Sleep Deficiency in Obstructive Sleep Apnea

INTRODUCTION

Obstructive sleep apnea (OSA) is the most common sleep disordered breathing syndrome, with prevalence ranging from 9% to 38% in the general population¹. OSA is highly burdensome because it contributes to the psychiatric, metabolic, and cardiovascular diseases (CVDs), such as depression, diabetes, hypertension, and stroke,^1–4 and importantly impairs daytime function by potentiating sleep deficiency. The National Institutes of Health defines sleep deficiency as abnormalities in sleep duration, circadian alignment, sleep quality, and sleep-related disorders.⁵

Sleep deficiency in OSA may be a direct consequence of upper airway obstruction, leading to hypoxemia, arousals from sleep, and sympathetic activation. These events result in poor quality sleep and decreased sleep duration, extensively described in prior literature.^6,7

Sleep deficiency in OSA, however, is also closely linked to comorbid disorders. These disorders may contribute to poor sleep directly or through interactions with OSA. Conditions such as insomnia, circadian misalignment, periodic limb movements of sleep (PLMS) can all impact sleep quantity and quality in patients with OSA thus worsening sleep deficiency. Here, we discuss these relationships as they relate to sleep deficiency in individuals with OSA.

COMORBID INSOMNIA AND OBSTRUCTIVE SLEEP APNEA

Epidemiology

The diagnostic characteristics of the insomnia disorder include difficulty initiating, maintaining, or early termination of sleep associated with daytime symptoms (eg, fatigue) or functional impairment. These are also common in those with OSA. For example, a recent systematic metanalysis by Zhang and colleagues⁸ examined the co-occurrence of insomnia symptoms and insomnia disorder in patients with OSA (apnea-hypopnea index [AHI] ≥ 5, N=28,252). Insomnia was defined based on the insomnia severity index (ISI) score of 15 or higher,⁹ Diagnostic Statistical Manual Mental Disorders,5^th edition (DSM-5) or the International Classification of Sleep Disorders (ICSD) criteria^10,11 or physician diagnosis.¹² The prevalence of insomnia was 38% (95% confidence interval, 15–64%).⁸ Difficulty maintaining sleep was the most common presenting symptom (42%). However, other signs such as short sleep duration owing to difficulty falling asleep and early morning awakenings occurred in 18% and 21% of patients with OSA, respectively. In contrast with previous studies,¹³ OSA severity did not influence the prevalence of insomnia, suggesting that clinicians should assess for insomnia in all patients with OSA, regardless of the AHI.

Pathophysiology

The co-occurrence of insomnia and OSA may be related to each disorder perpetuating the other (Fig. 1).¹⁴ Insomnia may increase susceptibility to apneic episodes. Physiological arousal is heightened in insomnia patients, as evidenced by elevated cortisol, metabolic rate, electroencephalography (EEG) activity, and prolonged sleep latency.^15–23 This state of hyperarousal increases the propensity for lighter sleep which in turn increases the vulnerability to apneic episodes.²⁴

Fig. 1.

Potential mechanisms by which OSA and insomnia interact. The physiologic hyperarousal of insomnia may manifest as a low arousal threshold and contribute to respiratory instability in OSA. The frequent arousals and sleep fragmentation from OSA may lead to a conditioned response to arousal and insomnia. The low sleep depth, reflected by the high ORP, may be the intrinsic trait that links OSA and insomnia, with increased susceptibility to arousal, destabilized sleep, and excessive wake time. EMG, electromyographic; Po₂, partial pressure of oxygen; Pco₂, partial pressure of carbon dioxide; UA, upper airway. (From Eckert DJ, Sweetman A. Impaired central control of sleep depth propensity as a common mechanism for excessive overnight wake time: implications for sleep apnea, insomnia and beyond. J Clin Sleep Med. 2020 Mar 15;16(3):341 – 343.)

