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Every once in a while a study comes along for which terms like “seminal” or “groundbreaking” seems appropriate. The 2020 Van Campen/Rowe/Visser study, “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“, is, for me, one of those. It’s a large study which carves out new diagnostic territory, clears up a mystery, and makes us look at chronic fatigue syndrome (ME/CFS) newly.

Visser, the senior author, is a well-published cardiologist who has been publishing studies for decades. Prior to his first exercise study on ME/CFS in 2010, he’d been pumping out study after study on all sorts of aspects of cardiology. After 2010, though, he’s devoted himself almost exclusively to ME/CFS research focused on exercise intolerance, orthostatic intolerance and dysautonomia. In 2013, he did a series of video interviews on ME/CFS.

Huge Study

The first thing to notice about the study is its huge size – over 400 patients. The study began with 714 possible ME/CFS patients seen from 2012-2018 at Stichting CardioZorg clinic in Hoofddorp, in the Netherlands. All 429 ME/CFS patients were given the opportunity to do an orthostatic stress (tilt table) test and/or an exercise stress test.

During the tilt table test (TTT), the patient lay supine for 20 minutes and then was tilted up to 70 degrees for a maximum of 30 minutes. During that time, their heart rate, blood pressure, and blood flows to the brain were measured. They were asked a wide variety of questions about their symptoms during the test.

In contrast to the “intracranial doppler” usually used to measure blood flows, something called “extracranial doppler” was used. Intracranial doppler doesn’t actually measure blood flows to the brain – it measures the velocity of blood flows to the brain.

Are narrowed blood vessels leading to the brain choking off blood flows in ME/CFS and POTS?

Because extracranial doppler, on the other hand, measures velocity and takes into account blood vessel diameter, it’s able to give a more accurate assessment of blood flows. This technique, which is rarely used, may be critical in ME/CFS because reduced CO2 levels in ME/CFS may be narrowing the blood vessels – resulting in reduced blood flows even when blood flow velocity is normal.

This isn’t the first time CO2 levels have been assessed in ME/CFS during a tilt table test. In a smaller 2007 study, Dr. Natelson found hypocapnia in about 20% of people with ME/CFS. Low CO2 levels were also found in POTS patients in 2006, and way back in 1999, Novak found them in orthostatic intolerance.

In 2018, Novak found that a considerable number of possible postural orthostatic tachycardia syndrome (POTS) patients had normal hearts rates but reduced CO2 levels and reduced blood flows to the brain. He called this form of orthostatic intolerance hypocapnic cerebral hypoperfusion. Only Novak assessed blood flows to the brain in POTS.

This study has four things going for it: its size, its accuracy (the first-time use of extracranial doppler), its combined testing of CO2 levels and blood flows to the brain, and finally, its focus on chronic fatigue syndrome (ME/CFS).

The Gist

  • Containing over 400 people, this is surely the largest orthostatic intolerance study done in ME/CFS.
  • Virtually everyone with ME/CFS has a form of orthostatic intolerance characterized by low blood flows to the brain and low blood CO2 levels.
  • At the end of the 10-minute tilt table test, the blood flows to the brain were on average reduced by 27% in ME/CFS and 7% in the healthy controls,
  • People with the lowest blood flows to the brain were the most symptomatic.
  • People with ME/CFS who did not have symptoms associated with orthostatic intolerance still had reduced blood flows to the brain.
  • People with a diagnosis of POTS or orthostatic hypotension (OH) also have low blood CO2 levels. In fact, POTS patients had the lowest CO2 levels of all.
  • Low blood CO2 levels can produce a narrowing of the arteries that reduces blood flows to the brain.
  • The cause of the reduced CO2 levels and the impact they are having is unclear. They could be caused by a number of factors (baroreceptor problems, problems with signaling, metabolic acidosis, etc.).
  • The success phenylephrine had in removing all symptoms of orthostatic intolerance during a tilt table test is a bit hard to understand given that the drug is a vasoconstrictor. It may have helped with baroreceptor activation or with blood vessel problems in the body.
  • ME/CFS patients without a diagnosis of POTS or orthostatic hypotension should, if possible, have a tilt table test done using extracranial doppler – a more precise method of measuring blood flows to the brain.

