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

[Trish]

Generally speaking about some of the engagement that might be frustrating for you: I must have seen similar approaches to theories for ME/CFS upwards of 50 times. Bits and pieces taken from here or there with a lot of "presumably". If one is convinced of any idea, one can always accrue evidence from different places to make a story, but that does not make said evidence convicing.

Indeed. We get people coming to the forum with such theories every few months. The process is always the same. Start with an idea, then look for evidence to support it, and join the dots with lots of assumptions.

I am reminded of scientists whose strategy for testing a hypothesis is the opposite of this. Start with the theory, then look for every possible way you can think of to disprove it. Only when the hive minds of lots of scientists have pointed out all the possible flaws they can think of, and every step in the hypothesis is tested throughly and all assumptions removed and replaced with replicated evidence, can we start to say this theory has a sound basis.

 

[nataliezzz]

That sounds like a good idea!

Notably there have been studies that have used a Polysomnography in ME/CFS, including the intramural study. There were no findings of relevance. Moreover a subset of those participants even underwent a 6 week trial of CPAP without there being any relevant improvements!

Can you provide a link to the CPAP study in ME/CFS? I would definitely like to look at that. One thing I will try to get into when I go more into depth with this (perhaps on a separate thread) is why not all CPAP treatment is equal (people are often just put on an auto-titrating setting which is designed to eliminate/reduce apneas/hypopneas, not necessarily flow limitation; people are very, very rarely manually titrated in a lab to eliminate flow limitation like Dr. Gold did in his studies of the GWI & fibromyalgia patients), and then there's the issue of many people tolerating/benefiting from BiPAP > CPAP. Yeah, I have a lot lol...

Generally speaking about some of the engagement that might be frustrating for you: I must have seen similar approaches to theories for ME/CFS upwards of 50 times. Bits and pieces taken from here or there with a lot of "presumably". If one is convinced of any idea, one can always accrue evidence from different places to make a story, but that does not make said evidence convicing. In this case it seems to me that an array of different studies have been posted (I only had time to even look at 2 studies somewhat closer and I suspect to look at the full evidence more closely will take anybody several days). This is an array of different studies that are all on somewhat related topics but that all have different results on differing conditions with different criteria and outcome measures and then making causative claims based on different correlations quickly becomes dubious.

I think the following would be helpful to know for people part of the discussion: Are there any results that are consistently replicated across studies (including accounting for all those studies with negative results, some of which will have never been published) and I'm not taking about somewhat related findings, I'm talking about consistent replication? And what is the evidence for those replicated findings being of relevance to ME/CFS beyond there being an overlap of symptoms and how do the negative findings fit into that?

No, we don't have that level of evidence. When I go in and flesh this out in greater detail, I will focus on the evidence I think is there for the connection between UARS/OSAS and fibromyalgia/GWI (as well as other disorders like chronic insomnia). There's no evidence specific to ME/CFS. I just happen to believe that all of these unexplained chronic disorders with high degree of overlap in symptoms (and diagnoses in those affected by them) are likely varying presentations of one underlying disorder, but this is just my personal opinion! Anything I say about the possibility of UARS/OSAS causing ME/CFS is just based on speculation and my personal experience.

 

[Utsikt]

No, we don't have that level of evidence. When I go in and flesh this out in greater detail, I will focus on the evidence I think is there for the connection between UARS/OSAS and fibromyalgia/GWI (as well as other disorders like chronic insomnia). There's no evidence specific to ME/CFS. I just happen to believe that all of these unexplained chronic disorders with high degree of overlap in symptoms (and diagnoses in those affected by them) are likely varying presentations of one underlying disorder, but this is just my personal opinion! Anything I say about the possibility of UARS/OSAS causing ME/CFS is just based on speculation and my personal experience.

Thank you for explaining that.

In that case, the title of the thread is misleading. The same with the current intro to your first post:

I think the evidence supports upper airway resistance syndrome (UARS) as a common underlying cause for many "chronic complex illnesses" (ME/CFS, fibromyalgia, Gulf War illness, etc.)

Here, you are saying that the evidence supports UARS as a cause of ME/CFS. But you now say that there is no evidence that ME/CFS is caused by UARS.

