Measuring cerebral hypoperfusion with Doppler ultrasound

[Jonathan Edwards]

I respecfully disagree. Normally I just accept what you post, because of your vast knowledge and experience; now I disagree.

I think you may have misunderstood the context of what I said. As indicated to Hutan, I suspect things are complicated.

I am quite certain ME/CFS is almost always associated with OI. The discussion of blacking out on standing was in response to Jem's question. I am not sure that it has much to do with the origin of OI in ME/CFS.

I have never seen a tilt table test being performed but it sounds a fairly artifactual exercise that nobody would normally put themselves through. Like the CPET test it may lead to conclusions about the origin of symptoms in real life in ME/CFS that are misleading.

It looks from some graphs as if cerebral flow may decline gradually over many minutes in some cases. That looks to be quite different from the drop in flow that a normal person like me gets on standing. I mentioned the shift in plasma protein and wonder if there is a failure to retain fluid in the blood compartment over several minutes.

I see a problem with making use of evidence on individuals in different contexts to try to build a simple story when it may be much more variable and messier. That may include a significant exacerbation of the problem for some people from spending a lot of time lying flat.

We know for a fact both that OI tends to make you lie down and lots of lying down tends to lead to OI. So it isn't going to be simple.

 

[Jonathan Edwards]

This seems like a reasonable explanation for some of the orthostatic issues that pw ME/CFS face. However, from my own experience I think it is unlikely that spending time laying down significantly contributes to orthostatic symptoms in all but some severe cases.

That may be a good analysis. At present I am focusing on the issue of managing OI and potential cerebral hypoperfusion in the context of very severe patients unable to eat and needing nasogastric feeding and trying to put out a viewpoint document on that. It is a problem that has been followed by some very bad outcomes, as we all know. We need evidence and not evidence dressed up by physicians or physios with private practices to sell a point - not saying that that applies here but so often it does. And so many of these studies turn out, if you look, to be retrospective - which tends to spell bad news.

But I think it may be of some relevance to quite a large number of people severely affected and needs to be considered carefully.

 

[Kitty]

At present I am focusing on the issue of managing OI and potential cerebral hypoperfusion in the context of very severe patients unable to eat and needing nasogastric feeding and trying to put out a viewpoint document on that.

One of the issues is that the presentation in severe and very severe ME is different to run-of-the-mill OI. Normally it's described as starting to feel ill after less than a minute of standing upright and still, but in severe ME, people start to feel ill as soon as they sit up.

It'd be interesting to know whether people with non-ME related OI experience that. I didn't in the years before I got ME, and although the OI got worse with the illness, I've still never had it from sitting upright.

 

[EndME]

One of the issues is that the presentation in severe and very severe ME is different to run-of-the-mill OI. Normally it's described as starting to feel ill after less than a minute of standing upright and still, but in severe ME, people start to feel ill as soon as they sit up.

It'd be interesting to know whether people with non-ME related OI experience that. I didn't in the years before I got ME, and although the OI got worse with the illness, I've still never had it from sitting upright.

When my sister, who has always been perfectly healthy (no ME/CFS, LC or anything else), was a teenager there was a time where she would blackout and faint. After this had occurred a few times my parents went to see a doctor, especially due to the significant dangers when you’re falling on your head after fainting. The doctor seemed very familiar with this phenomenon and just advised her to stand up slower. It seems that simple trick resolved all issues and my sister has long since outgrow those problems (or perhaps has become accustomed to standing up slower). I can't imagine that there was ever a time in which my sister and probably that doctor would have thought that was worth any diagnostic label such as OI, as everything was easily avoidable by getting up slower, nor did she ever feel ill in upright position. Essentially there is nothing worth discussing.

However, if someone is conducting a study purely based on measurements of heart rate and blood pressure this could probably fall under the category “feeling ill as soon as they stand up”, but has no relation to ME nor does it seem worthy of being investigated, even though I'm assuming it would also show up on a TTT in some form or another. So there's probably these rather meaningless phenomena one has to be aware of when looking at people "feeling ill as soon as they sit up" to make sure one isn't studying noise or simply a different phenomena than the one that one actually wants to study.

 

[Ken Turnbull]

@Ken Turnbull ,

I am wondering how reliable this test is as clinical information. Novak seems to have created this category of orthostatic cerebral hypo perfusion but I do not see any clear indication that it is meaningful. About 10% of a retrospective series were designated as this, having showed a greater drop in perfusion measured by doppler than the others, but it is not clear to me whether this is more than just natural variation in results on a population. It is also unclear to me whether it means anything clinically.

