Epic ME/CFS Hypothesis Series
Not many people have taken their shot at completely explaining chronic fatigue syndrome (ME/CFS), but of those that have, Wirth and Scheibenbogen’s epic three-part hypothesis series takes the cake.
If the goal of a hypothesis is to make the reader see the subject in a different way, this series has succeeded in spades. The first hypothesis proposed that dysfunctional B2AdR receptors and a hyperactive sympathetic nervous system were narrowing blood vessels and impeding blood flows in ME/CFS, triggering a massive compensatory response in the form of pain, fatigue and flu-producing vasodilators such as bradykinin – which no one had connected with ME/CFS before.
The second hypothesis proposed that the dysfunctional B2AdR receptors’ inability to effectively stimulate the Na+/K+-ATPase enzyme resulted in sodium overload in the muscles. That turned the tables on the cellular calcium pump and resulted in calcium being imported into the cell instead of getting exported out of it. That calcium overload then impaired the mitochondria and other metabolic parts of the cell from working properly and with that – bam! – another new factor (calcium overload) entered the ME/CFS scientific literature.
No Neuroinflammation Needed (!)
The third hypothesis paper, “An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome“, which essentially extends the ideas in the first two papers to the nervous system, brings yet another surprise – no neuroinflammation needed!
Problems with the endothelial cells lining the blood vessels played a major role in the first hypothesis and play a major role in the latest one as well.
Since 2020, several studies have amplified the role that underperforming endothelial cells may be playing in both ME/CFS and long COVID (PASC). Both laboratory and full-body studies have found reduced blood flows in both diseases. In fact, the Visser/Van Campen/Rowe group found an almost four times greater reduction in blood flows to the brain upon standing in people with ME/CFS than in healthy controls. The Bateman Horne Center’s novel “feet on the floor” assessment of functionality speaks to the problems people with ME/CFS – whether they are standing or even sitting down – have getting normal amounts of blood flowing to their brains.
It’s that problem – getting sufficient blood flowing to the brain – that underlies the latest Wirth/Scheibenbogen hypothesis. Those balky B2AdRs receptors they believe are causing so much havoc in the body are having the same effect in the brain.
That results in a brain that more quickly poops out when pushed to the test by engaging in cognitive challenges. The “psychomotor slowing” present – which makes it more difficult to take in conversation or “large” bits of information, and even the “motor functioning” (i.e. the movement, gait, and coordination problems which impair the ability to move smoothly and gracefully) could all, the authors believe, be explained by the reduced energy; i.e. reduced oxygen – caused by reduced blood flows to and within the brain.
The authors don’t believe, though, that the problem lies simply in reduced blood flows to the brain. A balky “neurovascular coupling” process, once the blood gets to the brain, causes trouble sending it to the right place in the right amounts.
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Being able to nimbly send blood to the correct areas is important as the brain doesn’t have enough resources for the entire brain to be lit up at once. It has to pick and choose the spots; it sends oxygen-laden blood to. The authors believe the vasodilators being pumped out in the attempt to open those narrowed blood vessels are interfering with the fine-tuned process of delivering the blood where it’s needed. At the very least, that would result in an inefficient brain that often lacks the resources to fully do its job.
The fascinating report of almost universal (83%) intracranial hypertension (increased spinal fluid pressure) and the increased prevalence of Tarlov cysts (as a result of that) in ME/CFS seems to make perfect sense in a system characterized by blood vessel (or should we just say “vessel”) vasoconstriction or narrowing. Indeed, the authors believe the intracranial hypertension/Tarlov cyst problem could be contributing to many of the sensory and pain issues found in these diseases.
Then there’s the potential bradykinin-blood-brain-barrier (BBB) effect. Bradykinin is one of the vasodilators the authors believe are producing so many symptoms in ME/CFS. Vasodilator that it is, though, bradykinin may also be prying apart the junctions in the blood-brain-barrier (BBB) – helping to produce intracranial hypertension – and possibly triggering the release of pain-invoking substances like CGRP and substance P.
Other oddities: a strange pupillary reflex which, when the eyes are exposed to light, causes the pupils to dilate after their initial contraction, suggests that, as is found in orthostatic intolerance, the autonomic nervous system is off-kilter and may be overshooting and then correcting.
As to neuroinflammation, the authors question how it could explain things like muscle weakness, altered pH in the skeletal muscles, PEM, and cardiovascular findings like hypovolemia with low RAAS activity – all of which their hypotheses potentially explain.
