Emerging research suggests the answer lies in the brain, not the airway.

CPAP works wonders on some patients. Some people with obstructive sleep apnea (OSA) are literally transformed overnight. They wake up alert and are able to be productive all day. They effusively thank the entire sleep medicine team at their next appointment. Other patients also show adherence per their CPAP data downloads, far surpassing Medicare’s compliance threshold. By many objective measures, they could be described as optimally treated. An apnea-hypopnea index below 5, no comorbidities, sleeping at least 7 hours a night, etc. But they continue to report one pesky problem: They are still sleepy. Really sleepy. Their Epworth Sleepiness Scale (ESS) score registers above 10 and, if objective testing is done (such as a multiple sleep latency test), excessive sleepiness manifests on that too.

No one knows for certain why some patients respond so well to CPAP and others don’t. But a growing body of research posits that though CPAP optimizes the airway, dysfunction can linger in the brain. Perhaps the brain has already suffered nonreversible damage prior to diagnosis.

Estimates vary widely for how many people have excessive sleepiness even after being optimally treated with CPAP. A 2012 review of retrospective studies estimated 10%, after excluding confounding causes of sleepiness.1 A 3-month multicenter clinical effectiveness study that assessed patients with moderate to severe OSA reported that 66% of participants who used CPAP for more than 5 hours a night and had abnormal ESS values at baseline had normal ESS scores at the trial’s conclusion—in other words, 34% of CPAP-adherent study participants were still sleepy. “Our study suggests that a greater percentage of patients achieve normal functioning with longer nightly CPAP duration of use, but a substantial proportion of patients will not normalize neurobehavioral responses despite seemingly adequate CPAP use,” the authors wrote.2

Perhaps most alarmingly, when CPAP users with severe OSA got behind the wheel of a driving simulator for a 90-minute road test, their steering deviation was worse than that of healthy controls (though it was better than the group’s average pre-treatment simulated performance). The OSA group had steering deviation of 46.7 cm versus the control group’s 36.1 cm. “These results add to the growing body of evidence that some neurobehavioral deficits in patients with severe OSA are not fully reversed by treatment,” the authors wrote.3

Less-than-normal outcomes are not limited to severe OSA cases. A study published this year reported that patients with mild to moderate OSA and on CPAP were significantly sleepier than community residents of a similar demography. “Some neuropsychological and mood outcomes were normalized with CPAP, but significant decrements persisted in most outcomes even in those participants with adequate device usage,” the authors wrote, adding that they saw no dose-response relationship between CPAP use and recovery of function in this milder end of the OSA spectrum.4

“The presence of persistent sleepiness is now clinically and scientifically recognized,” says Richard K. Bogan, MD, FCCP, FAASM, chief medical officer of SleepMed Inc, founder of Bogan Sleep Consultants LLC, and a paid consultant for Jazz Pharmaceuticals. “It should be evaluated and treated.”

Beginnings in the Brain

brain obstructive sleep apnea

Even after starting CPAP, some patients’ brains show structural abnormalities in their gray and white matter that may have been caused by their obstructive sleep apnea prior to beginning treatment.

Adult male mice subjected to long-term intermittent hypoxia in a study—modeling the hypoxia-reoxygenation events of OSA—experienced increased sleep time and objective sleepiness that continued weeks after they were back in normal oxygen conditions. Oxidative changes in the sleep-wake regions of the brainstem and basal forebrain were found 2 weeks later, including prominent nitration and carbonylation. “This work raises the possibility that [long-term intermittent hypoxia], as occurs in OSA, could potentiate oxidative injury in neurodegenerative processes,” the authors wrote.5

Several investigators from that same team later exposed a different group of mice to chronic sleep disruption (again, modeling sleep apnea) for 14 weeks to count the wake-active neurons before and after. They found these neurons decreased by 50% in the locus coeruleus and orexinergic neurons were down by 25%. Other neuronal damage was observed too. “[Chronic sleep disruption], as observed in sleep apnea, results in a composite of lasting wake impairments, loss of select neurons, a pro-inflammatory, pro-oxidative mitochondrial stress response in [wake-active neurons], consistent with a degenerative process with behavioral consequences,” the authors wrote.6