Indeed, a low arousal threshold, or propensity to awaken easily from a respiratory stimulus, is more common in those with comorbid insomnia and OSA (COMISA) versus OSA alone.²⁵ In those with a low arousal threshold, ventilatory overshoots during arousals lead to greater CO₂ reduction with resultant worsening in upper airway muscle tone and propensity for airway obstruction during sleep.²⁶ Data suggest that reducing arousability by pharmacotherapy or cognitive behavioral therapy for insomnia (CBT-I) may decrease the AHI.^27,28

Conversely, OSA contributes to insomnia symptoms. The repetitive arousals and post-arousal awakenings may be perceived as recurrent wakefulness during sleep and promote maladaptive cognition about sleep. Repetitive nights of sleep difficulties may activate the sympathetic nervous system and hypothalamic-pituitary-adrenal (HPA) axis.²⁹ The consistent association of the bedroom environment, the time of night, and the unmet desire to fall asleep along with sympathetic nervous system/HPA axis activation can become conditioned and underlie the development of psychophysiological or conditioned insomnia.^29,30

How deeply a patient sleeps as measured by the odds ratio product (ORP) may be an intrinsic trait that influences an individual’s tendency for arousal when exposed to internal or external stimuli and may be a pathogenic mechanism linking OSA and insomnia. The ORP quantifies the moment-to-moment sleep depth using EEG signal processing from standard polysomnography. An ORP of 2.5 indicates complete alertness/wakefulness, whereas 0 indicates deep sleep/zero likelihood of arousal. Younes and Giannouli²⁵ investigated the mechanistic origin of excessive wakefulness (defined as sleep efficiency < 80%) observed in both conditions. They measured the ORP in healthy controls and people referred for polysomnography with and without OSA, PLMS disorder (PLMD), and insomnia symptoms. They found that ORP was higher in those with insomnia symptoms (65% of participants) than those without. Sleep depth in the first 9 seconds after arousal was also lighter, increasing the risk for subsequent arousals.²⁵ Notably, those with excessive night wake time exhibited higher ORP than those without, regardless of the comorbid OSA or PLMD. These findings suggest that an individual’s sleep propensity is an important determinant of excessive wake time and is not solely owing to disorders characterized by repetitive arousals, such as OSA and PLMD.

Clinical Characteristics and Consequences of Comorbid Insomnia and Obstructive Sleep Apnea

Like all patients suffering from insomnia, individuals with COMISA have difficulty falling asleep, maintaining sleep owing to frequent awakenings or early morning awakenings, and non-restorative sleep. Objective sleep characteristics in age-matched individuals with COMISA show lower OSA severity compared to those with OSA alone and similar sleep duration, efficiency and stage distribution as those with insomnia alone.³¹ Subjectively, difficulty maintaining sleep is the most common COMISA symptom.^32,33 Individuals with this symptom are older, have a higher body mass index, AHI, and more daytime sleepiness as measured by the Epworth sleepiness score (ESS) compared to those with other symptoms.^32,34,35 Difficulty initiating sleep, in contrast, is associated with lower OSA severity,³⁵ and is more common in women with COMISA who smoke and manifest poor physical and mental quality of life.³² Particular attention should be paid to those suffering from mood disorders, chronic pain, and posttraumatic stress disorder, which predict severe insomnia (ISI scores of 23.1 ± 2.6) and are treatable precipitating and perpetuating factors.³⁶

COMISA is associated with adverse consequences, including higher use of sedative and psychotropic medications, greater daytime impairments, and poorer physical and mental quality of life.^32,37,38 Chronic pain is more common in those with COMISA vs. those with OSA alone (69% vs. 46% respectively³⁹). Among military personnel (54% women), COMISA was associated with worse subjective (but not objective) sleep duration, worse subjective cognition, and healthcare utilization compared to either condition alone.⁴⁰ Those with COMISA have lower adherence to continuous positive airway pressure (CPAP) therapy (OR, 0.81, p=.02) and decreased clinical response to mandibular advancement devices than individuals who have OSA alone.^33,41 CPAP therapy in COMISA improves middle-of-the-night sleep maintenance but may also be associated with the emergence of early morning awakenings.³⁴ A study by Lechat et al., in the Wisconsin sleep cohort found that all-cause mortality for individuals with COMISA was increased compared to those with OSA alone (hazard ratio, HR of 1.7 (1.0; 3.0) vs. 0.9 (0.5, 1.6) respectively) and higher in magnitude but not statistically different than for insomnia alone (1.04 (0.6, 2.0)) ⁴²