Desensitization of both the α2-adrenergic and the B2AdR receptors may produce a chronic stress response that results in autonomic nervous system hypervigilance and sympathetic nervous system hyperactivity. That hypervigilance could then cause higher levels of stimuli to be transmitted to the brain – thus causing the problems with stimuli (pain, light, noises, odors, etc.) that is often present.
The rather unsettling experience of hypervigilance being paired with mental fatigue results from a central nervous system that’s being overworked at the same time it’s being deprived of energy (via reduced blood flows). (Talk about being “wired and tired”.) We’ve seen this combination in the periphery as well when a seemingly amped-up system (high heart rate during sleep) buckles when confronted with an exercise stressor).
The nervous system overstimulation, and the amazing array of nasty sensory stimuli that result, in turn produce more mental fatigue and brain fog as people with ME/CFS try to grope their way past their body sensations and concentrate on tasks at hand. The gaps in the BBB which allow vasodilators like bradykinin and PGE2 to enter the brain only contribute to the overstimulation present.
Some researchers are now focusing on hypocapnia (low CO2 levels), hyperventilation, and otherwise disordered breathing problems that have been found in ME/CFS. The hypocapnia – which can be produced by hyperventilation – may be fundamentally important as it causes the blood vessels of the brain to vasoconstrict or narrow – a key theme in the authors’ hypotheses.
The authors believe that the hyperventilation results from an unbalanced autonomic nervous system which steps too hard on the sympathetic nervous system pedal, and they noted that hyperventilation during exercise has been shown, in ME/CFS, to contribute to ventilatory inefficiency or an inability to effectively move the air in and out of the lungs. We haven’t heard much about ventilatory inefficiency but it is starting to crop up in ME/CFS exercise studies.
An overstimulation of the respiratory center of the brain may result in the unpleasant sensation of “air hunger”, or dyspnea, that some people with ME/CFS experience. Since neurons in the muscles trigger respiratory actions during exercise, it’s possible that this respiratory problem originates in the muscles. (That brings to mind Alan Light’s finding of amazingly amped up metabolic muscle receptors in ME/CFS).
The hyperventilation-induced respiratory alkalosis then could then exacerbate the sodium/calcium proposed in Wirth/Scheibenbogen’s second hypothesis paper. The combination, then, of an unbalanced autonomic nervous system which overshoots – causing hyperventilation and respiratory alkalosis – serves to lock the metabolic issues in the muscles in place – producing a vicious circle.
The authors believe that chronically desensitized α2-autoreceptors trigger nuclei in the brainstem to release catecholamines that put the sympathetic nervous system on alert, and the brain on edge, trying to deal with an overload of stimuli.
That stimuli overload could naturally impair the brains’ ability to calm down and achieve a restful state during sleep, but that’s not all. The respiratory problems noted above could contribute as well if they persist into the sleep state. (Whether they do or not is not clear, but the authors believe there’s no reason to think that they don’t.)
In fact, they believe that the consequences of the disordered breathing patterns seen – which produce periods of hypoxia (low oxygen delivery) may be more consequential in ME/CFS than seen in sleep apnea. This is because the surges of sympathetic nervous system activity produced by the periods of low oxygen levels come on top of the already vasoconstricted state of ME/CFS patients’ blood vessels and their already hyperactivated sympathetic nervous systems.
Ironically, those sympathetic nervous system (SNS) surges could further narrow the blood vessels, thus further impairing blood flows. The SNS activation strategy would work if the blood vessels weren’t already narrowed, as it would increase the blood pressure, thus forcing more blood flows to the tissues. If the blood vessels were already too narrowed though, it could spark a compensatory release of vasodilators as the system tried a different way to maintain blood flows – and avoid the ultimate problem – low oxygen levels.
Those vasodilators, some of which produce pain, could then contribute to the often painful states that accompany wakening in ME/CFS. Certainly, this to and fro, up and down activity, is no recipe for restful sleep. It brings to mind easily the worst sleep problems I’ve ever heard in ME/CFS.
For decades, Darden Burns often quickly woke in a very unrestful state indeed – with her heart racing and with night sweats – both of which are reminiscent of the sympathetic nervous system surges that the authors suggest may be happening. With sleep doctors flummoxed by Darden’s strange sleep issues, she turned to alternative treatments, and was at times helped by several approaches (meditation, “oral balancing technique”) that probably improved her breathing and took pressure off her autonomic nervous system.