Whether in animals or in humans, study results are not straightforward. Some studies have even linked high levels of hypoxemia (compared to low levels) with better neurocognitive function. “It’s best not to have any hypoxemia,” says Mark Aloia, PhD, global lead for behavior change at Philips Sleep and Respiratory Care, and a co-investigator of a study with such findings.7 “But, if you have some, it may be worse for you to have a little than a moderate amount. This is because the body may need a certain amount to initiate its protective mechanism against hypoxemia. This was only a hypothesis, but it has been supported by other work.”

The authors who estimated the prevalence of patients who are on treatment but still sleepy at 10% wrote that in their opinion, it is unlikely that irreversible hypoxic brain lesions alone account for the persistence of sleepiness. “Residual sleepiness patients are younger (less exposure time to OSA) and suffer from less severe OSA (less hypoxia) than patients who respond to CPAP,” they wrote. They suggest genetics may ultimately provide a more satisfying cause-and-effect.1

A growing number of studies are delving into how the brain’s gray and white matter are impacted by OSA. Deep white matter shows hints of being particularly vulnerable to damage and is slow to recover (or perhaps, does not at all). “Oligodendrocytes, the myelin-forming cells of the central nervous system, have very little regenerative capacity. An episode of intermittent hypoxia-ischemia can cause different degree of damage to these particularly vulnerable cells,” wrote investigators who used diffusion tensor imaging to analyze white matter structural changes. They conclude that widespread white matter changes might be why OSA patients can respond differently to CPAP use.8

Perhaps the most hotly debated aspect by those who say the brain is altered by untreated OSA is whether the damage is reversible with long-term CPAP use. And if it is reversible, how long does it take?

Brain damage is reversible in epilepsy, Cushing syndrome, and chronic alcoholism, noted investigators who used magnetic resonance spectroscopy to look at whether cerebral metabolite changes may underlie abnormalities in OSA. But they found the frontal lobe differences were not reversed after 6 months of CPAP, though the hippocampus fared better. “The results of the current study suggest that this may be due to irreversible, or at least slowly reversible, differences in brain metabolism, particularly in the frontal lobes,” the authors wrote.9

But a Philips Respironics-supported study that used diffusion tensor imaging found improvements (albeit limited) when patients were examined after 3 months of CPAP; after 12 months, the same patients experienced an almost complete reversal of white matter abnormalities.10 “Many things happen with time,” says Aloia, a study investigator. “It is possible that time allows people to make further recovery—we have shown this in a paper on the local coverage determination criteria for reimbursement.11 People make recovery cognitively within the first 3 months but they continue to recovery even more with additional time. It may also be that untreated people get worse with time, making the difference greater between the groups.”

Identifying Excessive Sleepiness

Almost half of clinicians don’t frequently ask their OSA patients about daytime sleepiness, according to a Medscape member survey as well as published literature, says Thomas F. Finnegan, PhD, associate director of clinical strategy at Medscape Education. So Finnegan asked whether a 30-minute video (entitled “Improving Outcomes in OSA: The Importance of Excessive Daytime Sleepiness,” supported by an independent educational grant from Jazz Pharmaceuticals) would make a difference. “Given the extent of research on OSA and that sleepiness is a symptom that often accompanies the condition, I was most surprised that physician learners had very little pre-education knowledge of studies which identified risk factors for [excessive daytime sleepiness] in patients being treated for OSA with CPAP therapy,” Finnegan says.

The study by Finnegan et al, also supported by an independent educational grant from Jazz Pharmaceuticals, found that pulmonologists and neurologists who watched the video increased their knowledge of the minimum Epworth Sleepiness Scale score at OSA diagnosis and its link to an increased likelihood of having excessive sleepiness after CPAP treatment, and that the video improved neurologists’ and pulmonologists’ confidence—38% and 34%, respectively—in identifying sleepiness at patient follow-up.13 The results support the need for the development of additional educational programming on risk factors for excessive sleepiness in OSA, Finnegan says.

