OMF: Muscle Biopsy and Plasma Study into Post-Exertional Malaise, David Systrom, 2022

[Jonathan Edwards]

The problem for me is fitting any structural changes like basement membrane thickening with PEM . If there is a structural problem you are going to be weak to the same extent hour to hour, day to day. It does not tell us about the key issue of MECS, that you can be not too bad this morning and crashed out by supper time.

Also, if there are these changes why have they never been seen in hundreds of MECFS patients who have had muscle biopsy with EM analysis in the past?

Why have day 1 CPET results been pretty unremarkable?

 

[butter.]

The problem for me is fitting any structural changes like basement membrane thickening with PEM . If there is a structural problem you are going to be weak to the same extent hour to hour, day to day. It does not tell us about the key issue of MECS, that you can be not too bad this morning and crashed out by supper time.

Also, if there are these changes why have they never been seen in hundreds of MECFS patients who have had muscle biopsy with EM analysis in the past?

Why have day 1 CPET results been pretty unremarkable?

I think you might have a biased view of how ME/CFS presents if you believe there is no "generalized weakness."

Severe and very severe ME (not your average/standard account on here) patients almost always experience some form of persistent weakness. I'd also argue that "weakness" and other symptoms are not entirely static or evenly distributed even in diseases with clear tissue damage.

Of course, I’m biased too — but most people with ME that I know of who had a muscle biopsy showed some form of abnormality. I would not say there is a uniform pattern, that doesn't mean there could not be a similar pathological endpoint/symptoms, though.

What you’re describing, feeling relatively fine in the morning and much worse by evening, in relation to exertions is seen in many (like a lot!) diseases, including primary mitochondrial disorders.

Please also don't forget that many/maybe most adult patients with PMM or mitochondrial myopathy have multiple biopsies before anything is found. The pathology is usually very 'patchy', which is one of the main reasons that there has been a major shift towards genetic analysis as an add-on, by some it's used as the primary diagnostic modality.

Much of it might be a subgroup or nosological issue. You could have people with ME who have clearcut abnormalities without those being connected to their ME. Maybe severe forms are a different pathology all together. Many open questions.

 

[Trish]

If there is a structural problem you are going to be weak to the same extent hour to hour, day to day. It does not tell us about the key issue of MECS, that you can be not too bad this morning and crashed out by supper time.

That description ignores the rapid fatigability in ME/CFS. My experience and my understanding from others is that our muscles may feel 'not too bad' when rested, but as soon as we start any activity using muscles they rapidly weaken and may feel heavy, aching, painful. That's separate from the 'crashed out by supper time' effect.
I think the repeated handgrip strength tests for ME/CFS illustrate it.

Edit; The rapid muscle fatigability is also shown in the infamous misuse in the Walitt NIH study of the EEFRT rapid button pressing test, where they failed to take into account the fact that the pwME were less able to complete the longer repetition task.

 

[SNT Gatchaman]

When I was improving from severe, sufficient to sit for 30 minutes at a time and use my workstation, I could (touch) type. If I made an error I would backspace all the way back and type the section again. This was more efficient than using the mouse to select the error and overtype. I had to use the mouse to manipulate the image but minimised my movements. What was incredibly striking was that I had to drag my hand over the desk: I was too weak to lift it up against gravity to reposition. 30 minutes of that and then lie flat for 2 hours to recover.

Four years down the line I fatigue far more rapidly than normal, but I don't have the level of baseline weakness as when severe. I can type and mouse and move around the house reasonably unencumbered. I wonder whether part of that improvement was the fibre-type shifts that allow for a bit more normal strength via glycolytic fibres. If so perhaps part of the difference explaining people that deteriorate to and remain severe is the inability to fibre shift and the inability to boost mitochondrial function as suggested by Systrom.

 

[Jonathan Edwards]

@butter. I don't really buy those arguments. Yes prolle with severe MECFS are weak. But they think to explain is PEM which is an adverse change after exertion that is regarded as temporally quite different from myopathies. I have looked after people with muscle disease and worked in a unit that soecialisd in muscle histology. Jo Cambridge was an acknowledged authority on myositis. It isn't as grey as you suggest. Myositis has pathology which usually comes back on first biopsy and the CK is raised. The clinical picture looks nothing like MECFS.

 

[butter.]

@butter. I don't really buy those arguments. Yes prolle with severe MECFS are weak. But they think to explain is PEM which is an adverse change after exertion that is regarded as temporally quite different from myopathies. I have looked after people with muscle disease and worked in a unit that soecialisd in muscle histology. Jo Cambridge was an acknowledged authority on myositis. It isn't as grey as you suggest. Myositis has pathology which usually comes back on first biopsy and the CK is raised. The clinical picture looks nothing like MECFS.