Unfortunately, Darden’s system became completely unstabilized by a trial of bee venom – perhaps in combination with a nutrient rebalancing effort – and she lost her decades-long battle to get sleep.
Sleep was perhaps the last subject covered as the authors believe that the poor sleep in ME/CFS is secondary, not primary; i.e. they believe that insufficient blood flows and mitochondrial dysfunction in the muscles are the major culprits. Thus, while better sleep would undoubtedly improve the health of people with ME/CFS, it would not resolve the problems that cause it.
And so ends part three of the most extensive set of hypotheses explaining ME/CFS that I’ve seen.
- The epic 3-part Wirth/Scheibenbogen ME/CFS hypothesis series wraps up with a focus on the brain. Surprises were found at every turn. The big surprise in this paper was a hypothesis that could account for a boatload of symptoms without calling on neuroinflammation.
- Reduced blood flows and damaged endothelial cells in the blood vessels played, as they have in former posts, a major role. The authors believe that reduced blood flows to the brain in combination with deficiencies in “neurovascular coupling” have resulted in reduced blood flows to and within the brain.
- Massive releases of vasodilators like bradykinin that are attempting to open narrowed blood vessels may also be prying apart the junctions in the blood-brain barrier and triggering intracranial hypertension and Tarlov cysts – thus impacting sensory nerves – and causing pain, and stimuli hypersensitivity.
- The wired and tired experience results from an overworked central nervous system that’s being deprived of energy (via reduced blood flows) at the same time.
- The nervous system overstimulation and the amazing array of sensory stimuli that result in turn produce more mental fatigue and brain fog as people with ME/CFS try to grope their way past their body sensations and concentrate on tasks at hand.
- As the hypocapnia narrows the blood vessels, an overstimulation of the respiratory center of the brain (produced possibly by metabolic problems in the muscles) results in feelings of “air hunger”. To add insult to injury the hyperventilation-induced respiratory alkalosis is exacerbating the intracellular sodium/calcium imbalance the authors proposed lies at the heart of the mitochondrial dysfunction in ME/CFS.
- The authors don’t believe that sleep problems lie at the heart of ME/CFS but they do believe they’re exacerbated by sympathetic nervous system surges and respiratory problems that extend into sleep. The low oxygen levels that may at times be present during sleep in ME/CFS may be more impactful than those seen in sleep apnea.
- Time will tell how well this massive hypothesis fares. Wirth/Scheibenbogen’s ability to integrate so many factors, including unusual factors like the renin-angiotensin-aldosterone paradox, and low blood volume, is stunning.
- They are also German-born and reflect a tremendous upswing of interest in ME/CFS there that was birthed by Carmen Scheibenbogen. Studies are continuing to be published and a new hypothesis paper is expected to be published soon
The 3-part Wirth/Scheibenbogen hypothesis series has introduced a slew of possible new factors to consider. No major leaps were needed for this last one, as it simply applied factors from the previous hypotheses to the brain. Still, some surprises were in store. For one, the authors were able to produce a hypothesis of central nervous system dysfunction that could account for a boatload of symptoms that does not rely upon neuroinflammation.
As in the past hypotheses, reduced blood flows and damaged endothelial cells in the blood vessels play a major role. Reduced blood flows to the brain in combination with deficiencies in “neurovascular coupling” have resulted in reduced blood flows to and within the brain.
A massive bradykinin release may be prying apart the junctions in the blood-brain barrier and triggering intracranial hypertension and Tarlov cysts which, in turn, are disrupting sensory nerves – causing pain, and stimuli hypersensitivity.
The unsettling experience of hypervigilance being paired with mental fatigue (aka “wired and tired”) results from a central nervous system that’s being overworked while being deprived of energy (via reduced blood flows) at the same time.
The nervous system overstimulation and the amazing array of nasty sensory stimuli that result in turn produce more mental fatigue and brain fog as people with ME/CFS try to grope their way past their body sensations and concentrate on tasks at hand.
The hypocapnia found may be narrowing the blood vessels as well. An overstimulation of the respiratory center of the brain that results in “air hunger” may be triggered by metabolic problems in the muscles. Plus, the hyperventilation-induced respiratory alkalosis would likely exacerbate the intracellular sodium/calcium imbalance the authors proposed lies at the heart of the mitochondrial dysfunction in ME/CFS.
While the authors don’t believe that sleep problems lie at the heart of ME/CFS they believe they’re exacerbated by sympathetic nervous system surges and respiratory problems that extend into sleep. In fact, they propose that the low oxygen levels that may at times be present during sleep in ME/CFS may be more impactful than those seen in sleep apnea.