 

[nataliezzz]

Thank you for explaining that.

In that case, the title of the thread is misleading. The same with the current intro to your first post:

Here, you are saying that the evidence supports UARS as a cause of ME/CFS. But you now say that there is no evidence that ME/CFS is caused by UARS.

True. I will edit the post to reflect that. The title can probably remain since it has a ? and it is under the "Possible causes and predisposing factor discussion" forum (I'm not even sure I can change the title)

 

[Utsikt]

True. I will edit the post to reflect that. The title can probably remain since it has a ? and it is under the "Possible causes and predisposing factor discussion" forum (I'm not even sure I can change the title)

If your aim to explore if it is/could be the underlying cause of all chronic complex illnesses, sure. But that is in itself not a very useful concept because all chronic illnesses are complex in one way or another, so it essentially means «all chronic illnesses».

So it reads like «UARS: the unifying theory of everything?» (a bit of hyperbole)

The mods can change the title for you if you decide to do that. It’s probably easiest to use the «contact moderator» button on the first post.

 

[nataliezzz]

If your aim to explore if it is/could be the underlying cause of all chronic complex illnesses, sure. But that is in itself not a very useful concept because all chronic illnesses are complex in one way or another, so it essentially means «all chronic illnesses».

So it reads like «UARS: the unifying theory of everything?» (a bit of hyperbole)

The mods can change the title for you if you decide to do that. It’s probably easiest to use the «contact moderator» button on the first post.

It looks like I can change the title. Can you suggest an appropriate title? I want it to reflect that the discussion is about the theory that UARS could be a common underlying cause for these disorders (I'm not sure what else to call them besides "chronic complex illnesses" - unexplained chronic illnesses?)

 

[Utsikt]

It looks like I can change the title. Can you suggest an appropriate title? I want it to reflect that the discussion is about the theory that UARS could be a common underlying cause for these disorders (I'm not sure what else to call them besides "chronic complex illnesses" - unexplained chronic illnesses?)

I’m not quite sure.

From my perspective, it can look like you’re a bit too focused on «the theory» because there are so many leaps of faith in it. You’re essentially asking: could this be true, if we assume this is true, and this, and that, and also this. The discussion you want to have looks like it is too many degrees removed from the actual evidence.

 

[nataliezzz]

I’m not quite sure.

From my perspective, it can look like you’re a bit too focused on «the theory» because there are so many leaps of faith in it. You’re essentially asking: could this be true, if we assume this is true, and this, and that, and also this.

Yes, exactly, I want to discuss the evidence re: the theory. The evidence may be from studies with small sample sizes, but statistically significant findings are not invalid simply because they are from small sample sized studies. This is how science generally begins; with an observation (e.g. a sleep doctor noticing alpha-delta sleep - an objective finding associated with fibromyalgia - and frequent complaints of "functional somatic syndrome" symptoms in UARS patients without a fibromyalgia diagnosis) and some small studies with statistically significant findings (e.g. 18 GWI patients having 96%±5 of their breaths flow limited while 11 age/BMI-matched asymptomatic Gulf War vets had 36±25% of their breaths flow limited [p <.0001] and when treated with CPAP titrated to eliminate flow limitation, experiencing improvements in the symptoms of GWI that correlated with an objective finding [decreased sleep stage shifts]. Or a statistically significant inverse correlation between the AHI and the prevalence of alpha-delta sleep, sleep-onset insomnia, headaches & IBS in consecutively evaluated sleep-disordered breathing patients).

And a case report of disappearance of alpha-delta sleep (again, an objective finding associated with fibromyalgia) along with resolution of fibromyalgia symptoms when the patient was treated for sleep-disordered breathing with a mandibular advancement device.

You are free to write these findings off as irrelevant because they came from small sample sized studies and a case report. I'm here to discuss the possibility of how they may relate to the proposed theory of sensitization/stress response to inspiratory flow limitation during sleep causing symptoms like fatigue, body pain, and insomnia in sleep-disordered breathing patients with those who are interested in having that discussion.

I'll keep the title as it is (since it has the ? in it I think it makes it clear I'm not asserting it as a fact). Sorry for going beyond what the evidence supports in my original statements in the post. I have now edited it accordingly.

