creekside]

There are many abnormalities, and it's impossible to say whether they are downstream or play any causative role, in triggering or perpetuating, but there definitely are many.

I think I'm a poster child for abnormalities. I never had the physical limitations most PWME report, and I managed to cure myself of physically-induced PEM. I don't think one person's abnormalities completely invalidates a model; maybe I have a specific genetic variation that interferes with the normal communication pathway, but I might be one of some number of examples that show that PEM is downstream of the root cause, rather than an innate part of it. A model-killer needs to be really impossible, such as it involving a y-chromosome, yet occurs in people without one.

 

[Creekside]

Any model would need to explain the sensory hypersensitivities and food intolerances,

Hypersensitivities could be explained by some brain cells changing their functioning; even a slight change might change the amplification of the initial signal.

Food intolerances could be explained by immune response, microbiome activity, vagus nerve response, changing levels of chemicals in the blood, and possibly other mechanisms. I've had my ME symptoms respond to both t-cell response (type IV sensitivity) to foods and microbiome changes (lost a bacterial strain involved with digesting fermentable fibre). The model just needs to include "various inputs from the body can affect this part of the model". Are there any functions of the body that are absolutely independent of food intake?

 

[Creekside]

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?

I had several temporary remission in the early part of my ME. These became less frequent, but the last one was several years after the previous one, so I think it becomes less likely rather than absolutely impossible. While not full remissions, I've had several periods of significantly reduced severity, where instead of a 45 minute walk, I've enjoyed multi-hr hikes in hilly terrain, and those were abrupt transitions (lousy one day, hiking briskly the next). The last one was this winter, so the worse periods are not irreversible deterioration. I still believe that with tthe right chemical delivered to the right cells, my ME would switch off 100% within hours or even minutes.

 

[Creekside]

It's very hard to separate cognitive exertion from physical exertion.

No, it's quite easy ... for some PWME. Some of us required quite definite physical exertion to trigger PEM; holding a book or a short walk just wasn't nearly enough to trigger PEM. Other people are much more sensitive to even minor physical exertion. It seems reasonable that some people are more sensitive to cognitive exertion, so maybe the thought processes of putting clothes on would be enough to trigger PEM. Since the model for ME includes brain cells and all the interconnectivity of the body, those vary so much in terms of responses to inputs that that the model will be valid for a wide range of variables.

 

[rvallee]

I'd like it to account for the fact that some people feel better with an infection—and for a minority, very much better for a short time after some vaccines.

Worse and better are possible. Which is mind-boggling but it's probably things like that that help reduce the possible models enough to hone in on the correct(s) one(s). It's so bizarre, but it's precisely that it's so unusual that it only leaves a few valid paths.

I'm seeing this approach in a similar way that computers render visual scenes, like video games. The scene, made up of triangles in a 3D space, is rendered (turned into a 2D image) from a point, the camera, looking at an angle in space that is a projection of 3D space into a 2D canvas.

When you look in one direction, everything outside of the viewpoint, like anything right behind the camera, will never be part of the scene (except lights), so it can be discarded, don't need to be computed. When video renderers do this sort of thing, they basically ignore 90% or so of the scene, because they'd be useless calculations.

Once we eliminate all the stuff that doesn't fit into a valid model, we are still left with many possible options, but it becomes manageable.

 

[Creekside]

Combined I think these probably approach 100%

I had that sort of symptom, but only briefly (few months). If I did some activity that significantly elevated my heart rate and then abruptly stopped, I would start to get tunnel-vision, and had to sit or lie down for a few minutes until that passed. Other than that, I haven't noticed any related symptoms, so I would put that in the "downstream symptoms affecting some people" category. I also would put it in the "explainable by a few brain cells not functioning normally" category.

"A few brain cells functioning abnormally" is a model that can probably explain most of ME, but I'm not sure how useful it is. It does suggest experimenting with brain-altering treatments to see whether they affect ME symptoms.

 

[Creekside]

For EndME's checklist, I add:

The model has to account for very rapid full remission, and equally rapid return to full ME state. This rules out models that rely on long-term deterioration or processes that take a long time to show effects, such as heavy metal accumulation or healing of organs such as intestines or liver. I think this is a condition that rules out a lot of ME theories presently being funded.