Time will tell how well this massive hypothesis effort is, in the end, able to explain ME/CFS. B2AdR and A2 autoantibodies play a major role in this hypothesis and we don’t know yet how important they actually are. Wirth/Scheibenbogen’s ability to integrate so many factors, including factors like the renin-angiotensin-aldosterone paradox, and the low blood volume which most hypotheses simply don’t talk about, into one whole is simply stunning.
These hypotheses are special in another way – they are German-born. Ten years ago, no one could have predicted that Germany – which so far as I could tell had no history of ME/CFS research prior to this – could have become a research hotspot. We saw a similar eruption of interest in ME/CFS in Norway when a couple of enterprising researchers triggered the Rituximab studies and are continuing to dig into ME/CFS.
We can thank Carmen Scheibenbogen for the German outbreak – she basically birthed the ME/CFS research field there – and since 2014, has co-authored a remarkable 25 ME/CFS papers and studies. Klaus Wirth and his decades of experience in cardiovascular pharmacology added another (unique) layer to the German thrust. BC007 added a possible treatment option, plus a recent Berlin ME/CFS and long COVID endothelial study was published, and we should soon see the publication of another German hypothesis paper. Plus Wirth and Scheibenbogen recently published a paper examining the cause of the breathing problems in long COVID and ME/CFS.
With long COVID attracting international interest, one wonders which country is going to step up and surprise us next?
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Thanks again Cort, for explaining something really complicated.
Did they theorize about why exertion causes post exertional malaise? and why we have an exertion threshold we can’t go over? what is that threshold about? Why is the time to a crash about 24 hours, and why does recovery take a whole week?
Thank you so much for doing this work.
Cort, ME/CFS and CIRS just seem to be “rabbit hole” diseases. We are presented with a bradykinin hypothesis by one set of researchers, while Dr.David Systrom is using Pyridostigmine “off label” to vasoconstrict his ME/CFS patients. He is attempting to load the atria more effectively, so the ventricles can push a greater volume of blood to the periphery. No wonder we can not treat this disease. Any comment?
Thank u for all your effort in sharing info on me/cfs for us.
May I ask if you have any more info on BC 007 treatment?
I imagine that we’ll be hearing some things over the next 6 months but haven’t heard anything lately.
I can give you a short update. BerlinCures the company behind BC007 will run a big international study starting this summer for LongCovid to get a emergency marketing authorization. In addition to that the UK Erlangen will run two studies to better understand the mechanism of BC007. On will be focused on LongCovid and the other on ME/CFS. The studies should also start this summer. In general BerlinCures and the UK Erlangen are very convinced that BC007 is a effective treatment for LongCovid. However, there seems to be still a lack of funding why it is all taking a little bit longer.
Just in case any other UK-based folk get momentarily excited (like I did), in this case UK Erlangen means Universitätsklinikum Erlangen. It’s the University Clinic (hospital).
Still, I’m hugely excited that this research is happening and I hope we can all benefit from it soon.
Thanks for sharing, Timo und viele Grüße!
Great to hear. Lots of stuff going on. Thanks, Timo 🙂
Wow! This is exciting news! Thanks Cort, for the great explanation. This pretty much hits all the points in my experience. There is hope for a future without ME/CFS!
I always remember Robert Phair’s warning about beautiful hypotheses getting destroyed by our complex biology but it is really something to see how many different facets of ME/CFS this group has an explanation for.
I think that just as easily what they see as cause could be an effect..
Great article! Did they theorize what causes the autoantibodies to be released in the first place? I’ve been hearing a lot about viral persistence. Do they mention this at all?
Great question! I don’t know if anyone has posited a distinct reason these autoantibodies are impaired (?). As I remember, though, they are natural autoantibodies – they’re there in everyone and they serve a purpose. Apparently not all autoantibodies are bad – unless they’re not present in the right amounts – which I believe is the case here.
Something appears to be disturbing them – and I imagine that viral persistence is a possibility.
Gotcha. That makes a lot of sense. And would jive with what Bruce Patterson or Amy Proal have theorized. And would make sense for a post-viral condition.
I sure do appreciate “The Gist” in the box, Cort! Sometimes, especially at the end of the day, my brain cannot handle an entire article.
Neither can mine!