Again, going to try to take a break from this for several days (maybe a week); check back then if you are interested in discussing the topic and hopefully I will have something better up than what I have now.

ETA: It will definitely take me more than several days to add all the information here with multiple posts on sub-topics etc.

CHECK BACK ON 8/1 IF YOU ARE INTERESTED IN UARS.

-Natalie

 

[EndME]

Just a little heads up @nataliezzz to avoid you future frustration: I doubt you will get any meaningful feedback or valuable discussion if you lump together different conditions on the basis of overlapping symptoms and them being unexplained without providing a meaningful scientific justification for doing so, which would be a description of precise mechanisms based on a deep understanding on the exact pathways and dynamics involved (references to HPA axis and stress response and sensitisation are entirely insufficient because that has nothing to do with understanding the precise dynamics).

Overlapping symptoms is a horrible indication of common causal drivers involved, which would just end up with comments along the lines of "another quack theory" similar to how nobody would take a physicist serious that argues "all of these equations must have the same solution because what they have in common is that they look similar and nobody is able to solve them". I hope that may be helpful.

 

[nataliezzz]

Just a little heads up @nataliezzz to avoid you future frustration: I doubt you will get any meaningful feedback or valuable discussion if you lump together different conditions on the basis of overlapping symptoms and them being unexplained without providing a meaningful scientific justification for doing so, which would be a description of precise mechanisms based on a deep understanding on the exact pathways and dynamics involved (references to HPA axis and stress response are entirely insufficient because that has nothing to do with understanding the precise dynamics).

Overlapping symptoms is a horrible indication of common causal drivers involved, which would just end up with comments along the lines of "another quack theory" similar to how nobody would take a physicist serious that argues "all of these equations must have the same solution because what they have in common is that they look similar and nobody is able to solve them". I hope that may be helpful.

See my response to @Utsikt above. We can discuss the statistically significant findings of small studies as they pertain to this proposed theory (I imagine people do this on this forum all the time for other small studies as they pertain to possible theories?) Recall, there is an objective finding at play here too (as far as I am aware, alpha-delta sleep is the only consistently replicable objective finding in fibromyalgia, so I would encourage people not to ignore it).

There is evidence from a larger study supporting inspiratory flow limitation as a relevant factor in the symptomatology of SDB patients:
https://www.sciencedirect.com/science/article/abs/pii/S0012369223058233
In 998 suspected OSA patients referred for polysomnography, increased flow limitation frequency was associated with increased psychomotor vigilance task (PVT) lapses; AHI was not.

There is a specific hypothesized mechanism by which the stress response may be occurring (I've added a detailed description of the olfactory nerve hypothesis to the OP); yes, it's just a hypothesis, but the proposed "exact pathways and dynamics involved" are laid out (and as stated in the OP, there is another known disorder - temporal lobe epilepsy - for which airflow input to the limbic system via the olfactory nerve has been demonstrated to be associated with pathological consequences). So the hypothesis is not vague "references to HPA axis and stress response and sensitisation."

Will be coming back to this in a couple weeks.

 

[EndME]

Can you provide a link to the CPAP study in ME/CFS? I would definitely like to look at that.

I was refering to the NIH intramural study on ME/CFS. There are of course more studies that have done a Polysomnography in ME/CFS and there'll be findings which were never published. Before developing any hypothesis one has to try to gain an understanding of the totality of findings, in particular negative results.

See my response to @Utsikt above. We can discuss the statistically significant findings of small studies as they pertain to this proposed theory (I imagine people do this all the time for other small studies as they pertain to possible theories on this forum? Or do people always demand large randomized controlled trials to even consider evidence as it pertains to a theory?) Recall, there is an objective finding at play here too (as far as I am aware, alpha-delta sleep is the only consistently replicable objective finding in fibromyalgia, so I would encourage people not to ignore it).

Will be coming back to this in a couple weeks.

