"Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia... van Campen et al, 2020

[Hoopoe]

Out of curiosity: sometimes I felt like my respiratory volume was abnormally low, but without causing any apparent problems.

Is it possible that I'm adapted to a state of reduced oxygen consumption? Some of the research suggests there is reduced oxygen consumption but I don't know if that occurs to such a degree that it would be noticable to the patient.

 

[Ryan31337]

Out of curiosity: sometimes I felt like my respiratory volume was abnormally low, but without causing any apparent problems.

Is it possible that I'm adapted to a state of reduced oxygen consumption? Some of the research suggests there is reduced oxygen consumption but I don't know if that occurs to such a degree that it would be noticable to the patient.

Another way to look at that could be the low volume is compensatory to hypocapnia, correcting prior hyperventilation.

 

[Ryan31337]

An anecdote that's sort of on-topic that people might find thought provoking:

On holiday a few years back I woke up feeling awful, in a pool of sweat, hyperventilating (rapid breathing this time). It was notable for me because despite feeling relaxed, my breathing did not return to normal immediately as it would after waking from a nightmare.

A few hours prior i'd been stupid enough to go Scuba diving, despite not being well enough. I was promised a very gentle shallow dive, basically a paddle around, but instead got dropped into a ripping current and had to exert myself massively for a long time. I would hazard a guess that I'd experienced lactic acidosis and was hyperventilating to compensate for that.

It might've been complicated by gas exchange post-dive, but some time after that experience I was worked up in a myopathy clinic and had a blood lactate test, my levels were the highest the doctor had seen outside of ICU - when I looked it up my blood lactate level was similar to a healthy person post-marathon. I was late for the appointment and had walked quite briskly up a few flights of stairs before the test and felt similar levels of muscle burn to the diving experience...

 

[ME/CFS Skeptic]

I've only been able to read this study now. Here are my thoughts.

1) 28% of the ME/CFS patients were diagnosed with POTS but the majority had a normal heart rate and blood rate respond during the tilt table test. Given that daily life orthostatic intolerance symptoms were reported by 78% of those with a normal heart rate/blood pressure response, it would seem that the latter forms a poor explanation of orthostatic intolerance in patients with ME/CFS.

2) Patients were asked if several symptoms got worse after being tilted. I thought it was a little strange that the frequency of patients reporting these symptoms did not clearly increase from the 1st to the 10th minute of the tilt table test. Or does the % for the 10-minute measurement represent an additional increase since the start of the 1-minute measurement?




Perhaps patients were more focused on whether they had the symptom rather than whether it increased after standing. Also some of these symptoms like low-back pain and neck-shoulder muscle pain might not have been directly related to the OI that patients commonly report (which I think is more focused on fatigue/weakness/dizziness and no longer being able to stand or sit upright).

3) Then there’s the decrease in cerebral blood flow during the tilt test. I wonder whether this could be a consequence of deconditioning /sedentary lifestyle as the controls were not matched for activity levels. The authors also note that there might have been a selection bias as Visser’s clinic is known to do the tilt table test. I know that Belgian patients sometimes discuss whether they should travel to the Netherlands to get tested for POTS with Visser - for a long time that’s what he was known for. Also: if you look at the flow diagram, of the 714 patients screened because of a suspicion of ME/CFS, only 5% were not diagnosed with ME/CFS. That percentage is usually much larger.

 

[ME/CFS Skeptic]

Has anyone looked in-depth at cerebral perfusion in ME/CFS? I know there are quite a few studies that have reported this but is it a robust finding?

If so, what to make of the finding in this study by Van Campen/Visser that "Supine cerebral blood flow was not different between ME/CFS patients and controls"?

 

[Denise]

Formal publication version of article (open access)
https://www.sciencedirect.com/science/article/pii/S2467981X20300044

 

[MerryB]

An anecdote that's sort of on-topic that people might find thought provoking:

On holiday a few years back I woke up feeling awful, in a pool of sweat, hyperventilating (rapid breathing this time). It was notable for me because despite feeling relaxed, my breathing did not return to normal immediately as it would after waking from a nightmare.

A few hours prior i'd been stupid enough to go Scuba diving, despite not being well enough. I was promised a very gentle shallow dive, basically a paddle around, but instead got dropped into a ripping current and had to exert myself massively for a long time. I would hazard a guess that I'd experienced lactic acidosis and was hyperventilating to compensate for that.

It might've been complicated by gas exchange post-dive, but some time after that experience I was worked up in a myopathy clinic and had a blood lactate test, my levels were the highest the doctor had seen outside of ICU - when I looked it up my blood lactate level was similar to a healthy person post-marathon. I was late for the appointment and had walked quite briskly up a few flights of stairs before the test and felt similar levels of muscle burn to the diving experience...

