"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

[Denise]

Full title:
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: a quantitative, controlled study using Doppler echography

https://www.sciencedirect.com/science/article/pii/S2467981X20300044

Highlights
•
Extracranial Doppler technique to measure cerebral blood flow is feasible during head-up tilt testing.

•
Cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients is reduced during head-up tilt testing compared to healthy volunteers.

•
Using a lower limit of normal of the cerebral blood flow reduction during head-up tilt testing of 13%, 90 percent of ME/CFS patients showed an abnormal cerebral blood flow reduction.

•
Reduction in cerebral blood flow is correlated with symptoms of orthostatic intolerance.

Abstract
Objective
The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.

Methods
429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.

Results
End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P<.0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P<.0005).

Conclusions
During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.

Significance
This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.

Patients were classified as having CFS, chronic fatigue, or no chronic fatigue as defined by Fukuda and colleagues(Fukuda et al. , 1994) and as having ME or no ME as defined by Carruthers and colleagues(Carruthers et al. , 2011).


Hmmmm..... It may be that the definition and diagnosis of orthostatic intolerance needs to be revised.

 

[Tom Kindlon]

To facilitate sharing:

 

[Denise]

To facilitate sharing:

Just a heads up - this is a preprint so the final product may have some changes (though this has been reviewed, edited etc already).

 

[Hoopoe]

Very nice. Just the other day I was thinking that maybe the best treatment approach that we have at the moment would be to try and get blood flow working better. Other treatment directions are very speculative, but this one not as much.

I also suspect some genes related to orthostatic intolerance are going to show up on the GWAS study.

 

[Milo]

An important paper. It is interesting that the experiments were performed in the Netherlands. I hope this will provide a paradigm change over there and all around the world.

 

[Kitty]

I suspect some genes related to orthostatic intolerance are going to show up on the GWAS study.

Yes, that could be interesting – it seems to run in our family.

I've had it since childhood, and getting ME at 17 didn't make it any worse, but of course it's possible I might otherwise have grown out of it. My mum struggled with it all her life, but her sister (who would actually pass out if she had to queue) was better once she got into her 20s.

 

[rvallee]

Impressive N.

Interesting to note the direction of symptoms between patients and controls. For controls they almost all disappear by the 10-minute mark, whereas nearly half increase for patients. The questions asked are very pertinent, love to see people who ask the right questions. The image is poor quality, sadly:

Maybe random observation but: we are observing changes in PRBCs deformity, making oxygenation harder, especially in capilaries. Somehow the neurovascular system must compensate for that in order to keep oxygenation in good order, perhaps by constricting capilaries less than is needed, which has a cascading effect of having less blood pressure (which was observed here) and depriving some systems or organs of oxygen so as to keep the brain as best oxygenated in the circumstances? Which isn't even enough as it still leads to significant reduction of both flow and pressure.

 

[Milo]

Finally, most ME/CFS case definitions have recognized that there are heterogeneous precipitating and perpetuating factors, and most case definitions have recommended subtyping of the illness to define more homogenous samples(Fukuda et al., 1994, Carruthers et al., 2011). Our data suggest that the cerebral blood flow reduction is a common denominator of symptoms across subgroups in this population.

Bolding mine.

 

[Hoopoe]

Something else is that maybe the anecdotal positive effect of magnesium is related to improved brain blood flow.

 

[Kitty]

we are observing changes in PRBCs deformity, making oxygenation harder, especially in capilaries.

It would be interesting to look at people with other conditions causing stiff PRBCs, to see if they have the same response to it.... (Thinking ahead too quickly, as always – obviously the first priority would be bigger studies in ME!)

 

[Denise]

Impressive N.

Interesting to note the direction of symptoms between patients and controls. For controls they almost all disappear by the 10-minute mark, whereas nearly half increase for patients. The questions asked are very pertinent, love to see people who ask the right questions. The image is poor quality, sadly:

Maybe random observation but: we are observing changes in PRBCs deformity, making oxygenation harder, especially in capilaries. Somehow the neurovascular system must compensate for that in order to keep oxygenation in good order, perhaps by constricting capilaries less than is needed, which has a cascading effect of having less blood pressure (which was observed here) and depriving some systems or organs of oxygen so as to keep the brain as best oxygenated in the circumstances? Which isn't even enough as it still leads to significant reduction of both flow and pressure.

@rvallee - This is a pre-print version. Is it possible the image quality will improve in the final publication version?

 

[ahimsa]

The image is poor quality, sadly

I was able to download the PDF from the science direct web page. The download link is at the top of the screen.

It's a pre-print copy but the images are better than the one you posted.

 

[Grigor]

An important paper. It is interesting that the experiments were performed in the Netherlands. I hope this will provide a paradigm change over there and all around the world.

Sadly they are often considered quacks by many mainstream docs. It's slowly changing though.

 

[DokaGirl]

@Milo, thank you for pointing out the 90% number for pwME with CBF reduction. I believe a similar number has been noted in other studies for OI by Dr. Rowe, one of the authors in this study.

 

[Denise]

@Milo, thank you for pointing out the 90% number for pwME with CBF reduction. I believe a similar number has been noted in other studies for OI by Dr. Rowe, one of the authors in this study.

@DokaGirl - I think you are correct that other studies by Rowe have shown a high %age of OI but if I remember correctly those were (mostly?) in pediatric patients who often had pronounced OI symptoms. This study seems to indicate that when symptoms don't show up on a HITT practitioners might need to be more open to treating for OI and/or checking CBF.

 

[voner]

I found it a readable paper for the layperson. The validity of the measurement techniques they used is way beyond me, but this statement struck me:

...the largest group of ME/CFS patients were those with a normal heart rate/blood pressure response. Of this group, 82% had an abnormal cerebral blood flow decrease as defined by the lower limits of normal

They do not speculate on causation...

 

[Hutan]

We heard these findings last year, I think Peter Rowe spoke at the NIH conference?
Miriam Tucker covered it in an article here (you have to sign up to Medscape to see it).

Here are two threads where there was some discussion:
Members poll - orthostatic intolerance

Orthostatic intolerance

 

[Forbin]

link to larger image: https://ars.els-cdn.com/content/image/1-s2.0-S2467981X20300044-gr5_lrg.jpg

 

[ahimsa]

What I found most interesting in this study (assuming I've understood this) is that the reduction in cerebral blood flow (CBF) was correlated with symptoms *and* the CBF reduction was found even in ME/CFS patients who had normal heart rate and blood pressure on the tilt table test.

Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P<.0005) ...
During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.

Even if these percentages end up being lower in any repeat studies in the future, the fact that patients had reduced CBF, even when they had apparently normal tilt table tests, is quite interesting. It would explain several of the folks here on this forum who had symptoms during a tilt test (and who get symptoms while standing in line, taking a shower, etc) but still had "normal" results on the tilt test.

This assumes that this measurement is reliable (I know nothing about measuring CBF).

(edited to clarify one sentence)

 

[Milo]

I would be curious to know
-whether this happens with astronauts coming back from Space Station, and if yes, for how long
-then whether this happens for a healthy control who has been paid to spend 1-2 months horizontal.
-does this happen with other diseases, such as congestive heart failure, multiple sclerosis, Parkinson’s, and diabetes, just to name a few? How about post-concussion, both acute and long term?
-could it be considered a biomarker?