It is not a question of sample sizes and p-values. p-values and statistical significance are not any indicator of causality and going through papers looking at p-values are not a meaningful indicator of developing a biological theory as any statistician will tell you. It is exactly how hundreds of other ME/CFS hypotheses have been developed! As mentioned such things can be seen every other of month. There is a perfect correlation of people drinking water and people dying, but that doesn't mean water is the cause of death for all humans. That seems like a hyperbolic example, but there's hundreds of studies on ME/CFS where there are statistically significant findings, none of which carry any meaning. After all there is a replication crisis in medicine, which is why consistent replication is also important. You should never forget the psychology involved in doing research which hyperbolically means that everything will always be "statistically significant" (publication bias, sampling bias and other biases pose a massive problem, that is of course even stronger in smaller studies). If on top of that the study is of a low methodological standard it's not particularly wise to overemphasise p-values.

Will be coming back to this in a couple weeks.

See you then.

but the proposed "exact pathways and dynamics involved" are laid out

In my eyes they are not. I think there is a misunderstanding between what you call an understanding of dynamics and what I call an understanding of dynamics that may be insurmountable, but we'll see again in a few weeks. I'd be mainly interested in things pertaining specifically to ME/CFS (for starters OSA has a sex ratio that is almost the opposite of ME/CFS so one has to explain the mechanisms that cause these things with different symptom constellations etc), rather than other conditions where I have no idea what those conditions are even supposed to be and I have no idea on how the literature might even look like, including negative findings.

 

[Trish]

If you want to discuss the details of any research paper, it's best to start a thread on that research paper in the relevant subforum.

 

[Utsikt]

Yes, exactly, I want to discuss the evidence re: the theory. The evidence may be from studies with small sample sizes, but statistically significant findings are not invalid simply because they are from small sample sized studies.

I'm here to discuss the possibility of how they may relate to the proposed theory of sensitization/stress response to inspiratory flow limitation during sleep causing symptoms like fatigue, body pain, and insomnia in sleep-disordered breathing patients with those who are interested in having that discussion.

Again, you’ve started at the wrong end. You’ve seemingly chosen a theory and are trying to see if you can find evidence that fits (and you apparently accept correlation) with the theory.

You won’t have any luck here with that approach because it simply isn’t how science is done. Your theory is so far removed from the causal evidence that it doesn’t have any value to discuss it.

This exact kind of approach (of «starting with an observation») is why we have more than 500 different recognised psychological treatment modalities, but no real knowledge of how any of it actually works. Because they didn’t bother trying to do the basic research to see if the fundamental building blocks and assumptions of their theories are actually valid.

 

[Peter T]

It has taken me a while to get my head around this thread, given the extreme press of information. I found it very hard to see the wood for the trees. @nataliezzz is this a fair overview of what you are saying?

Symptom/phenomenon - upper airway resistance resulting in inspiratory flow limitation (IFL), for which management/treatment strategies exist (eg CPAP)

Proposed clinical entity - upper airway resistance syndrome (UARS) which overlaps with obstructive sleep apnea syndrome (OSAS)

Hypothesis - UARS involves a stress response disorder driven by inspiratory flow limitation (IFL), sensitising the limbic system via the olfactory nerve to perceive IFL as a noxious stimulus/stressor, and the resultant stress response becomes ingrained, driving ongoing symptoms in “chronic complex illnesses”. This occurs when hypothalamic-pituitary-adrenal axis is somehow primed by an additional stressor (infection, trauma, surgery, chemical/environmental exposure, etc.) which somehow sensitises the limbic system to perceive IFL as a noxious stimulus/stressor and the stress response becomes ingrained, driving further ongoing symptoms.

Correlations/relationships

• Fibromyalgia
• Gulf War Illness
• Functional Somatic Symptoms/Disorders (proposed clinical entity of Functional Somatic Syndrome?)
• Temporal Lobe Epilepsy

Evidence from Dr Gold’s clinical practice may be suggestive of a link between IFL and Fibromyalgia and provides anecdotes of managing IFL improving the Fibromyalgia. Experimental studies in Fibro and GWI may suggest an association between them both and IFL.

