Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine, 2022, Systrom et al

You're welcome.

Muscle weakness/burning was rarely (maybe never?) a problem for about 15+ years after my CFS diagnosis. When I was mild I would do dumb things like lift weights with friends, keeping up with them, then unsurprisingly get "sick" (PEM) for a week after.

It was only after a significant relapse and the emergence of more overt POTS symptoms that I noticed I now couldn't make it up a flight of stairs without using my hands to help because of legs burning. Or my arms would run out of energy brushing my teeth all of a sudden, that sort of thing. Essentially my dysautonomia became more immediately severe and disabling than the CFS I was used to.

Couldn't say if that represents a worsening of the existing CFS problem or a new problem entirely, but these results suggest to me it might be the former. Similar to the parallels with cerebral blood flow issues seen across POTS and now more recently CFS too.

 

Does anyone have a copy of the full article?

Results vary in healthy subjects.
The following study noted no difference in peak VO2, but did note lower resting heart rate.
https://www.scielo.br/j/abc/a/JHFWq5DrKgGr8PFLRwXfH4M/?format=pdf&lang=en

The following study noted an increase in peak VO2 in trained athletes, but not sedentary individuals.
https://elischolar.library.yale.edu/ymtdl/231/

 

Thanks.

So essentially it helped you with your brain fog? Interesting.

 

Ah I've been waiting for this study to be published.

I was prescribed Pyridostigmine last year and didn't notice any of the side effects listed on the leaflet, but when I tried to increase my dose from 15 to 30 mg my heart went nuts. Paramedic had to come, and the ECG trace was all over the place so I had to wait in A&E all night until the drug wore off.

Thankfully I was fine and I don't think this is a common side effect but just a word of warning to go slow and be vigilant if you're going to try it.

I have heard anecdotally of some people saying it's made a big difference to them though, especially people who have POTS.

 

Preliminary thoughts on this study - the reduction in VO2Peak on repeated CPET can only be due to one of two factors - the participant putting in less effort (as a participant in one of the studies I know this isn't the reason), or a reduction in blood volume circulating through the muscle. This is because VO2Max is limited by cardiovascular factors. We know it is not limited by mitochondrial capacity as motor unit recruitment is well below maximal at VO2Max.

So Pyridostigmine should in principle help. But by how much? In this study, there was a 1% increase in VO2Peak in the Pyridostigmine group and a 3% reduction in the placebo group. Scraping in with a P=0.04.

Or in the Authors words:

The improved performance is indeed likely related to the improvement in right atrial pressure in the Pyridostigmine group.

The manuscript itself has some issues, the first is male participants were excluded due to a supposed randomisation error (this is a little suspicious). The participants reached VO2Peak at relatively low heart rates, well below expected age maximums and the VO2Peak figures were very low suggesting sub-maximal effort or very low levels of fitness.

They claim that the reduced performance is due to neurovascular dysregulation precipitated by prior exercise but provide a vague explanation as to how this could occur. They then try to claim that there is "increased sympathetic outflow in ME/CFS is supported by elevated plasma catecholamine levels and increased sympathetic nerve activity to the heart, skeletal muscle arterioles, and adrenals during rest". Despite the fact that studies of adults with ME/CFS has shown no difference in resting catecholamine levels and if there was too much sympathetic stimulation, the why would more sympathetic stimulation and hence venoconstriction be desirable (see their Figure 3 as the proposed mechanism - "cholinergic stimulation of norepinephrine release at the post-ganglionic synapse").

Edit even for OI patients, as far back as 1988, it was known that patients have normal norepinephrine levels at rest, an it is upon orthostatic stress that any increased sympathetic stimulation is a response to venous pooling:
https://europepmc.org/article/MED/3343547

The manuscript then claims that there is evidence of hyperventilation in this group, but that is not true - the mean VE/VCO2 and VD/VT of the participants are in the normal range for exercising individuals. If they wish to claim that a few patients were hyperventilating, they are going to have to provide more specific evidence - how many reached a particular threshold for the various measures for example.

They then cite the Bohr effect without understanding that the Bohr effect is fairly small at physiological pressures in humans. Their reference is a prior Systrom study (that I had previously commented on), but that study does not provide any basis for claims about the importance of the Bohr effect, in fact the study they cite has the opposite conclusion.

This is despite the fact that some of the patient groups in that study had much higher VE/VCO2 slopes compared to the ME/CFS patients in the study of Systrom et al.

 

Lastly, this is part of Table 1:



The relatively high prevalence of positive ANA and SFN is interesting, though this is by no means a random cohort.

 

I took pyridostigmine starting at a low dose, eventually titrating up to 90mg tid. It had no discernible effect on my POTS or energy levels. I stopped taking it at the high dose because of gastrointestinal effects and it lowered my heart rate more than I was happy with, (into the 50's). I stopped taking my usual propranolol whilst I was on it. Once I stopped the pyridostigmine and restarted the propranolol I realised that the propranolol had a better beneficial effect, although far from curative.

 

Thank you for sharing your experience. I'm almost one week into my own n=1 beneficial experience. I was starting to have muscle weakness in addition to other ME symptoms, and Mestinon seemed to immediately improve that aspect: I have more spring in step & arm strength when I am upright. I haven't yet tested my physical stamina, since I'm primarily focused on restoring my cognitive stamina. I've been pleased/surprised that Mestinon also seems to help me cognitively. Still have PEM from cognitive effort, but already it seems to be trending to higher threshold & lower duration as you say. Will test out physical activity over the weekend.

Will emphasize again: this is n=1 & I'm only 1 week in. Will report back later with further updates.

 

Fantastic news, I hope it continues for you.

What dose are you taking? I have settled on 120mg morning, 120mg lunchtime, 60mg dinner time. I have been told I can increase to 180mg TID and will try to push it at some point to see if it aids physical activity further, currently I'm quite stable and generally have consistent cognitive energy levels if I avoid PEM.

 

Interesting how this improves cognition… would think that it would only impact physical symptoms.

 

Perhaps its correcting the CBF reduction and that is important.

 

OMF posted this link on twitter today:

https://www.omf.ngo/wp-content/uploads/2022/09/mest-rct.pdf

The tweet said "new publication" but I think it's the paper mentioned in the first post.

Can someone confirm? Thanks!

 

Yes, it's the same paper.