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Results

As so often happens, at baseline – when both the healthy controls and ME/CFS patients were lying supine – no differences in cerebral blood flows were seen.

Once tilted, though, things radically changed. At mid-tilt, blood flows to the brain dropped by about 23% in the ME/CFS patients and just 5% in the healthy controls (HCs). By the end of the test, the ME/CFS patients’ blood flows to their brains has taken a 27% hit, while the HCs had declined by just 7%.

It wasn’t surprising to see dramatic declines in blood flows to the brain in the ME/CFS patients with POTS or orthostatic hypotension. While it’s not exactly clear how, those conditions are believed to reduce blood flows to the brain.

But what about the chronic fatigue syndrome patients without a diagnosis of orthostatic intolerance (OI)? Why did so many of them (78%) report symptoms associated with orthostatic intolerance in their daily lives if they didn’t have it?

This was not a small group. They actually made up the bulk (57%) of the large study. Eighty-two percent of the ME/CFS patients without POTS (postural orthostatic tachycardia syndrome) or OH (orthostatic hypotension) still had abnormally low brain blood flows. What was causing the decline in brain blood flows in them?

The low CO2 levels (hypocapnia) found in these patients may be the cause. Low blood CO2 levels are associated with narrowed blood vessels and hyperventilation.

One website reported that the hyperventilation associated with low CO2 levels is associated with many conditions we hear a lot about in ME/CFS: cellular hypoxia, chronic inflammation, lactic acid accumulation, anaerobic energy production, overactive nerve cells, shortness of breath, and others.

The low brain blood flow/low CO2 problem was not relegated to the non-POTS/non-OH patients, however. CO2 levels during the tilt were reduced in all the ME/CFS patients – including the POTS and OH patients – compared to the healthy controls. In fact, CO2 levels were lowest in the POTS patients.

More work on CO2 needs to be done, but low CO2 levels could be reducing blood flows to the brain. Lowered CO2 levels were found throughout the ME/CFS group. (Image by Gerd Altmann from Pixabay)

It’s possible, but certainly not certain, that the low CO2 levels are playing a major role in reducing blood flows to the brain found throughout ME/CFS and in POTS. The patients with the lowest CO2 levels (<30 mmHg) had the lowest blood flows to the brain.

Plus, a symptom assessment indicated that the lower the blood flows to the brain, the more OI symptoms a person had – something that makes total sense.

More work needs to be done with the CO2 issue. In particular, the authors stated that dose-response data was necessary to pin down the effects the lower CO2 levels might be having.

The detailed symptom assessment taken found a voluminous and heterogeneous mix of symptoms showed up in the ME/CFS patients. Surprisingly, the chronic fatigue syndrome patients with just reduced brain blood flows (another form of OI) had more symptoms than those with orthostatic hypotension. It was the POTS patients, though, who really stood out: they had significantly more symptoms than either group.

One takeaway is that if you have symptoms of orthostatic intolerance – that is, if you experience symptoms of dizziness, fatigue, nausea, pain, cognitive issues, etc. while standing or sitting, but don’t meet the criteria for POTS, OH or other forms of orthostatic intolerance – you likely have a form of OI characterized by reduced blood flows to the brain. I fit in this group. I “passed” a tilt table test but felt awful while doing it.

The study also suggested that even if you don’t experience symptoms associated with orthostatic intolerance, you may still not be getting normal amounts of blood flows to the brain. ME/CFS patients who did not report symptoms associated with orthostatic intolerance still experienced, on the mean, double the drop in blood flows to their brains as did the healthy controls. Some patients without symptoms of OI experienced very high drops in blood flows, indeed, when tilted up (<46%).

Causes?

No one knows why brain blood flows are commonly reduced in ME/CFS and POTS. Novak suggested that baroreceptor problems interfering with “respiratory drive”, compensation for metabolic acidosis, orthostatic ventilation-perfusion mismatch, problems with the respiratory centers in the brain and others (reduced blood volume) could be in play.