How frequently should excessive sleepiness be measured? SleepMed’s Bogan says, “As we follow our patients for treatment efficacy, we must assess symptom status at each visit.”

But how that daytime sleepiness is measured is just as relevant as how often. Results of subjective and objective tests commonly don’t align.

A dose-response study found that a fifth to a half of participants had evidence of post-CPAP excessive sleepiness. But the fraction varied by how excessive sleepiness was measured. “Thresholds above which further improvements were less likely relative to nightly duration of CPAP were identified for Epworth Sleepiness Scale score (4 hours), Multiple Sleep Latency Test (6 hours), and Functional Outcomes associated with Sleepiness Questionnaire (7.5 hours),” the authors wrote.14

“Our current methods of evaluating sleepiness are flawed,” says Shannon Foster, DO, a sleep medicine staff physician at Wilford Hall Ambulatory Surgical Center Sleep Disorders Center in Joint Base San Antonio, Texas. “Currently, there is no guideline or recommendation for how to evaluate residual excessive daytime sleepiness in patients on PAP therapy. As a sleep community, we need to come to a consensus on how to properly evaluate and treat these patients with residual excessive sleepiness so we can avoid overtreatment and/or misdiagnosis.”

In an abstract presented at SLEEP 2018, Foster et al reported that despite subjective symptoms, the majority of OSA patients were not objectively sleepy per multiple sleep latency test (MSLT). Subjective and objective sleepiness synced up in only 32.2% of the 31 adults.15 “The number of patients with the mismatch in our cohort was more than expected,” Foster says, adding that this calls into question the practice of using wake-promoting agents in this population without objective testing or evaluating other possible causes of symptoms. “Many times these patients have already been started on a wake-promoting agent such as modafinil,” she says. “In our own clinic, we routinely do objective testing with the MSLT before starting wake-promoting agents, but that doesn’t always happen with patients who have been treated outside our clinic.”

David Plante, MD, PhD, assistant professor of psychiatry at the University of Wisconsin-Madison and medical director at the Wisconsin Center for Sleep and Consciousness, finds that even the MSLT misses a fair amount of people with significant sleepiness. A SLEEP 2018 abstract reported that the use of a multimodal hypersomnolence assessment in patients referred for PSG/MSLT more than doubled the proportion identified as having objective hypersomnolence.16 “Because of the required downtime between MSLT naps, it is relatively easy to interleave these tests within standard clinical care,” Plante says. His team added a computer-based psychomotor vigilance task and infrared pupillometry and let the patients sleep until natural morning wake during PSG (to quantify sleep duration).

Some researchers are interested in identifying OSA phenotypes, with the theory that patients at risk for excessive sleepiness could be monitored differently. “Vulnerability to sleep deprivation or sleep disturbances is a trait-like characteristic and could account for the inconsistent effect of CPAP on sleepiness in OSA patients,” wrote authors of a review. “Identifying a subgroup of OSA patients at risk for residual sleepiness at the time of diagnosis would allow closer monitoring and earlier management of residual symptoms.”1

Adam Benjafield, vice president, medical affairs, at ResMed, says, “As medicine in general moves towards P4 (predict, prevent, personalize, participate), this is also true for OSA. With better phenotyping of OSA and understanding of the differences, more efficient clinical pathways can be created to help get patients identified, diagnosed, and treated appropriately. Phenotyping OSA will help make sure patients get the best therapy for maximizing clinical outcomes the first time.”

Meanwhile, a specific clinical test for neuronal damage linked to post-CPAP excessive sleepiness does not yet exist. But it might one day. One white matter imaging study states, “We did not intend to establish a threshold [fractional anisotropy] or [mean diffusivity] value by which reversible sleepiness (i.e., non-sleepiness after CPAP therapy) can be distinguished from residual sleepiness. However, our study paves the way for developing such imaging-based quantitative markers to complement conventional clinical assessment of somnolence.”8

Treatments…And Their Impact on CPAP Use

Perhaps one day there will be a pill to protect the brain against injury caused by OSA or even to rehabilitate it quickly. But for now, other than encouraging patients on CPAP to participate in brain-healthy activities (such as exercising regularly), physicians typically treat patients with prescription pharmaceuticals that improve functioning.