Further Hypothesised

UARS involves sensitisation of the limbic system involving pre-existing IFL in conjunction with a triggering event (eg infection, trauma, etc) providing a CNS locus for causing the ongoing symptoms of ME/CFS

Evidence:

• Symptom overlap with other conditions Fibromyalgia, Gulf War Illness and Functional Somatic Disorder (see above)
• Sleep related symptoms
• @nataliezzz ’s experience of CPAP alleviating ME/CFS symptoms

Why is everything a syndrome? I find it off putting as it implies groupings that may or may not be clinically significant.

I feel this contains a number of assumptions and untested hypotheses that each require separate discussion; I am very wary of theories that are supposed to explain a very broad range of conditions and symptom variation within and between individuals in individual conditions; the proposed role of the limbic system seems highly speculative; I worry about reliance on concepts of stressors and sensitisation which are not always adequately defined; reference to functional disorders raises a red flag given there is such a lack of scientific rigour amongst proponents of such terms; it is perhaps a fault in me but I am very wary of highly enthusiastic speculation including a press of information as, particularly in relation to ME/CFS, we regularly see proponents of a particular idea getting carried away, be it sacrocranial surgery, micro blood clots, or specific diets or exercise programmes; we see the dangers of such over enthusiasm in the practice of such as Dr Myhil or even the proselytising of Prof Paul Garner; looking at a theory of everything creates a danger of uncritically accepting unevidenced propositions, such as suggesting that this approach might explain why brain retraining helps some people with ME/CFS when we have no reliable evidence other than personal testimony that it helps anyone; and we need more clarification on what the relationships between IFL and conditions under discussion are.

I personally would like a clearer understanding of what the phenomenon we are discussing is, before going off into flights of speculation about any hypothalamic-pituitary-adrenal axis involvement:

• We need assurances that any subject cohorts have conditions that are defined as well as possible by accepted criteria given this is an area where we see high levels of both false positives and false negatives in diagnosis.
• Are the anecdotes of managing IFL improving other conditions credible or could they be coincidental? (I suffer from B12 deficiency, and when I am in deficit a B12 injection might subjectively be interpreted as improving my ME/CFS, but longer term any B12 supplementation beyond what is necessary to avoid going back into deficit has no impact. So I am after several years of varying levels of supplementation fairy confident that B12 treats my vitamin deficiency not my ME/CFS.)
• Can we say with any confidence that everyone with the condition being considered had IFL prior to the condition’s onset?
• Can we say with confidence that there are higher levels of IFL in the patient populations under consideration when compared to other populations with other health issues? Using healthy controls may not be sufficient.
• Can we say that any study claiming managing IFL improves participant’s underlying condition is impacting the condition under investigation and not just treating a concurrent sleep disorder?

I think considering individual’s potential sleep issues is worth doing, and if studies demonstrate a higher level of IFL than in the general population that would be very useful, just as I think everyone with ME/CFS should be on the look out for food intolerances. That is not because everyone with ME/CFS has food intolerances, but rather that there are unusually high levels of food intolerances in ME/CFS the reasons for which we don’t currently understand. So being on the look out for food intolerances means we can improve the quality of life for those that have both.

Collectively on lots of threads I feel here we are coming to a consensus that given we do not yet understand the aetiology of such as ME/CFS, clear descriptions of the phenomenon are very important, but that speculation about possible causes should not be part of the clinical setting as that only serves to alienate those who disagree. I am sure many doctors will see Dr Gold as a quack, because he is using a theory that goes well beyond current evidence to prescribe treatment for fibromyalgia, which will not help getting the wider medical profession to ask has he identified a clinically significant issue. In terms of treatment, if a person with ME/CFS who also has IFL would see an improvement in their quality of life if that is treated that is fantastic. But then it is a separate academic issue explaining any etiological significance.

[edited to clarify and correct typos]

 

[Utsikt]

@Peter T would you be able to edit out the italic? You make some very good points, so it’s a shame they are difficult to read with the current formatting.

 

[Peter T]

@Peter T would you be able to edit out the italic? You make some very good points, so it’s a shame they are difficult to read with the current formatting.

Hope that is better, I had started to write the post in a note book and formatted there for me, then when I posted here I forgot that the italics became redundant. Unfortunately I also ended up posting far too much text, creating a ‘can’t see the wood for the trees’ situation myself. I must learn how to hide things under a spoiler alert, as all my personal comments could have been hidden under two spoiler buttons.