Both OSA and insomnia are also linked to CVD. The shared mechanistic pathways (Fig. 2) suggest the risk from COMISA may be increased compared with each condition alone.^43–50 OSA’s negative intrathoracic pressure swings increase transmural pressure of thoracic structures and left ventricular afterload. These changes impede stroke volume, increase myocardial oxygen demand and arrhythmogenesis.⁵¹ Hypoxia leads to pulmonary vasoconstriction, pulmonary hypertension, and right heart dysfunction.^51–53 Insomnia, in contrast, is associated with dysregulation of the hypothalamic-pituitary-adrenal axis. The HPA axis is in turn associated with increased heart rate, blood pressure, dyslipidemia, and mediators of the CVD pathway such as impaired glucose metabolism and diabetes.^54–56 Both sleep apnea and insomnia share the pathways of excessive arousals, autonomic dysregulation, increased systemic inflammation, insulin resistance, atherogenesis, and endothelial dysfunction^{48,51,52,57–60} Although all these factors are plausible mechanisms for increased risk of CVD in COMISA, further work is needed to determine if this plausibility translates into observed increased CVD risk in COMISA compared to OSA and insomnia alone.

Fig. 2.

Potential mechanistic pathways for cardiovascular disease in COMISA. BP, blood pressure; HR, heart rate; LV, left ventricle; PCWP, pulmonary capillary wedge pressure; RV, right ventricle.

Diagnosis and Treatment

The COMISA-specific diagnostic criteria are yet to be established. Thus, identifying this condition relies on the presence of insomnia and OSA according to current guidelines (Diagnostic Statistical Manual Mental Disorders, 5^th edition/ICSD and ICSD, respectively).^10,11 A general medical/psychiatric questionnaire, assessment of sleepiness (e.g., Epworth sleepiness score), insomnia severity measures (e.g., ISI), sleep logs (or actigraphy) in addition to polysomnography or polygraphy are essential to diagnosis and management.^61,62

Similar to diagnosis, although there are well-established guidelines for treating OSA and insomnia, such guidelines do not exist for COMISA. CPAP therapy is the most common treatment for OSA, with oral appliances, surgery, or upper airway stimulation used in some cases.^63,64 CPAP use, however, is hampered by poor adherence to therapy in those with insomnia symptoms.^65–69 CBT-I is the recommended first line treatment for insomnia. Recent data suggest that a combination of CBT-I with CPAP therapy may improve outcomes in COMISA.^62,70,71 Tables 1 and 2 summarize the observational and clinical trial studies on the treatment of patients with COMISA. Elsewhere in this article, we highlight the findings of the most recent randomized clinical trials addressing the effect of CBT-I, its delivery method, and when it might be best to administer CBT-I in relation to initiation of OSA therapy on patient-centered outcomes in COMISA.

Table 1.

Observational studies examining the impact of insomnia on therapy outcomes in patients with OSA