Hypocapnic Cerebral Hypoperfusion: New Kind of Orthostatic Intolerance Points to Key Factor in ME/CFS and Others

A POTS Option

A fascinating 2014 paper by Pozzi and Stewart, “Reduced Cerebral Blood Flow With Orthostasis Precedes Hypocapnic Hyperpnea, Sympathetic Activation, and Postural Tachycardia Syndrome“, (thanks to Peter Rowe for the tip). Every few minutes, this study tracked changes in HR, BP, CO2 level, sympathetic nervous system activity, etc. as POTS patients engaged in a tilt table test.

The researchers knew that when people with POTS stand up, blood tends to pool in the abdomen and lower body, thus reducing blood flows to the brain. They also knew that in healthy people, the very early stages of standing results in a short period of low blood pressure. After the arterial baroreflex and the autonomic nervous system kick in, all returns to normal.

The POTS patients (all suffering from shortness of breath) remained stuck in a state of low blood pressure – which caused the blood flows to their brain to plummet. That resulted (without their being aware of it) in their breathing more deeply than normal (hyperpnea), a reduction in their CO2 levels, and an uptick in sympathetic nervous system activity. The reduced CO2 levels further reduced their blood flows to the brain. The authors believed that the deep breathing and reduced CO2 levels resulted in a brain-wide narrowing (vasoconstriction) of their blood vessels and a state of hypoxia-ischemia (low oxygen levels/restriction of blood supply).

In this scenario, low CO2 levels are initially a reaction to reduced blood flows to the brain – not a cause of them. Once they show up, they make things worse, but they don’t start the process.

Communication Breakdown?

Another option may be a communication problem with the brainstem. When less blood (and oxygen) starts reaching your brain and/or your CO2 blood levels go squirrelly, chemoreflex receptors in your blood vessels tell your brainstem – a possibly problematic organ in ME/CFS – to increase your breathing rate. When CO2 levels get too high, those chemoreceptors tell your brainstem to decrease your breathing rate.

Both these auto-correction processes may be off in ME/CFS/POTS. The chemoreflex system in ME/CFS may be increasing breathing rates too much when brain blood oxygen levels fall, and then failing to reduce breathing rates enough when CO2 levels tank. The upshot of that could be hyperventilation and reduced CO2 levels.

The Phenylephrine Question

While treatment options are unclear, one small study funded by the National Institutes of Health (NIH) and the Solve ME/CFS Initiative (SMCI) used a drug called phenylephrine to attempt to increase blood flows to the brain. Phenylephrine stimulates the α-adrenergic receptors, leading increased in blood pressure, baroreflex stimulation, and a deep vagal stimulation with a reduction in heart rate.

When the ME/CFS patients were given phenylephrine, every physiological measure normalized during their tilt table test. Their heart and breathing rates, CO2 levels and blood flows to the brain all returned to normal levels. Even their performance on a cognitive test returned to normal. Their brain fog was gone.

Interestingly, phenylephrine is a vasoconstrictor – just the wrong drug one would think for a condition where low CO2 levels may be reducing blood flows to the brain. Because phenylephrine, though, does not make it to the brain, it could be vasoconstricting blood vessels in the body, thereby reducing blood pooling in the abdomen and legs, and increasing blood flows to the brain that way. It may also activate the baroreceptors.

Whatever it’s doing, it produced a fantastic effect.

Standing Clear: Drug Stops Orthostatic Intolerance in ME/CFS In Lab – Next Steps

Recommendations

The authors of the recent NASA Lean Study called this study “very important” and concluded that its findings were consistent with their own (very considerable) clinical findings.

NASA Lean Test: An Easy Way to Diagnose Orthostatic Intolerance in ME/CFS, Fibromyalgia and POTS

Most tilt table tests do not assess blood flows to the brain, and when they do, they usually use intracranial doppler – which is likely not accurate in ME/CFS.

The authors of this study asserted that cerebral blood flows should be assessed during tilt testing in ME/CFS using extracranial Doppler – particularly in patients who have symptoms of orthostatic intolerance assessment, but normal heart rate and blood pressure results on a tilt test. This is the only way to show that orthostatic intolerance exists in people who do not test positive for POTS or OH on a tilt table test.

Dr. Peter Rowe, one of the study’s co-authors, stated that he believed that “extracranial measurement of cerebral blood flow will soon become the gold standard test for orthostatic intolerance”. Rowe reported that 90% of adult and pediatric ME/CFS patients have orthostatic intolerance and the study “helps us understand why people with ME/CFS are so symptomatic when upright”.