This is very interesting. When I crash my breathing changes - it is like big gasps followed by very fast and hard expirations. Like someone would breathe if they had just run up a steep hill very fast and were very unfit.

Except I could have just been sitting in bed reading when it comes on, so not necessarily linked to physical exertion.

I tried to look up what might make that happen, and it seems closest to Kussmaul breathing which happens in acidosis.

I've never had my blood pH measured when in that state so I have no idea whether it has anything to do with that.

But t know it's not a lung problem as my lungs are perfectly clear and fine.

It feels to me like a metabolic problem - I feel myself getting gradually more and more exhausted as I continue an activity (not necessarily a physical activity - yesterday it happened after I exhausted myself writing a lab repot), and then suddenly I will collapse and have to lie down, and that heavy breathing pattern will start up.

It goes on very intensely for about 20 minutes or so, during which I just lie there panting and feeling extremely weak.

Then after a while it settles down. I feel like crap afterwards but I can e.g. get up and go get myself a drink, or use the bathroom.

So it's more like acute 'attacks' that I get which are precipitated by feeling a building sense if exhaustion, during relatively mild activity.

Of course this is probably a typical ME 'crash', but I have been wondering whether it could be some kind of acute collapse when blood lactate gets too high after putting strain on a dysfunctional metabolism, and then the heavy breathing and lying down for a while allows for the lactate to be cleared so I recover without e.g. needing to go to hospital like someone in diabetic ketoacidosis would need to.

I might be completely wrong, but I can see how this could happen theoretically if we are experiencing systemic hypoperfusion, impaired systemic oxygen extraction, and relying on anaerobic metabolism more than a healthy person would.

I would imagine this scenario could lead to acute 'attacks' of lactic acidosis which might be cleared with lying down and panting for a while.

 

[Ryan31337]

Thanks for sharing that @MerryB.

I would push for review at a Myopathy clinic, just in case. The approach at the NHS clinic I went to was a consultation and some blood tests, which led to a muscle biopsy. The biopsy didn't show any significant changes so it wasn't taken any further. If it had, they would've looked for genetic issues. Because I had a degree of muscle fatigability going on they also ruled out Myasthenia Gravis with some electrical nerve studies.

None of it pointed to any classic myopathy so I was discharged. I am significantly affected by POTS and SFN, so best guess is I have the sort of impaired oxygen extraction from poor microcirculation and mito dysfunction that is increasingly recognised with that.

 

[stuck]

For me it feels like the membrane has a leak - some pressure issue somewhere that drains off any energy before it gets delivered. As if my system has been thrown in reverse gear when I want to step on the gas. And the head pressure in sinus, other places with inflammation from PEM feels like a lack of proper drainage, which if there were a leak from one space into another could really mess up signaling. But, as a layperson, I don't have enough education to figure it out.

When I am laying down, pressure on the back of my neck helps. I wonder about a leaky brain fluid somewhere. There were leaky GUT studies, but my symptoms seemed to bring me back to the brainstem and the head fog didn't seem to be explained if it was in the gut.

Been really hopeful Jarred Younger's work would produce more definitive diagnostics with all the scans and contrast PETS.

There is this new article but sorry if it is old study news, I'm new to posting -- thought it was apropos:
https://www.eurekalert.org/pub_releases/2020-02/nu-tso022720.php
News Release 28-Feb-2020

Two sides of a coin: Our own immune cells damage the integrity of the blood-brain barrier
Nagoya University

The article, "Dual microglia effects on blood brain barrier permeability induced by systemic inflammation," was published in the journal Nature Communications at DOI: 10.1038/s41467-019-13812-z.

Moderator note: To discuss this research go to this thread:
Dual microglia effects on blood brain barrier permeability induced by systemic inflammation, 2019, Hiroaki Wake et al.

 

[stuck]

It goes on very intensely for about 20 minutes or so, during which I just lie there panting and feeling extremely weak.

Then after a while it settles down. I feel like crap afterwards but I can e.g. get up and go get myself a drink, or use the bathroom.

So it's more like acute 'attacks' that I get which are precipitated by feeling a building sense if exhaustion, during relatively mild activity.

Of course this is probably a typical ME 'crash', but I have been wondering whether it could be some kind of acute collapse when blood lactate gets too high after putting strain on a dysfunctional metabolism, and then the heavy breathing and lying down for a while allows for the lactate to be cleared so I recover without e.g. needing to go to hospital like someone in diabetic ketoacidosis would need to.

Yes. I wonder about this too! My family helps me with an ice pack to the back of the neck, a cup with 1/2tsp baking soda water and maybe 85% dark chocolate to also support recovery. My breathing also is very different. Most times very shallow and every once in awhile a deep breath making my daughter wonder what she did wrong (she is home schooled to help me) and has just gotten used to me saying "breathing!"