Study	Design / setting	Sample size	Baseline characteristics (Mean ± SD)	Exposure / control	Outcome(s)	Findings
Nguyen et al, 84 2010	Prospective cohort/ Sleep clinic (France).	148	Age (years) 54.8 ± 11.8 BMI (kg/m2) 29.1 ± 6.3 AHI (#/hr) 39.0 ± 21.3	High (ISI ≥15) vs. low (ISI < 15) insomnia groups	CPAP use at 1 and 6 months	Insomnia groups did not predict CPAP use or CPAP cessation rates
Wickwire et al, 33 2010	Retrospective cohort /Sleep clinic (USA.)	232	Age 53.6 ± 12.4 BMI 43.4 ± 7.7 AHI 41.8 ± 27.7	Initial (DIS), middle (DMS), and early morning insomnia (EMA) via self-report	CPAP use: average hours/night, and Adherence: ≥ 4 h/night CPAP use in 70% of the nights in the last 4 weeks	Prevalence: DMS (23.7%), EMA (20.6%), DIS (16.6%). DMS associated with a 12 mins/night lower CPAP use and 19% lower adherence (Odds ratio 0.81)
Bjornsdottir et al, 34 2013	Prospective cohort /University hospital (Iceland)	705	Age 54.9 ± 10.2 BMI 33.7 ± 5.6 AHI 45.5 ± 20.5	DIS, DMS, EMA insomnia (Basic Nordic sleep questionnaire)	Adherence to PAP: • 53% APAP • 43% CPAP • 3% BiPAP • 1% ASV Change in Insomnia subtype prevalence in patients using or not using CPAP at 24 months	Prevalence of DIS, DMS and EMA Insomnia at baseline: 12.9%, 59.4% and 23.3% in PAP users and 20.8%, 59.1% and 36.6% in non PAP users. DIS insomnia at baseline predicted PAP non adherence at 24 months. DIS and EMA insomnia at baseline were less likely to adhere to PAP therapy.
Nguyen et al, 85 2013	Prospective cohort/ Sleep clinic (France)	80	Age 54.9±10.6 BMI 30.5 ± 6.0 AHI 45.0 ± 24.6	N/A. OSA patients receiving APAP therapy.	Change in ISI score from baseline to 24-months Responders: ≥ 9-point decline on ISI over 24-months	Overall ISI decreased from 14 to 8. Of the 39 with Insomnia (ISI >= 15), 51% had a decrease in ISI of ≥ 9 points from baseline to 24-months.
Pieh et al, 86 2013	Prospective cohort / Sleep center (Germany).	73	Age 55.1 ± 11.5 BMI 30.8 ± 5.0 AHI 39.2 ± 26.7	Insomnia. Regensburg Insomnia Scale (RIS.)	Parameters influencing CPAP adherence	Insomnia scores correlate with 6-month CPAP adherence: Adherence declines by 2.6 h/night per 1 SD of RIS score
Wallace et al, 87 2013	Retrospective cross-sectional / Veteran Affairs sleep clinic (USA).	248	Age 59 ± 11 years BMI 33.0 ± 5.0 AHI 40.0 ± 30.0	Factors influencing CPAP adherence	CPAP Adherence	Black race-ethnicity, insomnia symptoms, and self-efficacy associated with mean daily CPAP use. Adherence declines by 1 h/night per 10-unit ISI increase
Glidewell et al, 88 2014	Retrospective cohort/ Sleep center (USA).	68	Age 47.5 ± 12.4 BMI 32.2 ± 7.3 AHI 34.7 ± 32.2	PAP therapy	Change ISI score	Lower baseline ISI scores, higher baseline RDI and PAP use predict marked reduction of ISI scores (reduction to none/mild) on PAP therapy. 55% had persistent (moderate or worse) insomnia, exhibited 1.1 h/night lower PAP use
Wohlgemuth et al, 89 2015	Retrospective cohort/ Veteran Affairs sleep clinic (USA).	207	Age 58.4 ± 11.9 BMI 32.4 ± 5.0 AHI 40.0 ± 29.4	CPAP therapy	CPAP user profiles/subtypes Predictors of CPAP subgroup membership	Three subgroups were identified and labeled “Non-Adherers,” “Attempters,” and “Adherers” 1-unit increase in ISI score increased likelihood of being an “Attempter” by 9% (OR 1.09) and “Non-Adherer” by 16% (OR 1.16).
Eysteinsdottir et al, 90 2017	Prospective cohort / Sleep clinic (Iceland).	796	Age 54.4 ± 10.6 BMI 33.5 ± 5.7 AHI 44.9 ± 20.7	None	CPAP adherence	Initial and late insomnia predicted CPAP cessation at 1 year only in participants with BMI. < 30 kg/m2. Higher BMI., AHI and ESS predicted adherence.
Fung et al, 912016	Prospective cohort / Veteran Affairs sleep clinic (USA).	134	Age > 60 years BMI AHI < 15 /hour	CBT-I (vs. sleep education)	Changes in sleep quality (Pittsburgh Sleep Quality Index) Sleep latency, duration	CBT-I improved sleep onset latency and sleep quality regardless of presence of OSA (AHI <5 vs AHI 5 to <15 /hour)
Krakow B et al, 92 2017	Retrospective cohort/ Sleep clinic (USA)	302	Age 53.4 ± 14.2 BMI 31.6 ± 8.0 AHI 32.0 ± 28.2 “Complex insomnia”: those who “failed CPAP” due to intolerance or emergence of treatment-emergent central apneas	Advanced PAP devices (Auto BPAP/ASV)	Changes in ISI	Total weekly hours of PAP use correlated inversely with change in ISI scores. In full PAP-users (≥20 h/week, 82% of sample) ISI scores improved by 0.7, 0.9 and 0.7 standard deviations for DIS, DMS and EMA subtypes. No difference between ASV and Auto-BPAP
Sweetman A et al, 71 2017	Retrospective cohort /Sleep center (Australia)	141	Age 51.7 ± 15.7 BMI 26.3 ± 4.9 AHI 14.3 ± 8.0	CBT-I	Change in insomnia and other patient-centered outcomes at 3-mo	10-unit decline in ISI score 58-min increase in duration of sleep 19% improvement in sleep efficiency Marked improvement in stress, depressive and anxiety symptoms

