Could there be an on/off switch for ME/CFS and if there is, what would that tell us??

[Sasha]

From another thread:

5/5/24, Long Covid Podcast: Dr. Wes Ely - What is Immuno-modulation & how could it help with Long Covid?

“what we learned is that months later, there's this ongoing problem with the immune system. It's almost like a light switch got turned on and we need that light switch to be turned back off again for the body to rest.

“And the body needs to rest, but it can't because that immune system is still going until the light switch gets turned off. So what we're studying now is would it be helpful to turn off the light switch of Long Covid, i.e. normalize the immune system, by doing things like affecting interferons and immunoglobulins and all kinds of TNF and interleukins, et cetera.

This reminds me of Ron Davis's idea (in relation to the itaconate shunt hypothesis?) that there could be an on/off switch for ME/CFS, and of sporadic reports from PwME of their illness abruptly 'switching off' (wholly or mostly temporarily, if I recall correctly).

So, two questions:

(1) Biologically, does it seem possible/plausible/likely that there could be an on/off switch for ME/CFS? (Or for any other chronic disease, for that matter.)

(2) If we could be sure that PwME have had sudden and total recoveries (that is, have had their disease 'turned off'), would that give us any pointers as to disease mechanism?

 

[Jonathan Edwards]

(1) Biologically, does it seem possible/plausible/likely that there could be an on/off switch for ME/CFS? (Or for any other chronic disease, for that matter.)

Yes, highly plausible. If the process is perpetuated by signals in a re-entrant loop and one arm of that loop gets blocked efficiently enough the process could switch off completely. This happens rather rarely in most autoimmune diseases although there are some where it is quite common (e.g. idiopathic thrombocytopenia purpura).

What I think is weak in Ely's account is the idea that somehow it is just a question of 'more' or 'less' 'immune activity'. If perpetuating loops occur they will be based on very very precise signals. So it is not going to be to do with TNF or immunoglobulins in general. It will be dependent on something unexpected.

For rheumatoid it is interesting that the only drug that is reasonably well documented to turn the disease off for good (if in only maybe one in twenty or one in fifty cases) is gold thiomalate. And nobody has any idea why it does that. It probably interferes with some crucial connecting signal in the complement pathway or something like that, that blocks a circuit from continuing.

 

[Sasha]

Yes, highly plausible. If the process is perpetuated by signals in a re-entrant loop and one arm of that loop gets blocked efficiently enough the process could switch off completely.

Very interesting! Is there any way of determining whether that is the case? For example, would the results of DecodeME help? Is there a restricted list of candidates that could feasibly be investigated?

What I think is weak in Ely's account is the idea that somehow it is just a question of 'more' or 'less' 'immune activity'. If perpetuating loops occur they will be based on very very precise signals. So it is not going to be to do with TNF or immunoglobulins in general. It will be dependent on something unexpected.

Is there any way of narrowing down on that unexpected thing?

For rheumatoid it is interesting that the only drug that is reasonably well documented to turn the disease off for good (if in only maybe one in twenty or one in fifty cases) is gold thiomalate. And nobody has any idea why it does that. It probably interferes with some crucial connecting signal in the complement pathway or something like that, that blocks a circuit from continuing.

That's fascinating. If no one has any idea why gold thiomalate works, how did it get tried in the first place? Do all PwRA get given a course of gold thiomalate on the off-chance that it might cure them? Unless it's massively toxic, those don't seem like bad odds for switching off a life-changing disease.

 

[Kitty]

I wonder about the almost-remissions. That could be something different, or maybe it's possible for the loop to be partially blocked?

I had very good function during my remissions, but sometimes I'd still get the distinct pattern of symptoms I now know is PEM. I don't think the signal was ever completely switched off, but it was attenuated.

 

[Jonathan Edwards]

For example, would the results of DecodeME help?

They are as likely as anything to.

If no one has any idea why gold thiomalate works, how did it get tried in the first place?

Heavy metals were traditional in early medicine. Gold was almost insoluble but could be dissolved using sulfhydryl containing organic acids like thiomalate (a bit like the EDTA used for limescale). Gold sodium thiomalate (GSTM) was tried for consumption (TB) and someone suggested RA was a bit like TB so it was tried in RA. Heavy metals fell out of favour but in the 1960s enough rheumatologists thought that GSTM actually worked for a trial to be set up in the UK. It was one of the first proper controlled trials and came out clearly positive. Interestingly, thirty years later bismuth was shown to work for stomach ulcers after all, too.

The effect of GSTM is likely to be something to do with the sulfhydryl group coming free and binding to some signal in macrophages or lymphocytes. The gold may not be important but nobody has found a better drug without the gold part. Penicillamine also has sulfhydryl groups and probably works nearly as well as gold but does not seem to produce the long lasting remissions. Both produce toxicity associated with immune complexes - nephritis and thrombocytopenia. Gold is probably still worth trying but toxicity is serious. The real problem is that most physicians have never tried to understand enough about how drugs interact with the disease process. To use drugs like gold and rituximab you need to see patients frequently and adjust what you do repeatedly in response to the way the disease is responding. Gold treatment used to be delegated to nurses using protocols that did not do that.