 

[MerryB]

Thanks for sharing that @MerryB.

I would push for review at a Myopathy clinic, just in case. The approach at the NHS clinic I went to was a consultation and some blood tests, which led to a muscle biopsy. The biopsy didn't show any significant changes so it wasn't taken any further. If it had, they would've looked for genetic issues. Because I had a degree of muscle fatigability going on they also ruled out Myasthenia Gravis with some electrical nerve studies.

None of it pointed to any classic myopathy so I was discharged. I am significantly affected by POTS and SFN, so best guess is I have the sort of impaired oxygen extraction from poor microcirculation and mito dysfunction that is increasingly recognised with that.

Thank you for the suggestion. If my current new medication trial doesn't help (Midodrine) then I will discuss this with GP. I found it interesting that Systrom has found impaired systemic oxygen extraction in ME patients, which he reckons can be caused by mitochondrial myopathy in some people.

 

[Ryan31337]

Thank you for the suggestion. If my current new medication trial doesn't help (Midodrine) then I will discuss this with GP. I found it interesting that Systrom has found impaired systemic oxygen extraction in ME patients, which he reckons can be caused by mitochondrial myopathy in some people.

I haven't read that study for a while but i'm not sure if he went so far as to say there's definite mito disease in these patients. I suspect its more mito dysfunction (which can be secondary to a number of other problems).

Good luck with the Midodrine

 

[MerryB]

I haven't read that study for a while but i'm not sure if he went so far as to say there's definite mito disease in these patients. I suspect its more mito dysfunction (which can be secondary to a number of other problems).

Good luck with the Midodrine

Thanks! He used the term mitochondrial myopathy but it was a small sample size. 22 patients with a clinical diagnosis of mitochondrial myopathy, but only 3 of them had confirmatory genetic mutation analysis I believe, so it was 'clinically suspected' based on the fact that their iCPET profiles were very similar to those of people with confirmed mitochondrial myopathy (from other studies).

So if this is a defined subgroup I think further study on a larger cohort with more in-depth testing would be necessary. He said as their referral database grows they will try to study this further to identify whether this is an actual subgroup.

Anyway, I managed to get off the topic of cerebral perfusion. The reason I thought of Systrom's study was because he also proposed that dysautonomia affecting hemodynamics (microcirculatory dysfunction) could result in impaired systemic oxygen extraction, and that hyperventilation might be a means of the body trying to compensate for this.

 

[Ryan31337]

Thanks! He used the term mitochondrial myopathy but it was a small sample size. 22 patients with a clinical diagnosis of mitochondrial myopathy, but only 3 of them had confirmatory genetic mutation analysis I believe, so it was 'clinically suspected' based on the fact that their iCPET profiles were very similar to those of people with confirmed mitochondrial myopathy (from other studies).

Ah, my mistake, I read that paper again and see the author (Systrom was just a contributor) used the term mito myopathy to describe both primary and secondary mito issues.

Personally I think it makes more sense to label mito issues that are only secondary as dysfunction, rather than a disease (myopathy). Looking back through some other publications and video interviews with Systrom he seems to use the term mito dysfunction when referring more broadly to 'syndromic' patients (fibro, hypermobility, CFS). I'm sure there'll be some bona fide primary mito disease in the cohort but I don't think it'll be large, at least not by the way we currently identify mitochondrial myopathy.

 

[tralfamadorian97]

Commenting because I read this recently.

What's remarkable to me about this paper is the very strong separation in orthostatic cerebral blood flow reduction between patients and controls.

From my reading of the ME/CFS literature, this seems rare. Usually the distributions of a physiological variable for ME/CFS patients and controls will substantially overlap, even if the means of the two distributions are different.

In contrast, the authors of this paper report that:

Assuming a lower limit of normal of 2 SD below the mean for healthy controls, the lower limit of a normal % cerebral blood flow decrease during the tilt was 13%. Using this cut-off value, 384/429 ME/CFS patients (90%) showed a more than 13% reduction: 82% of patients with a normal heart rate and blood pressure response, 98% of delayed orthostatic hypotension patients, and 100% of POTS patients.

which indicates remarkable separation. If these findings are accurate, they hint that cerebral blood flow is closely related to the core pathophysiology of ME/CFS. I would suggest that efforts to replicate this study in a different cohort with different investigators should be high priority.

 

[Utsikt]

If these findings are accurate, they hint that cerebral blood flow is closely related to the core pathophysiology of ME/CFS.

Why would it be a hint that it’s at the core of ME/CFS? It’s purely correlation, and the severe and very severe are lying down all day, yet they are still the most affected.

And what about controlling for activity levels, deconditioning, etc? They only checked the BMI in this study.