There is a study from 1995 that confirms that doppler measures blood flow in a way that correlates with a more reliable PET method but it did not correlate with brain metabolism, so it may not tell you anything about availability of oxygen.

I know very little about this field but wonder if it is really validated. Has anyone other than Novak confirmed the validity of the concept and the clinical relevance of the test?

I'm sorry it's taken me a while to log back in and reply.

There are various researchers who have reported abnormal levels of cerebral hypoperfusion in patients with orthostatic intolerance on tilt table testing, including in patient groups that have other signs that can be measured as abnormal during the test (e.g. blood pressure, heart rate).

There are a couple of research groups who used other measurement modalities, or more than one modality.

As to whether the entity of OCHOS (cerebral hypoperfusion in the absence of any other signs or previously known causes) can be said to be validated, I'm not sure.

There was a South Korean group who seem to have found the same entity, although they called it OINH.
https://pubmed.ncbi.nlm.nih.gov/26427910/

And Visser, van Campen et al have reported on what seems to be the same entity in their work with ME/CFS patients.

But these might all be retrospective studies.

I agree it needs more work.

You probably saw the recent thread about the letter to the editor on the subject:
https://www.s4me.info/threads/is-it...ing-head-up-tilt-testing-2024-mitchell.38582/

The authors acknowledge various problems with using Doppler ultrasound, although I don't think they answer your question about clinical relevance.

Can PET be done standing up?

Nobody really mentions oxygenation or metabolism. I think those topics might be more relevant to ME/CFS, in which cerebral hypoperfusion isn't the only problem affecting brain function.


***
On an anecdotal note, my daughter improved suddenly upon taking a vasodilator, after 18 years of OI symptoms, and Dr Novak has stated that hypertensive-type OCHOS responds to vasodilators.

As an observer, I saw the colour return to her face and her old self returning.

There is a lot more to the story, and my daughter could probably write an essay on all the things that were considered and ruled out over the past five years, but suffice to say OCHOS is the only diagnosis left on the table that matches her situation.

If we find out anything to the contrary, we will of course revise that. But for now she is feeling somewhat better on vasodilators, although she is limited to a less-than-ideal dose by side effects.

EDIT: Just realised I made a mistake in my post. "Cerebral hypoperfusion" is of course by definition abnormal. What I meant was that researchers noticed a more marked drop in cerebral blood flow than that experienced by healthy controls of the same age. I have read that there is a lack of normative data, but in the studies I looked at controls would experience a drop of up to 10% and those with orthostatic intolerance would experience a drop of about 20%.

(Studies were from Visser, van Campen et al and Novak.)

 

[Ken Turnbull]

@Jonathan Edwards, one other thing I should have mentioned is that Dr Novak has stated that cerebral hypoperfusion is the primary cause of only one condition, hypertensive-type OCHOS.

These patients have orthostatic intolerance symptoms, plus what appears to be "standard" hypertension (as you would find related to ageing or lifestyle or genetics), and no unusual changes to blood pressure or heart rate during tilt table testing.

He suspects that an auto-immune problem is interfering with the function of the cerebral arterioles, causing them to constrict abnormally on orthostasis and reduce blood flow to the brain. Arterioles are key resistance vessels and seem to have the most power of increasing vascular resistance, so that is why he suspects the constriction is happening there.

I suppose you could say he has tested this idea by giving patients in that group vasodilators and having them report improvement, and I presume he has repeated the tilt table test and seen that blood flow no longer changes drastically on orthostasis once they are on that treatment. (I don't think he has published on this though.)

For all other types of OI, he believes that cerebral hypoperfusion is a part of the picture, in line with other autonomic and ME/CFS researchers.

This press release might shed a little light on how he came to approach it:
https://www.brighamandwomensfaulkne...-to-pinpoint-cases-of-orthostatic-intolerance

(The info that I gave above came out later in snippets in various papers, a textbook, and some lectures.)

You might then ask: Can there be auto-antibodies that would only affect cerebral blood vessels? And the answer seems to be that this is possible. For example, we have a drug that has shown selectivity for cerebral blood vessels (nimodipine).

 

[darrellpf]

When I stand for several minutes I feel the urge to lie down. Even sitting is a problem. My mind is active lying down but turns almost off when vertical.

For cerebral perfusion drugs there is also Viagra. One of the side effects is headaches, possibly from cerebral vasodilation.

Ritanovir is used as a booster for other HIV drugs. It delays the liver from clearing some drugs, including Viagra.