 

[Mij]

I remember patients with arthritis wearing gold bracelets firmly believing that they worked despite the lack of scientific proof.

 

[rvallee]

(1) Biologically, does it seem possible/plausible/likely that there could be an on/off switch for ME/CFS? (Or for any other chronic disease, for that matter.)

(2) If we could be sure that PwME have had sudden and total recoveries (that is, have had their disease 'turned off'), would that give us any pointers as to disease mechanism?

I have no doubt about that. I've seen too many reports of people experiencing sudden improvements, as in suddenly one day they wake up and most or all of their symptoms are gone. It usually doesn't stick, though. Returns eventually. But absolutely there must be some switch that can be affected, turning off the whole disease state when the root cause is fixed.

Which makes it all so frustrating. It's all fixable, but the medical profession has convinced itself that it isn't even worth trying. An illness that they could easily completely eradicate, and unlike some diseases it would be forever unless the solution is somehow forgotten, and they're not interested because even though they can, they believe they can't. Which ironically is what they convinced themselves about us. Because it's all projection.

 

[Mij]

There were many times that I had spontaneous 'recoveries' earlier in the illness when I stopped exercising. As soon as I started exercising again years later is when the reality of delayed PEM started.

 

[CorAnd]

This is such an interesting question. I had a very weird experience once, which made me wonder if there is an off switch.

Two years ago I had major surgery to remove a benign breast tumor. A couple of hours after the surgery, I was in my hospital room, resting in the bed and SUDDENLY all my ME/CFS symptoms disappeared.

The exhaustion was gone, the poisoned feeling gone, the light sensitivity, the internal tremor, the brain fog, everything just gone. I felt normal for the first time in 12 years.

So I got up from my bed, walked with such ease and energy to the window and opened the curtains. The bright light did not bother me one bit. I then walked to the bathroom and looked at myself in the mirror and started laughing - what was happening, I thought, was I cured? Is this a miracle?

Exactly half an hour later, like a wave, all the symptoms returned.

 

[Eleanor]

I have no doubt about that. I've seen too many reports of people experiencing sudden improvements, as in suddenly one day they wake up and most or all of their symptoms are gone. It usually doesn't stick, though. Returns eventually. But absolutely there must be some switch that can be affected, turning off the whole disease state when the root cause is fixed.

Or even on a smaller scale; it seems quite a common experience that trying a new medication causes a small improvement and then the problems come back. OK, placebo effect, regression to the mean, etc etc. But it would also be consistent with a feedback loop being temporarily disrupted and then reasserting itself.

Possibly useful analogy: it takes two tools to pick a lock; one to move the pins inside the mechanism, and one to hold back the pins you've already moved while you go on to the next one.

 

[Sasha]

Two years ago I had major surgery to remove a benign breast tumor. A couple of hours after the surgery, I was in my hospital room, resting in the bed and SUDDENLY all my ME/CFS symptoms disappeared. [...] Exactly half an hour later, like a wave, all the symptoms returned.

That's an amazing story! Immediate full remission of symptoms like that must surely be a gigantic clue to the mechanism of ME/CFS. And so must the nature of the things that immediately precede these instant recoveries.

Any thoughts, @Jonathan Edwards? Would it be worth starting a poll asking for stories of immediate remission?

 

[Sly Saint]

This is such an interesting question. I had a very weird experience once, which made me wonder if there is an off switch.

Two years ago I had major surgery to remove a benign breast tumor. A couple of hours after the surgery, I was in my hospital room, resting in the bed and SUDDENLY all my ME/CFS symptoms disappeared.

The exhaustion was gone, the poisoned feeling gone, the light sensitivity, the internal tremor, the brain fog, everything just gone. I felt normal for the first time in 12 years.

So I got up from my bed, walked with such ease and energy to the window and opened the curtains. The bright light did not bother me one bit. I then walked to the bathroom and looked at myself in the mirror and started laughing - what was happening, I thought, was I cured? Is this a miracle?

Exactly half an hour later, like a wave, all the symptoms returned.

Pretty similar to how it was for me early on

For the next few weeks I would have short periods of feeling OK (hours not days) but then this wave of feeling heavy, dizzy, and generally unwell would come over me. It was like a dodgy electrical fault that one day switched off power and just never came back on.

https://www.s4me.info/threads/was-t...r-and-onset-of-your-me-cfs.40505/#post-557473

The big difference is that, for me anyway, this is not constant. So it's not muscle weakness. One minute I can lift something fairly heavy without much of a problem, then another this 'wave' of heaviness comes along and it's like it's glued to the floor. But it's not fatigue or tiredness as it's not gradual.