“There is moderate-quality evidence in favor of reduced excessive sleepiness (as measured by the ESS), increased wakefulness (as measured by the MWT in minutes), and clinical effectiveness (as measured by the CGI-C) with psychostimulant treatment, with a mean duration of six weeks, in CPAP-treated patients with OSAS,” wrote the authors of a systematic review and meta-analysis published in 2016. “In clinical trials, approximately 2.9 patients had to receive psychostimulants to yield one instance of improvement measurable with the CGI-C as compared with placebo, for a number needed to treat (NNT) of 2.9. On separate analysis, modafinil had an NNT of 2.7, and armodafinil, an NNT of 3.5.”17

The review offered reassurance for physicians who worry that patients prescribed wake-promoting drugs will quit CPAP. “Only one study has reported a statistically significant difference in the reduction in the duration of CPAP use per night, but without clinical impact, on the group that was prescribed modafinil,” they wrote. “Conversely, other studies have found that the magnitude of change in the nightly duration of CPAP use was relatively small, and that CPAP use remained high.”

A new selective dopamine and norepinephrine reuptake inhibitor is in development for treatment of excessive sleepiness in adult patients with OSA who are on CPAP. Licensed by Jazz Pharmaceuticals, the investigational drug is known as “solriamfetol” and “JZP-110.” As of press time, it hasn’t been approved by the US FDA. A Jazz Pharmaceutical-supported abstract presented at SLEEP 2018 found that solriamfetol (75 mg, 150 mg, and 300 mg) in people with OSA was linked with sustained improvement in wakefulness, as measured by the Maintenance of Wakefulness Test, in post-dosing hours 1 through 9.18 “The data indicate no change in use of CPAP during the 12 weeks of the study,” says corresponding author Paula K. Schweitzer, PhD, director of research of the Sleep Medicine & Research Center at St. Luke’s Hospital in Chesterfield, Mo. “This is an important issue, however, so further examination of durations longer than 12 weeks is needed. Physicians should continue to monitor CPAP usage.”

Jed Black, MD, senior vice president of Sleep and CNS Medicine at Jazz Pharmaceuticals, says that Jazz put solriamfetol on the path to FDA approval to bring healthcare providers new treatments for excessive sleepiness. “In our market research, we determined that many patients are not satisfied with their current [excessive sleepiness] treatment,” he says. “Approximately one third to one half of patients are intolerant of, or not receiving sufficient benefit from, their current therapies. In fact, approximately 50% of [excessive sleepiness] patients fail one or more pharmacotherapies.”

Black adds, “We have presented data that demonstrate no difference from baseline or from placebo in CPAP use in patients randomized to solriamfetol.18 Additionally, an external, non-Jazz sponsored study found no difference in CPAP adherence/compliance in drug-treated patients versus those on placebo.19 Based on these data, we do not have concerns regarding patients’ continued use of primary OSA treatment when adding an appropriate agent to address excessive sleepiness.”

ResMed’s Benjafield says ResMed doesn’t expect a change in the market for CPAP devices if solriamfetol (JZP-110) gets FDA approval. “There is no evidence that JZP-110 has any positive impact on patients’ apnea-hypopnea index (AHI), so medications like JZP-110 are adjunct therapies,” Benjafield says. “It will be important for clinicians to make sure their patients are aware of what each therapy does or doesn’t do so that best clinical outcomes can be achieved.”

It will also be important for research to continue on why some patients on CPAP are still sleepy. Particularly since clarifying the mechanisms behind excessive sleepiness could prompt people who suspect they might have OSA to get to a sleep physician more quickly and be more adherent to prescribed therapies once they are diagnosed. “We really do not know the true story,” says Philips’ Aloia. “I know that if I had OSA, I would assume that I could improve with treatment and that would be a piece of my self-motivational message for sticking with my treatment regimen.”