 

[EndME]

Commenting because I read this recently.

What's remarkable to me about this paper is the very strong separation in orthostatic cerebral blood flow reduction between patients and controls.

From my reading of the ME/CFS literature, this seems rare. Usually the distributions of a physiological variable for ME/CFS patients and controls will substantially overlap, even if the means of the two distributions are different.

In contrast, the authors of this paper report that:



which indicates remarkable separation. If these findings are accurate, they hint that cerebral blood flow is closely related to the core pathophysiology of ME/CFS. I would suggest that efforts to replicate this study in a different cohort with different investigators should be high priority.

I agree that a strong separation is a remarkable and very rare result, given that usually as you state there is little separation even if the means differ.

However, one should be wary of the fact that this argument might be very circular in the case of this clinic or at least biased by recruitment from what I've heard. If you talk to patients that visit this clinic (@ME/CFS Skeptic writes something similar above) it sometimes seems to me that the clinicans tend to diagnose ME/CFS largely focusing on the results of exactly this tilt-table test, including the cerebral blood flow measurements, rather than focusing on ME/CFS symptoms and diagnosis of exclusion (the reason why people visit this clinic is essentially to get a POTS diagnosis via tilt-table and a prescription for medication). So one could possibly hyperbolically say that the separation might simply exist by construction, rather than anything else.

It would seem necessary that someone would have to replicate such findings in a CCC ME/CFS cohort and control for deconditioning before much can be said. I know that some of the "fancy new LC clinics" use transcranial doppler.

 

[tralfamadorian97]

And what about controlling for activity levels, deconditioning, etc? They only checked the BMI in this study.

I absolutely agree that studies should control for these things: that's definitely something any follow-up study or replication attempt should do. But I would say that the strength of the distributional separation between controls and cases does mitigate against the possibility of confounding: van Campen and Visser have a range of severities in their patient population, and thus a range of activity levels. Mild ME/CFS patients can be expected to spend most of their day upright. The fact that despite this, almost no patients are in the normal range of cerebral blood flow reduction argues against confounding by activity level.

Why would it be a hint that it’s at the core of ME/CFS? It’s purely correlation, and the severe and very severe are lying down all day, yet they are still the most affected.

Sorry, I should have been more clear. What I meant by "closely related to the core pathology" is not that orthostatic blood flow reduction is the cause of ME/CFS. Instead, I meant that blood flow reduction is a highly deterministic direct physiological consequence of whatever is the underlying mechanism of ME/CFS. An alternative explanation is that ME/CFS causes behavioral changes that in turn causes orthostatic cerebral blood flow reduction. But given that different people alter their behavior in response to getting ME/CFS in different ways, I would not expect such strong distributional separation in the case of a behavioral mechanism.

it sometimes seems to me that the clinicans tend to diagnose ME/CFS largely focusing on the results of exactly this tilt-table test

Thanks for bringing this up. I was not aware of this point. As you say, this an additional argument for independent replication.

 

[tralfamadorian97]

some of the "fancy new LC clinics" use transcranial doppler.

Transcranial doppler is better than nothing, but as the author's describe, there is the risk of confounding due to changes changes in vessel diameter. I hope someone additionally tries to use van Campen and Visser's method

 

[Utsikt]

But I would say that the strength of the distributional separation between controls and cases does mitigate against the possibility of confounding: van Campen and Visser have a range of severities in their patient population, and thus a range of activity levels.

They tested mild and moderate patients in a clinic that is internationally known for testing for OI. Can we assume that the ranges of activity levels for mild overlaps with healthy people?

You also have to consider for how long the participants have been at their activity levels. Most pwME/CFS have been sick for years before they even get a diagnosis. That’s plenty of time to cause substantial changes to the cardiovascular systems.

Mild ME/CFS patients can be expected to spend most of their day upright. The fact that despite this, almost no patients are in the normal range of cerebral blood flow reduction argues against confounding by activity level.

Time spent upright isn’t a very good proxy for overall load on the cardiovascular system over time.

Sorry, I should have been more clear. What I meant by "closely related to the core pathology" is not that orthostatic blood flow reduction is the cause of ME/CFS. Instead, I meant that blood flow reduction is a highly deterministic direct physiological consequence of whatever is the underlying mechanism of ME/CFS. An alternative explanation is that ME/CFS causes behavioral changes that in turn causes orthostatic cerebral blood flow reduction. But given that different people alter their behavior in response to getting ME/CFS in different ways, I would not expect such strong distributional separation in the case of a behavioral mechanism.

Essentially the same as above: Do you have any data that supports the assertion that pwME/CFS’s activity patterns substantially overlaps with those of healthy people? People adapt differently initially, but PEM will eventually force your to limit yourself one way or another.

This illustration comes to mind when talking about activity levels: