Upper Airway Resistance Syndrome (UARS): a common underlying cause for all "chronic complex illnesses"? (ME/CFS, fibro, GWI, etc.)

[Trish]

The connection to ME/CFS specifically is speculative. There is actual evidence re: a connection to fibromyalgia and Gulf War illness that people can debate the strength of though. ~1/3 of people with ME/CFS meet criteria for fibromyalgia (and the reverse may be even higher); many people with GWI have PEM/meet criteria for ME/CFS, etc. No one has ever identified an organic pathology explaining any of these disorders that all highly overlap in the individuals meeting criteria for them.

I find your logic hard to follow. You might just as well claim ME/CFS is caused by migraines, since a lot of pwME get migraines, or that IBS and ME/CFS are the same condition because some pwME have IBS symptoms, or that GERD causes ME/CFS since lots of pwME have acid reflux. Overlaps in symptoms between conditions defined by sets of symptoms are hardly surprising, and say nothing about causes.

 

[Utsikt]

The connection to ME/CFS specifically is speculative

And that’s what people have been trying to say - there is no real connection here to go off of.

I do not believe ME/CFS behaves like a 100% organic disease

Everything is physical/organic, so I don’t understand this argument.

(this does not mean it is psychological) - just take the way many ME/CFS patients report that CNS depressants/sedatives like benzodiazepines and dextromethorphan (yep, that even made it into the Bateman Horn clinical care guide!) can both prevent/reduce severity of PEM when taken ahead of exertion, as well as rapidly reducing symptoms of PEM (& ME/CFS in general).

Bateman has a history of including unevidenced statements in their guides. I have no seen any studies that substantiates those claims.

The fact that PEM can be triggered by emotional distress or sensory input alone (or in some severe patients, even things like the stress of having someone in the same room as them not even making noise/in sight); all of these things point towards CNS sensitization and a dysregulated CNS stress response being involved (in my personal opinion).

They also point a million other directions. The only thing we know is that nerves and/or neurons have to be involved in some way upstream, and possibly at the core.

The concepts of sensitisation and stress response in this context are pure speculation.

 

[nataliezzz]

I find your logic hard to follow. You might just as well claim ME/CFS is caused by migraines, since a lot of pwME get migraines, or that IBS and ME/CFS are the same condition because some pwME have IBS symptoms, or that GERD causes ME/CFS since lots of pwME have acid reflux. Overlaps in symptoms between conditions defined by sets of symptoms are hardly surprising, and say nothing about causes.

I was making the inference based on the existing evidence that (I think) supports UARS being a cause for (at least some cases) of fibromyalgia & Gulf War illness. UARS has also been demonstrated to cause low blood pressure and orthostatic intolerance/hypotension. ME/CFS = the symptoms of fibromyalgia/GWI + orthostatic intolerance + PEM (PEM is not an established symptom of UARS, but again PEM being able to be triggered by things like emotional distress alone suggests it may have something to do with a disturbance to the parts of our brain involved in modulating emotions/stress/etc. - i.e. the limbic system). That is where I was coming from there.

The fact that a high % of individuals with GWI, fibro, ME/CFS will meet criteria for more than one of these disorders also provides support, but I'm not making the inference on that alone.

 

[richie]

Yes, sorry Trish, I am going to do that. I do think it would be difficult to accurately convey all the information in my thread here, but I will do my best.

Hi Nataliezzz
Any chance that restrictive patterns found in sarcoid might have similar outcomes ?
Just anecdotally when my sarcoid was most evident on CT I went through a period where I was hyperaroused and though I felt I could relax, once relaxed I would drift towards sleep and then immediately come round in a state of great arousal (not psychological alarm/anxiety, though the experience was awful) I also had nickel intoxication and have read that nickel fires up the hypoxia response, so i wonder if that may have contributed.
Unexplained fatigue in sarcoid is so common that I wonder if compromised respiration at night or all the time might be affecting the limbic system. Same question strikes me for long Covid.

 

[nataliezzz]

Hi Nataliezzz
Any chance that restrictive patterns found in sarcoid might have similar outcomes ?
Just anecdotally when my sarcoid was most evident on CT I went through a period where I was hyperaroused and though I felt I could relax, once relaxed I would drift towards sleep and then immediately come round in a state of great arousal (not psychological alarm/anxiety, though the experience was awful) I also had nickel intoxication and have read that nickel fires up the hypoxia response, so i wonder if that may have contributed.
Unexplained fatigue in sarcoid is so common that I wonder if compromised respiration at night or all the time might be affecting the limbic system. Same question strikes me for long Covid.

Hi Richie, I'm sorry, I don't know anything about sarcoid.

 

[Utsikt]

I was making the inference based on the existing evidence that (I think) supports UARS being a cause for (at least some cases) of fibromyalgia & Gulf War illness.

There is always the possibility that the people that had a diagnosis of FM or GWI, and improved with CPAP, did not actually have whatever FM or GWI turns out to be.

We know these labels gets thrown around a lot, and they are very loose as well. The might not have any practical use in medicine, and as JE pointed out - we might need new ones when we figure out what’s actually going on.

UARS has also been demonstrated to cause low blood pressure and orthostatic intolerance/hypotension.

Where has it been demonstrated as the cause? I’m loosing track of the articles.

ME/CFS = the symptoms of fibromyalgia/GWI + orthostatic intolerance + PEM (PEM is not an established symptom of UARS, but again PEM being able to be triggered by things like emotional distress alone suggests it may have something to do with a disturbance to the parts of our brain involved in modulating emotions/stress/etc. - i.e. the limbic system).

The bolded part here is just vague handwaving. We know very little about how our brains work at all. As mentioned above, all it actually suggests is that nerves and/or neurons are at least involved upstreams, and possibly at the core. That’s all. We can’t make any more inferences out of it without taking too many leaps of faith.

The fact that a high % of individuals with GWI, fibro, ME/CFS will meet criteria for more than one of these disorders also provides support, but I'm not making the inference on that alone.

That is not support in terms of scientific evidence. It’s correlation at best. And the symptoms are too generic (except for PEM), but in your own words the connection to ME/CFS is speculative so it doesn’t take us anywhere.

 

[nataliezzz]

There is always the possibility that the people that had a diagnosis of FM or GWI, and improved with CPAP, did not actually have whatever FM or GWI turns out to be.

Lol yeah, this is always the argument, right?

Where has it been demonstrated as the cause? I’m loosing track of the articles.

I shared the article with you. You said it could just be "correlation" that 93/400 UARS patients (100% of whom had an abnormally small oral cavity based on objective measurements) have low BP, yet provided no plausible explanatory "correlating" factor (by the way, many of the studies I have been referencing are now linked in my original post):
Sleep-disordered Breathing and Hypotension
Here is a study that specifically measured abnormal ANS responses to inspiratory flow limitation during sleep that may be contributing:
Exploring the Abnormal Modulation of the Autonomic Systems during Nasal Flow Limitation in Upper Airway Resistance Syndrome by Hilbert–Huang Transform

 

[Jonathan Edwards]

a practicing sleep medicine doctor who has treated hundreds of patients with these disorders and seen the symptoms of fibromyalgia improve with treatment of sleep-disordered breathing

Now hang on. This Dr Gold is a poor old simple practicing clinician who does not have the time and resources to do research? So he has no controlled observations. So, as I said earlier, he is treating people without reliable evidence.

People always say they got better. It is one of the first things you learn as a junior doctor (or should learn). If they are really better they say so. If they aren't they stil say so because it is easier than the faff of disappointing the doc and having to try something else that doesn't work. Dr Gold's patients will be better just as Trudie Chalder's patients are better and the homeopath's patients are better. We have no evidence for that having anything to do with a theory or a treatment.

If you want a theory to be taken seriously here, @nataliezzz, you have to play by the proper rules, just as we expect the BPS people to do (and they don't). Paul Garner says brain re-training works wonders because his friends say so. We have to do better than that.

 

[Jonathan Edwards]

Can you tell us what led you to take an interest in this particular theory @nataliezzz ?

 

[nataliezzz]

Now hang on. This Dr Gold is a poor old simple practicing clinician who does not have the time and resources to do research? So he has no controlled observations. So, as I said earlier, he is treating people without reliable evidence.

People always say they got better. It is one of the first things you learn as a junior doctor (or should learn). If they are really better they say so. If they aren't they stil say so because it is easier than the faff of disappointing the doc and having to try something else that doesn't work. Dr Gold's patients will be better just as Trudie Chalder's patients are better and the homeopath's patients are better. We have no evidence for that having anything to do with a theory or a treatment.

If you want a theory to be taken seriously here, @nataliezzz, you have to play by the proper rules, just as we expect the BPS people to do (and they don't). Paul Garner says brain re-training works wonders because his friends say so. We have to do better than that.

I've now linked many of the studies in my original post, including studies from Dr. Gold and others, so feel free to go check those out. Dr. Gold's controlled study of GWI patients showed that the symptoms of GWI were improved by CPAP (improvements were correlated with an objective finding - decreased sleep stage shifts - and patients on sham CPAP did not experience decreased sleep stage shifts and got slightly worse). As I stated, one of the fibromyalgia patients in his study (that did not have a control group) who was unemployed due to symptoms returned to full employment after getting on CPAP so that is a pretty good indication of a treatment effect too.

His clinical experience of (almost) never seeing a patient with fibromyalgia who does not have sleep-disordered breathing/inspiratory flow limitation provides additional support (not everyone has inspiratory flow limitation - e.g. you can see in the individual data from the GWI study that 2/11 controls had 0% flow limitation), but you can feel free to disregard that and just focused on the peer-reviewed published research.

 

[nataliezzz]

Can you tell us what led you to take an interest in this particular theory @nataliezzz ?

Sure! I used to be a speech therapist, so it feels a little bit in my wheelhouse. When I learned about UARS and the anatomical features that are often associated with it like more narrow recessed jaws/dental arches, narrow/high-arched palate (apparently a common feature in hEDS though I know you are skeptical of the concept of hEDS), vertical maxillary hyperplasia/gummy smile (= high-arched palate), I immediately suspected I had UARS since I have many of these features. I also began to notice that many other ME/CFS patients have them as well (not everyone, and there can be many factors that contribute to sleep-disordered breathing that are not readily visible like rhinitis/nasal obstruction, a larger tongue, connective tissue laxity causing increased collapsibility of the upper airway, etc.)

 

[nataliezzz]

Can you tell us what led you to take an interest in this particular theory @nataliezzz ?

Also, the significant improvements I have had in all of my ME/CFS symptoms (including PEM) after getting on BiPAP, including being able to stop bupropion which was previously controlling my OH-type symptoms (lightheadedness/losing vision on standing) without return of those acute symptoms on standing (I still have other dysautonomia symptoms like tachycardia on exertion). Pain has probably been the biggest improvement (my body-wide muscle pain is ~70% improved; I still have some tenderness on palpation but the constant aching/burning is gone), but all of my symptoms including fatigue & PEM are improved. I do not believe CPAP/BiPAP is a cure for most people, likely because it also acts as a stressor on a sensitized nervous system, and if Dr. Gold's olfactory nerve hypothesis is correct (I know you are cringing right now), breathing pressurized air is likely providing a different stimulus to the limbic system in terms of nasal airflow/pressure than what the brain "wants" from completely normal and unobstructed breathing.

So I want to bring this information to more people (I suspect most people with ME/CFS who find something that greatly helps them feel the same!)

 

[Utsikt]

Lol yeah, this is always the argument, right?

I’m not saying it’s the argument. I’m saying that you have to entertain the possibility when the requirements for a diagnosis are so loose and we know that it’s practiced very differently.

And differential diagnoses have to be considered. You don’t have X because you fit the symptoms, you have X because you have whatever X means in terms of biological causes. With diagnoses that only consist of subjective symptoms without known causes, you’re bound to get mixups of all kinds of causes. That doesn’t make X into all of them.

Those factors most be considered because the results are only as good as the inputs - and if the inputs are bad, well, the output will be just as bad or worse.

I shared the article with you. You said it could just be "correlation" that 93/400 UARS patients (100% of whom had an abnormally small oral cavity based on objective measurements) have low BP, yet provided no plausible explanatory "correlating" factor (by the way, many of the studies I have been referencing are now linked in my original post):
Sleep-disordered Breathing and Hypotension

I’m sorry, but I’m getting the feeling that you do not understand what correlation means.

Correlation is a statistical measure that expresses the extent to which two variables are linearly related. You don’t need to provide a probable alternative explanation in order for something to be considered correlation.

Causation, on the other hand, is about one thing directly causing another. That has an absolute threshold of evidence that has too be met - it can never be assumed in absence of that evidence.

A very common logical fallacy is to assume that observed correlation implies that one of the correlated variables is causally linked to the other. In other words, to assume that correlation implies causation.

Here is a study that specifically measured abnormal ANS responses to inspiratory flow limitation during sleep that may be contributing:
Exploring the Abnormal Modulation of the Autonomic Systems during Nasal Flow Limitation in Upper Airway Resistance Syndrome by Hilbert–Huang Transform

That is another study that shows correlation. You talked explicitly about causation. Those are very different things. You need to be precise with your language.

Also, the study isn’t about low BP or OI..

UARS has also been demonstrated to cause low blood pressure and orthostatic intolerance/hypotension.

 

[nataliezzz]

I’m not saying it’s the argument. I’m saying that you have to entertain the possibility when the requirements for a diagnosis are so loose and we know that it’s practiced very differently.

And differential diagnoses have to be considered. You don’t have X because you fit the symptoms, you have X because you have whatever X means in terms of biological causes. With diagnoses that only consist of subjective symptoms without known causes, you’re bound to get mixups of all kinds of causes. That doesn’t make X into all of them.

Those factors most be considered because the results are only as good as the inputs - and if the inputs are bad, well, the output will be just as bad or worse.

Yeah, it's kind of funny. @Jonathan Edwards was basically making the argument above that fibromyalgia is a nebulous concept because it's just based on subjective symptoms. Well, the same is true for ME/CFS lol. Despite what some people would like to believe, there is no reliable objective test for PEM (I think @ME/CFS Skeptic 's analysis of 2-day CPET data confirmed that). The modest overall differences between ME/CFS patients and controls could easily be due to some correlational factor (as I'm sure you would agree) and have nothing to do with the underlying pathophysiology of PEM (or they could be a modest downstream effect in some individuals of whatever the underlying cause of PEM is).

https://mecfsskeptic.com/the-biggest-2-day-exercise-study/

PEM is just a subjective symptom (although it is sometimes accompanied by objective signs like fever/swollen lymph nodes), as is the chronic widespread muscle pain/tenderness in fibromyalgia. By this logic, PEM could just as easily be a symptom of multiple disorders; there is no reason to believe that ME/CFS is one underlying disorder if there is no reason to believe that fibromyalgia is one disorder. These same arguments of Dr. Edwards can be used to argue that "the whole idea of 'diagnosing ME/CFS' is unhelpful at this point."

Very difficult to know. But rheumatologists don't trust rheumatologists either - they just pretend to. Throughout my career as an academic rheumatologist I never made the diagnosis because it appeared to me to be so vague that it wouldn't help clinical care. It may well be that the whole idea of 'diagnosing fibromyalgia' is unhelpful at this point.

Most rheumatologists use the diagnosis of fibromyalgia either to provide a cover for the real diagnosis of 'annoying person with nothing wrong' or to pamper their egos as 'holistic practitioners' and conductors of an orchestra of minion therapists. A small number 'specialise' in fibromyalgia because there is no shortage of patients prepared to pay large sums for bogus advice.

I am sure there is one or more uncommon condition with disabling widespread pain due to some process we so far have no idea of. When we do start getting some idea we will probably need some more specific names.

I’m sorry, but I’m getting the feeling that you do not understand what correlation means.

Correlation is a statistical measure that expresses the extent to which two variables are linearly related. You don’t need to provide a probable alternative explanation in order for something to be considered correlation.

Causation, on the other hand, is about one thing directly causing another. That has an absolute threshold of evidence that has too be met - it can never be assumed in absence of that evidence.

A very common logical fallacy is to assume that observed correlation implies that one of the correlated variables is causally linked to the other. In other words, to assume that correlation implies causation.

So let's presume that UARS is not directly causing low BP. I'm curious if you can think of any correlational factor that could account for 93/400 UARS patients having low BP? This factor would also need to correlate with having an abnormally small oral cavity (based on objective measurements) since 400/400 randomly selected people would not have an abnormally small oral cavity.

 

[nataliezzz]

I will say, these statements about not needing any data because their conclusion is so obvious do appear ridiculous.

I can't seem to find the paper. I mean I can find it on Pubmed, but the link to the publisher page is missing.

Yes, I actually access paywalled papers from sci-hub.st (ethically questionable perhaps, but I couldn't do this without it)

Punjabi and Lim do go on to make some actual arguments in the paper (see below), I don't want to make it seem like what I quoted was all they said (it was just kind of shocking that they actually said experimental/observational data was not required). I think their arguments are weak ones, however, as they never provide evidence for the claim of sleep fragmentation by arousals being the cause of sleepiness in OSA patients. They cite evidence for a relationship between poor sleep quality and sleepiness in sleep apnea, and state that the poor sleep quality is caused by recurrent arousals/awakenings, but do not provide citations for this claim. Randomized studies showing that "alleviating sleep fragmentation in patients with poor sleep quality from sleep apnea" is associated with improvements in daytime sleepiness does not prove that sleep fragmentation was the cause of their sleepiness (e.g. if you buy into Dr. Gold's theory, removing the stressor of inspiratory flow limitation during sleep with CPAP may be the cause of improvement in sleepiness - reduction in arousals may also occur but this doesn't mean arousals are the [primary] cause of sleepiness). They also discuss induction of sleep fragmentation in healthy volunteers causing sleepiness, but as Dr. Gold stated in his reply "the effects of sleep fragmentation in normal volunteers do not inform a debate on the cause of hypersomnolence among patients with OSA." (I'm not sure it's entirely irrelevant, but we don't know if the ways sleep fragmentation/arousals are induced - acoustic stimulus in the study they cited - results in a comparable response in the brain to that of an arousal related to a respiratory event [apnea/hyopopnea]).

 

[Jonathan Edwards]

Yeah, it's kind of funny. @Jonathan Edwards was basically making the argument above that fibromyalgia is a nebulous concept because it's just based on subjective symptoms.

No, I am making the argument based on work indicating that the uncertainty of diagnostic ascertainment is in the order of 100-fold for FM. The uncertainty of diagnostic ascertainent for ME/CFS is around fivefold (0.2-1.0%). That may sound problematic, and it is to an extent but it is not so different from other conditions. In RA we have specific categories of possible and probably diagnosis to cover what is probably a 2-3-fold uncertainty. For ANA-related autoimmune disorders it is worse - maybe as bad as ME/CFS.

The uncertainty for 'hEDS' is a remarkable 1000-fold, ranging from one in five thousand to one in five. In fact, something like 40% of young women have enough flexibility to be scored by some physicians. And since there is no evidence for a monogenic problem in more than one about a hundred thousand for hypermobility-type EDS the whole thing is a joke.

 

[Jonathan Edwards]

Dr. Gold's controlled study of GWI patients

Presumably an unblinded study with subjective outcomes like the PACE trial?

 

[Jonathan Edwards]

Sure! I used to be a speech therapist, so it feels a little bit in my wheelhouse. When I learned about UARS and the anatomical features

Thanks, I get the picture @nataliezzz.

There is no harm in airing your thoughts here because we are well versed in critical scientific thinking but do be careful putting this stuff out to the general public, please. Otherwise it is likely that a lot of people will waste their money on another unproven therapy.

 

[nataliezzz]

No, I am making the argument based on work indicating that the uncertainty of diagnostic ascertainment is in the order of 100-fold for FM. The uncertainty of diagnostic ascertainent for ME/CFS is around fivefold (0.2-1.0%). That may sound problematic, and it is to an extent but it is not so different from other conditions. In RA we have specific categories of possible and probably diagnosis to cover what is probably a 2-3-fold uncertainty. For ANA-related autoimmune disorders it is worse - maybe as bad as ME/CFS.

I'm actually not familiar with how "diagnostic ascertainment" is established. Since the diagnosis of ME/CFS is based on self reported symptoms and there is no objective biomarker for ME/CFS, I'm not sure how the diagnosis could be definitively confirmed/rejected.

 

[nataliezzz]

Presumably an unblinded study with subjective outcomes like the PACE trial?

I already explained discussed in detail with @forestglip earlier how sham CPAP works and how effective the blinding may/may not be, you are welcome to scroll up and read that discussion. And I also explained that the subjective reports in the improvement of GWI symptoms were correlated with an objective finding (decreased sleep stage shifts), and that one fibromyalgia patient who remained on CPAP who was previously unemployed due to symptoms returned to full employment. The fact that you are asking for a large-scale randomized controlled trial to even consider the evidence regarding this is ridiculous - as you likely know, science generally starts with statistically significant findings from small studies and then larger studies take place. Sleep medicine will never call for those types of studies because as I've shared, they defend their preferred sleep fragmentation theory with arguments like: there is no need for experimental or even observational data in understanding the cause of sleepiness and fatigue in sleep-disordered breathing patients.

There is no harm in airing your thoughts here because we are well versed in critical scientific thinking but do be careful putting this stuff out to the general public, please. Otherwise it is likely that a lot of people will waste their money on another unproven therapy.

Lol! Sorry, that is ridiculous too. Getting a sleep study is not a "waste of money" for ME/CFS patients (you yourself said you suspect ME/CFS is a sleep disorder), everyone with ME/CFS should be evaluated for UARS/OSAS since unrefreshing sleep, fatigue, and cognitive dysfunction are all well established symptoms of both UARS/OSAS and ME/CFS. CPAP is an almost no risk treatment and if people meet criteria for OSA insurance will cover it. So yeah, not buying the I need to be "careful" encouraging ME/CFS patients to pursue evaluation for UARS/OSAS at all.

Also, I'll just leave this here for posterity (you openly admitted that you wrote this all off as a "nonsense quack theory" without actually reading any of the evidence).