Sree Roy is editor of Sleep Review.


1. Launois SH, Tamisier R, Lévy P, Pépin JL. On treatment but still sleepy: cause and management of residual sleepiness in obstructive sleep apnea. Curr Opin Pulm Med. 2013 Nov;19(6):601-8.
2. Antic NA, Catcheside P, Buchan C, et al. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep. 2011;34(1):111-9.
3. Vakulin A, Baulk SD, Catcheside PG, et al. Driving simulator performance remains impaired In patients with severe OSA after CPAP treatment. J Clin Sleep Med. 2011 Jun 15; 7(3): 246–53.
4. Jackson ML, McEvoy RD, Banks S, Barnes M. Neurobehavioral impairment and CPAP treatment response in mild-moderate obstructive sleep apnea. J Clin Sleep Med. 2018;14(1):47–56.
5. Veasey SC, Davis CW, Fenik P, et al. Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleep-wake brain regions. Sleep. 2004 Mar 15;27(2):194-201.
6. Zhu Y, Fenik P, Zhan G, et al. Selective loss of catecholaminergic wake active neurons in a murine sleep apnea model. J Neurosci. 2007 Sep 12;27(37):10060-71.
7. Hoth KR, Zimmerman, ME, Meschede KA, et al. Obstructive sleep apnea: impact of hypoxemia on memory. Sleep Breath. 2013 May; 17(2): 811–7.
8. Xiong Y, Zhou XJ, Nisi RA, et al. Brain white matter changes in CPAP-treated obstructive sleep apnea patients with residual sleepiness. J Magn Reson Imaging. 2017 May;45(5):1371-8.
9. O’Donoghue FJ, Wellard RM, Rochford PD, et al. Magnetic resonance spectroscopy and neurocognitive dysfunction in obstructive sleep apnea before and after CPAP treatment. Sleep. 2012 Jan 1;35(1):41-8.
10. Castronovo V, Scifo P, Castellano A, et al. White matter integrity in obstructive sleep apnea before and after treatment. Sleep. 2014 Sep 1;37(9):1465-75.
11. Aloia MS, Knoepke CE, Lee-Chiong T. The new local coverage determination criteria for adherence to positive airway pressure treatment: testing the limits? Chest. 2010 Oct; 138(4): 875–9.
12. Zee PC, Strollo PJ. Improving outcomes in OSA: the importance of excessive daytime sleepiness. Medscape Education Neurology & Neurosurgery. 22 June 2017. Available at https://www.medscape.org/viewarticle/876759.
13. Finnegan T, Hughes S, Zee P. 0585 Understanding excessive daytime sleepiness In obstructive sleep apnea: the effect of online medical education on neurologists and pulmonologists. Sleep. 27 April 2018;41(suppl_1):A217–8.
14. Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711-9.
15. Foster S, Mysliwiec V, Matsangas P. 0515 Excessive daytime somnolence in patients with obstructive sleep apnea adequately treated with positive airway pressure. Sleep. 27 April 2018;41(suppl_1):A193.
16. Plante DT, Cook JD, Prairie ML. 0613 Multimodal hypersomnolence assessment substantially increases objective identification of hypersomnolence in patients referred for multiple sleep latency testing. Sleep. 27 April 2018;41(suppl_1):A227–8.
17. Avellar ABCC, Carvalho LBC, Prado GF, Prado LBF. Pharmacotherapy for residual excessive sleepiness and cognition in CPAP-treated patients with obstructive sleep apnea syndrome: a systematic review and meta-analysis. Sleep Medicine Rev. 30(2016):97-107.
18. Schweitzer PK, Strohl KP, A Malhotra A, et al. 0622 Solriamfetol (JZP-110) in the treatment of excessive sleepiness in narcolepsy and obstructive sleep apnea: maintenance of wakefulness test results across the day. Sleep. 27 April 2018;41(suppl_1):A231.
19. Chapman JL, Vakulin A, Hedner J, et al. Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis. Eur Respir J. 2016 May;47(5):1420-8.