Abbreviations: AHI, apnea- hypopnea index; APAP, auto positive airway pressure; ASV, Adaptive-Servo ventilator; BiPAP, bilevel positive airway pressure; BMI, body mass index; COM- ISA, comorbid insomnia and obstructive sleep apnea; DIS, difficulty initiating sleep; DMS, difficulty maintaining sleep; EMA, early morning awakening; RIS, Regensburg Insomnia Scale.

Non-adherers used CPAP for an average of 37 min nightly, used CPAP 18.2% of nights, and used CPAP for more than 4 h 6.2% of nights. Attempters used CPAP for 156 min on average, used CPAP 68.2% of nights, and used CPAP for more than 4 h 29.3% of nights. Adherers used CPAP for 392 min, used CPAP 95.4% of nights, and used CPAP for more than 4 h 86.2% of nights.

Table 2.

Recent randomized controlled trials on CBT-I and PAP therapy in patients with COMISA

Study	Sample	Characteristics	Control	Intervention(s)	Outcome(s)	Findings
Alessi et al, 722021	125	US Veterans Overall Age (years) 63.2 ± 7.1 Male 96%	5 weekly sleep education sessions delivered with CPAP use.	5 weekly CBT-I and CPAP adherence program delivered by a sleep coach.	Primary: CPAP adherence at 3-months Subjective (D from diary) and objective (A from actigraphy) measures at 3 months: SOL-D, SE-D, SE-A, WASO-D	CBT-I vs. control: 3.2 vs. 1.9 h/night CPAP use Greater improvement in SOL-D 16.2 mins SE-D 10.5% SE-A 4.4% WASO-D no difference Findings persisted at 6 months
Bjorvatn et al, 73 2018	164	Control vs. intervention Age (years) 57.0 ± 12.1 vs 55.0 ± 11.6 Male 75% vs 68% BMI 31.9 ± 5.6 vs 32.3 ± 6.0 kg/m2 AHI 24.9 ± 18.1 vs 25.6 ± 19.9 /hour	Sleep hygiene advice with CPAP	Delivered self-help CBT-I book with CPAP	Primary: Insomnia severity based on Bergen Insomnia Scale (BIS) and Insomnia Severity Index (ISI). Secondary: CPAP adherence	There was significant improvement in BIS and ISI scores in both groups, no effect of intervention compared to control. No difference in CPAP adherence.
Ong et al, 76 2020	121	Overall Age (years) 50.0 ± 13.1 Female 53% OSA severity: Mild (51, 43.2%) Moderate/severe (67, 56.8%)	CPAP only group	CBT-I prior to CPAP and CBT-I concurrently with CPAP	Primary: CPAP adherence over 90 days (≥4 h on ≥70% of nights during a 30-days) Secondary: ISI and PSQI scores and others	No differences in primary outcome between intervention groups vs control group. Significant reduction in ISI scores and improvement in PSQI scores in intervention vs. control groups. No differences between intervention groups.
Sweetman et al, 74 2019	145	Cont. vs. Interv. Age (years) ± 9.9 vs. 57.3 ± 9.9) BMI 34.5 ± 6.3 vs. ± 6.5 kg/m2 AHI 33.2 ± 19.8 vs. 35.8 ± 23.9 /hour	Treatment as usual	Four session CBT-I prior to CPAP therapy	Primary: Average CPAP adherence over 6 months Secondary: CPAP acceptance, insomnia severity, diary sleep metrics, daytime function and others	CBT-I group with 1h/night greater CPAP adherence 10% greater CPAP acceptance Significant improvement in ISI scores No differences in diary measured sleep metrics No differences in functional outcomes