Myositis and mitochondrial myopathy are not the same. In mitochondrial myopathy (MM), CK is not always elevated, and many patients require multiple (!) biopsies before anything abnormal is found. I have close friends who went through this.

As for ME/CFS: PEM might — or might not — explain 'weakness' in any given patient. And let’s not forget: we still don’t really know what PEM is.

 

[Jonathan Edwards]

You are right , @Trish, to pick me up on using weak rather than unable to continue with exertion, but I am by no means ignoring that.

Actually, a basement membrane thickening would not fit with weakness - another point against butter.'s argument. It would produce formal muscle fatiguability a bit like myasthenia. That certainly might seem to fit with what you are describing but no physician has ever been able to demonstrate it on the sort of formal testing that should show it. There is so.ething happening but if it was shortage of oxygen I suspect it would be apparent clinically.

But the original point was that if we invoke capillary thickening for fatiguability in moderate to severe cases we still have to explain With another mechanism the temporal fluctuation of not just PEM but also the "daily spoon count" which wouldn't be explained by oxygen pathways.

If we still need another mechanism then maybe that other mechanism explains everything.

The wider point is that researching disease mechanisms isn't about collecting loads of different abnormal findings, which, if looked at carefully, don't fit together. It is about combining lots of both positive and normal findings into a story that explains all of them. That may be kyboshed by there being three diseases instead of one but sorting that out is part of the exercise.

 

[butter.]

You are right , @Trish, to pick me up on using weak rather than unable to continue with exertion, but I am by no means ignoring that.

Actually, a basement membrane thickening would not fit with weakness - another point against butter.'s argument. It would produce formal muscle fatiguability a bit like myasthenia. That certainly might seem to fit with what you are describing but no physician has ever been able to demonstrate it on the sort of formal testing that should show it. There is so.ething happening but if it was shortage of oxygen I suspect it would be apparent clinically.

But the original point was that if we invoke capillary thickening for fatiguability in moderate to severe cases we still have to explain With another mechanism the temporal fluctuation of not just PEM but also the "daily spoon count" which wouldn't be explained by oxygen pathways.

If we still need another mechanism then maybe that other mechanism explains everything.

The wider point is that researching disease mechanisms isn't about collecting loads of different abnormal findings, which, if looked at carefully, don't fit together. It is about combining lots of both positive and normal findings into a story that explains all of them. That may be kyboshed by there being three diseases instead of one but sorting that out is part of the exercise.

How would it be apparent clinically if it was an 'oxygen issue?'

It isn't apparent in MM, so why would it necessarily be in ME/CFS? (I am not saying ME is MM.)

I have been part of a small group of patients who had a metabolon which found hypoxanthine increased in all patients (not exactly subtly). That's a marker for hypoxia.

PEM could be many things, it could be downstream of hypoxia, it might not be, it might be different things for different patients. I am not convinced by the 'surely we would know by now' line of reasoning.

Oxygen deprivation would/can/will cause delayed effects that could look like PEM, that would not surprise anyone. I am not saying that's what it is, I am saying assuming that it isn't is still somewhat premature.

 

[Jesse]

@butter. I don't really buy those arguments. Yes prolle with severe MECFS are weak. But they think to explain is PEM which is an adverse change after exertion that is regarded as temporally quite different from myopathies. I have looked after people with muscle disease and worked in a unit that soecialisd in muscle histology. Jo Cambridge was an acknowledged authority on myositis. It isn't as grey as you suggest. Myositis has pathology which usually comes back on first biopsy and the CK is raised. The clinical picture looks nothing like MECFS.

I don't think these findings are intended to explain PEM? Isn't this where they're comparing muscles from ME/CFS and LC patients with deconditioned (through bed rest) healthy controls. It could help explain reduced functioning in ME/CFS right?

If we still need another mechanism then maybe that other mechanism explains everything.

I'm not opposed to this thinking though.

Maybe if they manage to replicate their LC PEM muscle biopsy findings in ME/CFS we can hypothesize more about PEM's effect on muscles.

 

[V.R.T.]

But the original point was that if we invoke capillary thickening for fatiguability in moderate to severe cases we still have to explain With another mechanism the temporal fluctuation of not just PEM but also the "daily spoon count" which wouldn't be explained by oxygen pathways.

If we still need another mechanism then maybe that other mechanism explains everything.