My son, who has cfs, made an interesting discovery today and I wonder if it’s blood vessel related. He got a Fitbit type of device and wore it while doing some light exercise. He worked out out on his recumbent bike, pedaled hard and fast, but his heart rate never went very high. He then lifted a 10 pound medicine ball above his head a few times and his heart rate shot up within 30 seconds. There’s evidently a big difference between using your legs and your upper body.
Your son could have TOS (thoracic outlet syndrome).
Just an observations… my mother was generally fine but could not lift her hands high above her head without feeling like she was going to pass out.
In her case it was mooted to be due to carotid artery blockage.
I too have a child(now 26, but ill since she was 13) with CFS. Hard for the person and hard for the parent.
Wishing you both well.
Thank you, Linda. My son has been Ill since he was 12 and he’ll be turning 21 in a couple weeks. I also have cfs and we suffer through this together. Other positions bother us a lot – like crouching down on your haunches and standing up with no support.
So much information! The bits that seem relevant to me are: I do believe my microglia in my brain are activated but that’s not necessarily linked to my brain seizing up, after trying to read something long and complicated (needing processing).
When activated (microglia, Jarred Younger PhD and Michael VanElzakker PhD), I call it irritable brain syndrome, I can’t remember things, I can’t think properly, my mental health plummets etc. But when I’ve cognitively over exerted, then my brain feels like it’s run aground – like a boat getting stuck in the silt, in low water levels. I kind of feel I’m literally trying to squeeze out the last drops, to read a long and complicated article. There’s loads I haven’t read because I can’t keep up, in addition to all the other things I do. I think now, that’s related to brain blood flow issues.
Also, I have ongoing issues with sympathetic nervous system activation and continually focus on trying to be more in parasympathetic and stay out of sns and especially freeze – dorsal vagal. I have an inclination to unconsciously hold my breath. I only notice because it sets off my ectopic heartbeats.
Another aspect of all this I think, is that my sns and microglia are activated by my digestive system becoming irritated. So if I have gastritis or IBS then that’ll trigger a rise in HR and BP and brain issues. I think this is probably due to signalling via the vagus nerve to the brain stem and then onto the microglia.
Now that I can function better and am not continually suffering from cognitive, sns and energy issues, I notice more when I am triggered back into them. The energy issues took me a very long time to improve. Generally I’m no longer dragging myself around etc. I’m definitely in a different zone now but I make sure I stay back a bit from the edge and rest and catch up when I can.
Hi, Tracy. Your brain fatigue and SNS hyperactivity sound very similar to what I experience. You mentioned that you are now able to function better. I am curious as to if there was anything specific that helped you gain better functioning?
It’s a great hypothesis. Hopefully it now pulls together in a way that finds meaningful ways to treat, if not ‘cure’, the condition.
If MECFS is treated successfully in the planned Studie this summer the hypothesis is properly right. I hope we will get further answers soon.
Thank you for the summary!
Im also a big fan of the „Gist“ section
I think we should not forget a few things: low blood volume, and also stiff blood. And the deformability of red blood cells. What role are they playing in these hypothesis?
You mention someone sent into an unrestful state due to bee venom.
Bee venom sent me into a yearlong flair! Terrible for the nervous system..
Isn’t that something… It was Darden’s nervous system that seemed to be so affected as well. You just never know.
Hi from france !
It is very interesting. thank you for this document.
one question haunts me:
what to say about craniocervical i instability in this context?
Right. I just looked and didn’t see mention of CCI in the paper. They did focus on intracranial hypertension, Tarlov cysts, and brainstem issues – which, at least to my laymen’s mind, occur in the same general area but I don’t think they got into connective tissue issues.
They have a lot to say about that, in the first paper. More than I understand heheh. Google and read for yourself: “5.3. The high prevalence of ME/CFS in patients with craniocervical and atlantoaxial instability
Prevalence of ME/CFS is high in in patients with craniocervical and atlantoaxial instability…..”
I’m confused about Tarlov cysts. Normally they occur in the lumbar region of the spine and are associated with nerve roots. Are you saying they are finding them in the brain?
Tarlov cysts are not uncommon in EDSers. Wondering if there is some kind of connection considering the high levels of fatigue in both Ehlers-Danlos and ME/CFS.
This hypothesis was focused on the central nervous system which includes the spinal cord. The cysts may be forming because of intracranial hypertension.
If this theory pans out, is there a cure associated with this theory?
Finally beginning to restore some hope for a future without ME/CFS 🙏🏻
Tudca may reduce levels of CGRP, one of the pain signaling compounds mentioned in the article.
We are very fortunate to have Cort, as reporter of medical science of myalgic encephalomyelitis.