Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients, 2021, Van Campen, Rowe, Visser

Highlights
•
Cerebral blood flow in ME/CFS patients remains abnormal 5 minutes post-tilt test.

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Post cerebral blood flow abnormalities do not depend on hemodynamic results and on end-tidal carbon dioxide pressures during the tilt-test.

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Post cerebral blood flow abnormalities are most severe in more severely diseased ME/CFS patients.

Abstract
Objective
Orthostatic symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be caused by an abnormal reduction in cerebral blood flow. An abnormal cerebral blood flow reduction was shown in previous studies, without information on the recovery pace of cerebral blood flow. This study examined the prevalence and risk factors for delayed recovery of cerebral blood flow in ME/CFS patients.

Methods
60 ME/CFS adults were studied: 30 patients had a normal heart rate and blood pressure response during the tilt test, 4 developed delayed orthostatic hypotension, and 26 developed postural orthostatic tachycardia syndrome (POTS) during the tilt. Cerebral blood flow measurements, using extracranial Doppler, were made in the supine position pre-tilt, at end-tilt, and in the supine position at 5 minutes post-tilt. Also, cardiac index measurements were performed, using suprasternal Doppler imaging, as well as end-tidal PCO2 measurements. The change in cerebral blood flow from supine to end-tilt was expressed as a percent reduction with mean and (SD). Disease severity was scored as mild (approximately 50% reduction in activity), moderate (mostly housebound), or severe (mostly bedbound).

Results
End-tilt cerebral blood flow reduction was -29 (6)%, improving to -16 (7)% at post-tilt. No differences in either end-tilt or post-tilt measurements were found when patients with a normal heart rate and blood pressure were compared to those with POTS, or between patients with normocapnia (end-tidal PCO2 ≥30 mmHg) versus hypocapnia (end-tidal PCO2 <30 mmHg) at end-tilt. A significant difference was found in the degree of abnormal cerebral blood flow reduction in the supine post-test in mild, moderate, and severe ME/CFS: mild: cerebral blood flow: -7 (2)%, moderate: -16 (3)%, and severe :-25 (4)% (p all <0.0001). Cardiac index declined significantly during the tilt test in all 3 severity groups, with no significant differences between the groups. In the supine post-test cardiac index returned to normal in all patients.

Conclusions
During tilt testing , extracranial Doppler measurements show that cerebral blood flow is reduced in ME/CFS patients and recovery to normal supine values is incomplete, despite cardiac index returning to pre-tilt values. The delayed recovery of cerebral blood flow was independent of the hemodynamic findings of the tilt test (normal heart rate and blood pressure response, POTS, or delayed orthostatic hypotension), or the presence/absence of hypocapnia, and was only related to clinical ME/CFS severity grading. We observed a significantly slower recovery in cerebral blood flow in the most severely ill ME/CFS patients.

Significance
The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients.

https://www.sciencedirect.com/science/article/pii/S2467981X21000408

 

Apologies if this is already a well-discussed concept. I'm interested due to my personal illness experience of POTS/PEM development.

Assuming multiple potential entry points to this pathological state, perhaps a self-perpetuation cycle might be at play in a significant subset of patients.

Reduced Cerebral Blood Flow --> Neuroinflammation --> Orthostatic Intolerance
^......................................................................................|
|_________________________________________________ v


I can see how increased background elevated body inflammation mirrored in the brain, autonomic imbalance and an acute infection could get us into this state. This is what I think happened to me and seems a common story.

In this model PEM could be caused by increasing neuroinflammation: either globally in the brain by reducing CBF as muscles take more; or focally as some (cognitively/emotionally) overactive brain areas take limited resource at the expense of other brain areas.

You can imagine a slippery slope of severity that becomes increasingly hard to recover from. Similarly on the recovery side, avoiding PEM and slowly having neuroinflammation settle could reduce OI and increase CBF over time.

So these researchers have shown orthostatic stress -> reduced CBF.

Proving or showing mechanisms for the development of neuroinflammation with reduced CBF (sounds intuitive) and
showing how OI could develop from neuroinflammation (brainstem/vagus) would be useful.

I guess Blitshteyn, Younger, Naviaux and VanElzakker would be some of the key researchers for these concepts.

 

Related:

Reduced Cerebral Blood Flow -> Neuroinflammation

• Children with Orthostatic Intolerance Exhibit Elevated Markers of Inflammation in the Dorsal Medulla (2019) Shaltout et al

Neuroinflammation -> Orthostatic Intolerance

• Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies, Dani et al, 2021
• Is postural orthostatic tachycardia syndrome (POTS) a central nervous system disorder?, 2021 Blitshteyn

 

This may be a case of chicken and the egg, and more complex than your hypothesis. The problem is how do you quantify neuroinflammation, which is a very general concept.

Then, if you have reduced cerebral blood flow, it means that you have a diversion of some sort in the peripheral and central circulation. Which executive command does that? Does it have to do with energy metabolism of certain cells? Would endothelial dysfunction be involved?

 

Oh for sure - I'm quite certain it's a lot more complex than the above summary. I was just trying to simplify the components of a possible positive feedback loop that seems to relate well to my own experience. Admittedly, I've only been in this for eight months.

As the researchers always note, evaluating neuroinflammation is very hard (you can't just go biopsying the brain) so secondary indicators are all we've got. I think neuro-imaging (MRI and PET) will start being used much more to try and quantify this, both in research and clinical practice.

I'm not sure reduced cerebral blood flow requires a diversion in all cases. For example, if in cardiac failure, all organs would be underperfused, including brain. But we're not in cardiac failure, so I guess the mechanisms behind orthostatic intolerance represent the diversion, in that the circulatory system can't get blood up to the brain adequately while upright. It more easily goes to lower limbs, abdominal organs etc. OI wouldn't have to be a failure of executive function, merely a failure of autonomic control initiated at brainstem level.

Impaired energy metabolism might be a downstream effect of neuroinflammation, but also presumably feeding back in to the vicious cycle. The endothelial dysfunction I'll leave in TBA form for now.

 

This set of authors produced another paper published

. 2021 May 4;19(1):193.
doi: 10.1186/s12967-021-02819-0.
Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)
C Linda M C van Campen 1, Peter C Rowe 2, Frans C Visser 3
Affiliations

• PMID: 33947430
  
• PMCID: PMC8097965
  
• DOI: 10.1186/s12967-021-02819-0

Free PMC article
Abstract


Background: Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).

Methods and results: In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% = no deconditioning, %peak VO2 65-85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.

Conclusion: This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.

Keywords: Cardiopulmonary exercise test; Cerebral blood flow; Chronic fatigue syndrome; Deconditioning; Head-up tilt testing; Myalgic encephalomyelitis; Orthostatic hypotension; Orthostatic intolerance; POTS; Peak oxygen consumption.

Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.”

I was wondering if this type of objective measures might be helpful in telling the difference between ME patient who might gain some benefit from exercises versus those who definitely wouldn’t. Hence get rid of the blind guessing which seems to be happening?

 

Thanks Trish…..I see now that I had seen this back in May.

My memory clearly getting wonky too.