Extracranial Doppler measurements do not appear to have been widely adopted and Rowe said it will likely take some time for labs to adopt them as a standard practice. Rowe did say that labs which do vascular ultrasounds and carotid artery studies should be able to learn how to do them without great difficulty.

Just What is ME/CFS?

This huge study begs the question of what is ME/CFS? Could it be a circulatory disorder? There are so many tantalizing findings in ME/CFS right now, but the blood vessel / blood flow issue must be near the top of the list.

reduced cognition

The question remains: what is causing the low blood flows to the brain?

David Systrom believes that n theblood loss issue may be occurring between the arterial and venous systems. (Blood has also been found to collect in the abdomen and lower body in POTS patients.) Wirth and Scheibenbogen propose that clamped down blood vessels, plus a rather nasty compensatory response involving vasodilators play a role.  Barnden has documented problems in the brainstem which it appears could affect blood vessel functioning, breathing, heart rate, etc.. Other studies suggest reduced blood flows to the muscles are occurring as well.

At the end of the paper, the authors asked whether the orthostatic intolerance found in ME/CFS is similar to the circulatory dysfunction found in autonomic neuropathy. Autonomic neuropathy signifies damage to the nerves of the autonomic nervous system. Systrom, Oaklander and Scheibenbogen have all speculated that an autoimmune process may have damaged the small nerve fibers that carry sensory and autonomic nervous system signals; i.e. that ME/CFS could be an autoimmune-induced autonomic neuropathy.

Exercise Tests Suggest Autoimmunity Causes the Exertion Problems in Chronic Fatigue Syndrome, Fibromyalgia and POTS

Other possibilities, of course, are present, but it does feel like we’re getting closer.

Conclusions

Containing over 400 people, this is also surely the largest orthostatic intolerance study done in ME/CFS. This study used an unusual technique (extracranial doppler) to clear up a mystery, introduce a new diagnostic category and possibly identify a fundamental issue in ME/CFS (low blood CO2 levels upon being tilted).

The study explained why so many people with ME/CFS with symptoms of orthostatic intolerance (OI) have not tested positive for it, and suggested that virtually everyone with ME/CFS has a form of orthostatic intolerance. That may come as a shock to some doctors, but will probably not come as a surprise to most of us. We’ve just been waiting for the right technology to uncover what’s going on.

The study found that virtually everyone with ME/CFS had a form of orthostatic intolerance characterized by low blood CO2 levels and low blood flows to the brain. While the study was not able to show that low CO2 levels are contributing to the low blood flows, low CO2 levels can produce a narrowing of the arteries that reduces blood flows to the brain.

At the end of the 10-minute tilt table test, blood flows to the brain were on average reduced by 27% in ME/CFS and 7% in the healthy controls.

The fact that people with the lowest blood flows to their brains were the most symptomatic suggested that low blood flow to the brain is the key factor in OI. Even some people with ME/CFS without symptoms associated with orthostatic intolerance still had reduced blood flows to the brain.

ME/CFS patients with a diagnosis of POTS or orthostatic hypotension also have low blood CO2 levels. In fact, POTS patients had the lowest CO2 levels of all.

ME/CFS patients without a diagnosis of POTS or orthostatic hypotension should, if possible, have a tilt table test done using extracranial doppler to measure their blood flows to the brain. That is the only way that most people with ME/CFS will get diagnosed with OI.

The cause of the reduced CO2 levels is unclear but could be due to a number of factors (baroreceptor problems, problems with signaling, metabolic acidosis, a result of low blood flows to the brain, etc.).

The success phenylephrine had in removing all symptoms of orthostatic intolerance during a tilt table test is a bit hard to understand given that the drug is a vasoconstrictor, but the drug may have helped with baroreceptor activation or with blood vessel problems in the body.

  • We’re not done at all done withthe  Van Campen, Rowe and Visser team. Coming up: overviews of studies on blood volume, exercise intolerance, tilt tests for the severely ill, and brain fog.
  • Plus coming up – a way to increase blood volume that’s as effective as saline.

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