Surely it is possible that there is one mechanism for the fatiguability and another one for PEM, and that they show up together in ME/CFS because the capillary thickening is caused by a process downstream of the one that triggers PEM?

On the other hand, weren't these biopsies taken from mild and moderate patients though? So if the thickening is only an issue in people with PEM we wouldn't expect to have the uniform finding Wust et al report.

Although my experience of mild ME was that I did feel at baseline more tired and easily fatiguabe than when I was healthy.

 

[Jonathan Edwards]

@V.R.T.
To quote Wilde's Lady Bracknell,

"To have a disease with one almost invisible mechanism may be considered a misfortune; to have a disease with two..."

Yes it is possible but it still doesn't really fit.

We know what it is like to have leg muscles that cannot access oxygen from blood quickly enough. The symptom is called claudication. That is not a feature of MECFS.

The presentation in the video was clear but partly because it greatly oversimplified what the question is.

 

[Utsikt]

@Jonathan Edwards
So you’re saying that if X is true, Y will happen? But we don’t see Y, so X can’t be true.

And that A would only explain B, but we need to explain C to N as well. We might have better luck by trying to explain B to N in one go, instead of looking at letters in isolation?

 

[V.R.T.]

@Jonathan Edwards
So you’re saying that if X is true, Y will happen? But we don’t see Y, so X can’t be true.

And that A would only explain B, but we need to explain C to N as well. We might have better luck by trying to explain B to N in one go, instead of looking at letters in isolation?

It's probably a mark of how bad my brain fog is today that I can't tell if this post is a joke

 

[Utsikt]

It's probably a mark of how bad my brain fog is today that I can't tell if this post is a joke

And a mark of how terribly I explained it! I’m just trying to see if my foggy brain actually understood what he was saying.

 

[V.R.T.]

And a mark of how terribly I explained it! I’m just trying to see if my foggy brain actually understood what he was saying.

No it's probably me! I felt like I could almost grasp it the second time I read it

 

[Sean]

If there is a structural problem you are going to be weak to the same extent hour to hour, day to day.

What is the definition of structural in medicine?

Is it confined to a specific tissue or group of morphologically coherent tissues (e.g. red blood cells, bone, muscle, an organ)?

In particular, does structural pathology have to be either more-or-less static (e.g. a missing limb), or which only changes relatively slowly (e.g. tumour, congestive heart failure, RA). Or can it be something that might also have a somewhat dynamic aspect in the short-term, like immune responses?

 

[butter.]

To quote Wilde's Lady Bracknell,

"To have a disease with one almost invisible mechanism may be considered a misfortune; to have a disease with two..."

That's an interesting choice, as Wilde used Lady Bracknell to mock the ignorance of the Victorian upper class.

"Ignorance is like a delicate exotic fruit; touch it and the bloom is gone", is an original quote.

 

[Jonathan Edwards]

@Sean, Structural is just plain English in this case.

Structural problems are as static as far as the relevant layer of structure is static. Thickening of capillaries will be static over hours and days. The structure of a macrophage is not so static - it can move around in seconds in the blood and change shape in many minutes. The overall structure of a nerve cell axon takes weeks to change. The structure of individual synapses can change overnight. The nanostructure in terms of ion channel conformations change in microseconds. It is all relative.

I was referring to vessel basement membrane structure specifically but more generally to the level of structure in muscle tissue that would limit oxygen flow.

This is also an argument against the microclot theory of course - which again claims poor oxygen or nutrient supply through structural changes in vesels that will not alter over hours or days much.

 

[SNT Gatchaman]

We know what it is like to have leg muscles that cannot access oxygen from blood quickly enough. The symptom is called claudication. That is not a feature of MECFS.

People with diabetic microangiopathy have capillary basement membrane thickening, though that is not isolated to just skeletal muscle, but involves skin, nerves etc in limbs (plus retina, kidney). If they have zero peripheral arterial disease, do they get symptoms of claudication?

 

[Jonathan Edwards]

People with diabetic microangiopathy have capillary basement membrane thickening, though that is not isolated to just skeletal muscle, but involves skin, nerves etc in limbs (plus retina, kidney). If they have zero peripheral arterial disease, do they get symptoms of claudication?

No, but their muscles work OK.

My point is that if capillary basement thickening was impeding oxygen supply to muscle cells and that was causing symptoms in ME/CFS it would cause claudication. Presumably if there is baement membrane thickening it isn't causing shortage of oxygen supply, so the link to ME/CFS symptoms seems misplaced.

As far as I know capillary basement membrane thickening, as in amyloid, does not produce symptoms as such, unless it is associated with a permeability change, when you get oedema.