I think the thing that makes it more noticeable is that for occasional brief moments of 'almost normality' everything (including me) feels so much lighter

https://www.s4me.info/threads/heaviness-could-it-be-used-as-a-measurement.7247/#post-129367

apart from the going to sleep bit, yes it sounds 'normal' to me. A moment of exertion can trigger it off, and it comes over in a sort of wave like a change in gravity.
eg lifting something, doing something too quickly.

https://www.s4me.info/threads/suddenly-feeling-very-tired.23704/#post-396103

 

[Kitty]

But absolutely there must be some switch that can be affected

Last time it happened to me was my first Covid jab, the AstraZeneca. I felt great for nearly a week, and there didn't seem to be much limitation on what I could do. Then the symptoms gradually reverted to normal over two days.

Second dose had a similar effect, but not quite as strong and not as long lasting.

 

[Creekside]

A blocked loop is one possibility. A positive feedback loop can also cause a bistable state. There can even be multiple loops, so you might switch one loop, but that causes a delayed response from another loop or part of that loop which switches the whole system back to the unwanted state.

Intermittent problems are a nightmare for diagnosis, because it's hard to catch the fault, or in this case, the temporary good state. If the switching off of ME was repeatable, then researchers could look for what changes, but in my experience, these temporary remissions trigger once or twice, then stop responding to that specific trigger.

I think the main value of these temporary remissions is that they rule out a lot of other theories. When I see a theory about ME, I ask myself whether it could fit the rapid state-switching we observe. If it fails that test, I write off that theory.

 

[darrellpf]

My analogy is being marooned on a deserted island with a slow starvation level of food.

Seeing a ship in distance can be enough to raise you energy levels for days. The next ship has a lesser effect. Even after a long hiatus, seeing a ship doesn't work as well as it did the first time.

If family passes by and waves, your energy level goes up. When your energy fades we get the family to pass by twice a day. Again, for a while energy levels improve but eventually start to fade.

In the mean time the increased energy output causes you to get even more tired

Over the course of years one found that almost anything works... Spa treatments, late nights without sleep, various supplements and diets. Eventually "doubling the dose when the effects fade" just doesn't work any more. I take that as a sign that the only cure will be getting off the island.

 

[boolybooly]

I have heard of post anaesthetic remission before for PWME. My guess is it is such complete rest that it allows a short window of remission until the usual crash occurs just from normal activity. It suggests deep relaxation might be a viable management tool, along with pacing.

I also think its possible there is a signal or switch mechanism at the root of ME symptoms because I think it is likely to be due to an immune response which is jammed on and therefore chronic.

The problem is why the immune signal is jammed on?

In my case I have clear evidence of immune dysfunction in the form of chronic viral recurrence, which appears to meet criteria for Atypical Chronic Active Infection ACAI. The same viruses recur cyclically, sometimes changing virus. This began 4 years after glandular fever due to EBV mononucleosis diagnosed via NHS Paul-Bunnell test.

If the ME is a chronic immune reaction, switching it off might not be beneficial in my situation unless the immune dysfunction was a byproduct of the chronic activation and therefore self perpetuating. There is no knowing if it is or why it is jammed on in other people and it raises the prospect it might be unnecessarily active and like an asthma attack might be switched off with the right drug.

Alternatively if chronicity is due to interference in the immune system by EBV causing immune dysfunction and viral recurrence, this would need to be treated before the immune "switch" could safely revert to normal.

 

[Sasha]

I have heard of post anaesthetic remission before for PWME. My guess is it is such complete rest that it allows a short window of remission until the usual crash occurs just from normal activity. It suggests deep relaxation might be a viable management tool, along with pacing.

I think that if deep relaxation produced immediate remission, we'd know about it - lots of PwME have tried deep relaxation. Even sleep, which ought to be deeply relaxing, doesn't produce remission every morning (in fact, quite the opposite). I suspect lots of us feel better after deep rest during the daytime but without thinking that we're temporarily cured - just that we've got a few more spoons for a short while.

I think the experience with anaesthetic must point to something else, and it's interesting that you've seen several reports of post-anaesthetic remission. I wonder what that thing could be?

 

[duncan]

Alternatively if chronicity is due to interference in the immune system by EBV causing immune dysfunction and viral recurrence, this would need to be treated before the immune "switch" could safely revert to normal.

Or a third party antigen allowing for this EBV emergence, i.e. there's an immune dysfunction that provides for the reactivation of EBV that was established though a different pathogen.

I'm not clear on how either could be turned on or off by any mechanism; that doesn't mean it can't happen.

 

[Sasha]

For example, would the results of DecodeME help?

They are as likely as anything to.

How about the mysterious 'something in the blood'?

 

[MeSci]

Copied from https://www.s4me.info/threads/discr...-me-cfs-mcardle-et-al-2020.16398/#post-281766

"Healthy cells with ME/CFS plasma behave like patient samples, while ME/CFS cells with healthy plasma behave like healthy controls i.e. no increase in impedance."

From https://www.s4me.info/threads/ronal...tation-at-the-iimec13.5793/page-2#post-105495