A few studies during the era when both HIV drugs and Viagra were fairly new showed that ritanovir boosted Viagra effects a great deal. Users of that combination were warned to take much less Viagra.

Personal experience says that the combination has a lasting effect on mental acuity (around a full day) with few of the other "side effects" somewhat contrary to warnings of hours long erections.

I'm very cautious about using the combination without more studies, but I'd really like to see them.

 

[Ken Turnbull]

I just wanted to add something that might be helpful based on my reading over the past few years.

Experiencing orthostatic intolerance occasionally or mildly is a part of the human experience, just like the occasional episode of vomiting or diarrhoea is. It seems to be the price paid for being bipedal.

I would say that the term "orthostatic intolerance" has nuances.

It can describe normal variations in body's capacity to quickly route enough blood to the upper part of the body to keep the brain perfused when we move from horizontal to upright because the autonomic nervous system (ANS) is not perfect.

It can describe a temporary disruption to ANS function explainable by circumstances, e.g. dehydration, recent surgery, general frailty.

And it can also be found as a chronic malfunction of the ANS, with potential causes ranging from concussion to nerve damage t̶o̶ ̶c̶o̶l̶l̶a̶g̶e̶n̶ ̶d̶i̶s̶o̶r̶d̶e̶r̶s̶ to autoimmunity.

 

[Hutan]

Can there be auto-antibodies that would only affect cerebral blood vessels?

I think my circulation problem is more widespread than just cerebral blood vessels - so I don't think we are necessarily looking for something that just affects cerebral blood vessels. For example, when things are worse, I wake up every morning with a "dead" part of an arm. This morning it was just a little finger. I know everyone gets a dead limb from time to time, but this is every morning.

Also there's the pins and needles and numbness when arms are held up above a table when eating or when hanging out washing, and when arms are held up for more than 20 minutes of driving. The latter gets so bad that I end up using alternate hands, while the other hand rests in my lap for a bit.

And then there's the pitting (pitting oedema?) in my finger tips. I can press into a finger tip with a finger nail, not really hard and just momentarily. Today the dent in my fingertip stays for at least two minutes, I got bored with watching it. It might stay for much more than that. If I rub the fingertip it returns to its rounded shape. On a bad day, dents made with the knuckle of a finger will stay in my forearms.

I don't think this is normal. To me the problem feels as though the blood goes into the tissue, there isn't enough liquid in circulation. I don't want to take things off-topic, but perhaps hypoperfusion in other parts of the body could be measured too or instead?

For cerebral perfusion drugs there is also Viagra.

That combination you mention does sound interesting to try. There's some discussion about viagra here
Use of sildenafil (viagra) to alter fatigue, functional status and impaired cerebral blood flow in ... CFS, 2020, Friedman (Pfizer)

And it can also be found as a chronic malfunction of the ANS, with potential causes ranging from concussion to nerve damage to collagen disorders to autoimmunity.

How do collagen disorders affect the function of the ANS?

 

[Ken Turnbull]

@Hutan, apologies, I got my wires crossed there. It might be that people with EDS and similar have "floppy veins" leading to poor venous return but this isn't a malfunction of the ANS as you rightly point out. Please forgive my tired brain.

Also, I should have been clearer that I was talking about one disorder, hypertensive-type OCHOS, in which antibodies seem to be exclusively affecting cerebral perfusion.

Professor Novak has postulated that there are two varieties of cerebral hypoperfusion in OI patients:

• that caused by abnormal cerebral vasoconstriction (new entity caused by autoimmunity)
  
• that caused by blood pooling in the lower body, low blood volume, poor venous return, etc. (the problems normally associated with POTS, OH; caused by autonomic dysfunction)

So in the first one the arterioles (next step down from arteries) are actively shutting out some of the cerebral blood flow by constricting abnormally. These patients tend to have hypertension. They respond to vasodilators.

(This is what my daughter seems to have.)

And in the second one, the blood just isn't making it up to the head for various reasons. Classical OI, if you like. The OCHOS patients in this group tend to have hypotension. Other patients have various blood pressure abnormalities, some orthostatic, some generalised. They respond to the usual OI interventions.

 

[Ken Turnbull]

On a personal note, I have to report that my daughter’s Doppler ultrasound testing did not happen.

It is a very long story stretching back a year, so I won’t go into it, but her specialist’s poor communication scuppered her chances of getting a clear result, so she cancelled the test.

We are not too upset about it. She plans to part ways with the specialist – a relief. She has medications in place that do not require his input any more. Onwards and upwards.