OK, I've had a look at the CPAP trial in the
intramural ME/CFS study; it is mentioned in the
supplement:
All PI-ME/CFS participants underwent polysomnography in a sleep laboratory. Two had mild periodic limb movements (PLM Index ≥ 5, < 25), two had mild sleep apnea (Apnea Hypopnea Index ≥ 5, < 15 per hour), and one had moderate sleep apnea (Apnea Hypopnea Index ≥ 15, < 30 per hour). None of these individuals noted substantial improvement after a six-week trial of CPAP. Sleep fragmentation was noted in 10 PI-ME/CFS participants (three mild, five moderate, two severe). Thus, PI-ME/CFS participants reported moderate sleep dysfunction not explained by polysomnographic evaluation.
So 3/17 ME/CFS patients met criteria for OSA* and none of these 3 noted substantial improvement after a 6-week trial of CPAP -- that's all that's stated about it in the supplement. I had AI search the supplementary data ZIP folder (24 Excel spreadsheets) for any mention of a CPAP trial and it didn't find anything. So as far as I can tell, there were no official outcome measures used to assess changes in symptoms, no description of CPAP titration protocol, and no CPAP compliance data (how many hours a night/how many nights etc. the patients actually used CPAP). It seems like they were basically just using this as a way to rule out OSA as the actual cause of some patients' symptoms, expecting that if OSA was driving their symptoms they would all report dramatic improvement on CPAP.
Here's some reasons why I don't necessarily think that is the case.
First of all, CPAP, as it is conventionally prescribed, does not actually seem to work that well for many OSA patients. In the European Sleep Apnea Database cohort of 4,853 CPAP-treated patients,
Bonsignore et al. (2021) found that excessive daytime sleepiness (EDS, Epworth Sleepiness Scale >10) declined form 56% at baseline to 28.2% at follow-up (median 5 months), although longer treatment time made a difference: EDS was 40% at 0-3 month first follow-up visit and declined to 13–19% at 4 months - 2 years first follow-up visit. Incomplete resolution of apneas/hypopneas and/or poor CPAP adherence occurred with similar frequency in patients with and without persistent EDS, suggesting that residual symptoms are not simply a product of inadequate treatment hours or residual apnea/hypopnea events.
If you've been following along, you'll know that the Epworth Sleepiness Scale (ESS) actually
measures a mix of objective sleepiness and fatigue, which are uncorrelated symptoms in OSA patients. I'll get into some reasons why I think CPAP may not work that well (at least on a shorter time scale) for many OSA patients with objective sleepiness in a later write-up, but that's not the type of OSA we are concerned with here when it comes to a potential connection to ME/CFS; we're concerned with the fatigue subtype of OSA (/UARS -
there is no separate UARS), which is proposed to be driven by a physiological stress response to inspiratory flow limitation (IFL).
Which brings me to my next point: historically, CPAP titration protocols have been designed to eliminate apneas/hypopneas, but not necessarily IFL. There was one trial comparing a conventional titration protocol to an IFL-targeted titration protocol (see below), but considering ESS and maintenance of wakefulness test were the outcome measures -- and not fatigue/other symptoms relevant to this subtype of OSA -- I don't think the results are necessarily that informative, even though IFL-targeted titration did seem to result in better outcomes on some of the measures assessed.
Meurice et al. (1998) compared IFL-targeted vs. conventional titration and found that while mean maintenance of wakefulness test (MWT: a measure of ability to sustain wakefulness sitting in a quiet, dimly lit environment) and ESS outcomes did not differ significantly between groups, conventional titration produced highly variable outcomes with 3 patients showing no MWT improvement whatsoever, while IFL-targeted titration produced uniformly improved scores and significantly better CPAP adherence (7.3 vs. 6.0 hours/night). Final MWT was uncorrelated with AHI, arousal index, or oxygen saturation, but correlated positively with CPAP adherence and residual IFL burden, suggesting that eliminating IFL may improve both treatment efficacy and tolerability.
If someone has the IFL-driven fatigue OSA subtype and they are titrated on CPAP to a pressure that only resolves apneas/hypopneas but not IFL, you would likely not expect them to feel significantly better; in fact, there's an argument that they might actually feel worse if they are now spending less time in apnea (complete cessation of airflow) and more time in IFL (and according to
Dr. Gold's hypothesis of prolonged decreases in nasal pressure during IFL activating the limbic system, it's actually milder IFL that would be expected to activate the limbic system more than hypopnea [which is also a form of IFL] due to greater prolonged decreases in nasal pressure, as there is less airflow/negative nasal pressure during hypopnea than milder IFL). So CPAP potentially shifting people from hypopnea-dominant breathing to milder IFL-dominant breathing could also theoretically make things worse. You've also added the stress of CPAP (mask on your face, and pressurized air itself -- especially in the case of CPAP over bilevel devices -- acting as a unique stressor too; see following thread for a discussion of that:
Sleep-disordered breathing (UARS/OSA) and chronic insomnia).
So, in a discussion of a possible connection between sleep-disordered breathing and ME/CFS, I would say this finding is worth noting, but with context; for example:
"3/17 patients in the intramural ME/CFS study trialed CPAP for 6 weeks (no description of titration protocol, no compliance data reported) and did not report substantial improvement (no specific outcome measures reported)."
*I've stopped placing much importance at all on % patients meeting criteria for OSA in various studies -- unless it is the same research group showing a difference in % meeting OSA criteria between different patient groups (blinded of course). I recently came across
a large population-based study from Switzerland (n=2,121) that found using home PSG with nasal pressure transducers that 84% of men and 61% of women (ages 40-85) met criteria for OSA (AHI ≥5) when using the
current recommended AASM scoring guidelines for hypopnea. See also
Obstructive sleep apnea is a common disorder in the population—a review on the epidemiology of sleep apnea, 2015, Franklin et al for highly variable OSA prevalence rates between studies. Various factors likely contribute (beyond geographical population factors like obesity rates, craniofacial anatomy differences, etc.) including use of thermistors (less sensitive measure of airflow) vs. nasal pressure transducers (most clinics should probably be using pressure transducers by now) and use of different hypopnea criteria (to see how different hypopnea criteria can dramatically affect OSA diagnosis rates, see
this study and
this study).