Abbreviations: BIS, Bergen Insomnia Scale;; PSQI, Pittsburgh Sleep Quality Index; SE-a, sleep efficiency by 7-day actigraphy; SE-d, sleep efficiency by sleep diary; SOL-d, sleep onset latency by sleep diary; WASO-d, wake after sleep onset by sleep diary

A good sleeper is defined as a PSQI total score of less than 5 at the study end point; insomnia remission is defined as an ISI score of less than 8 at the study end point; insomnia response is defined as a decrease in the ISI score of more than 7 points from baseline to the study end point.

Alessi and colleagues⁷² compared the effect of concurrent delivery of a 5-session combined CBT-I and behavioral CPAP adherence program administered by trained sleep coaches versus a sleep education control program on insomnia symptoms and CPAP use at 6 months. The CBT-I/adherence intervention was delivered to 125 adult Veterans (96% male) with insomnia and an AHI of 15 or more per hour. Compared with sleep education alone, the CBT-I group showed a greater improvement in actigraphy-measured sleep onset latency and efficiency, a clinically significant 6-point reduction in ISI and 78- and 48- min greater adherence to CPAP therapy at the 3- and 6- month follow-ups, respectively. Notably, a study by Bjorvatn and colleagues⁷³ shows that delivery of CBT-I via a self-help book is not sufficient to derive benefits among patients with COMISA.

To determine if CBT-I administered before OSA therapy can improve outcomes, Sweetman and colleagues compared CBT-I to treatment-as-usual before positive airway pressure (PAP) therapy in 145 patients with COMISA.⁷⁴ The CBT-I group demonstrated higher PAP treatment acceptance (99% vs. 89%; p=.034), nightly adherence to PAP (61 minutes higher, p=.023), and greater improvement in insomnia at 6 months (ISI 18.5 vs. 9.0, p=.001). Notably, the authors identified a 15% increase in sleepiness the week after administering sleep restriction as part of CBT-I that returned to pretreatment levels in the subsequent weeks.⁷⁵ Thus, it may be important to inform patients that a transient worsening in sleepiness may occur, but overall, sleep deficiency will improve.

Finally, Ong and colleagues⁷⁶ conducted a 3-arm randomized controlled trial among 121 adults with COMISA comparing the timing of CBT-I and PAP initiation (PAP alone vs. CBT-I concurrent with PAP vs. CBT-I followed by PAP). Compared with PAP alone, the 2 CBT-I treatment arms reported a significantly greater decrease from baseline in insomnia severity. They had a greater percentage of participants categorized as good sleepers and remitters from insomnia. No significant differences were found between the CBT-I followed by PAP vs. concurrent CBT-I/PAP arms on any outcome measure.

In summary, CBT-I, when used with CPAP in patients with COMISA, is more efficacious than CPAP alone^74,76. Although no data support CBT-I use before versus along with PAP initiation, it is clear that treating insomnia and OSA at least concurrently is needed to improve important patient outcomes.

Owing to the limited availability of qualified CBT-I providers, sedative-hypnotics are often used in patients with COMISA.⁷⁷ There are concerns about worsening airway collapsibility in COMISA with hypnotics. Notably, however, the nonbenzodiazepine hypnotics such as eszopiclone or zolpidem do not worsen airway collapsibility among patients with non-severe OSA^78,79 In an unselected OSA population, eszopiclone also improved the effectiveness of CPAP titration and initial CPAP adherence (21% more nights and 1.1 more hours per night of CPAP use) at 6 months compared with placebo.^80,81 A notable finding from Sweetman and colleagues work is that the CBT-I group exhibited a decrease in the AHI that was 7.5 events/hour greater than in the control group, suggesting that addressing mechanisms of insomnia and improving sleep quality may also improve OSA control.²⁸ Targeting patients with OSA and low arousal threshold, which can present as insomnia and responds to nonbenzodiazepine hypnotics, may be an effective way to make therapy for COMISA more precise.⁸²

Future directions

Research is needed to elucidate the relationship between mechanisms of insomnia and respiratory events. The concept of sleep depth as measured by the ORP is promising. It may be used to investigate the interplay between sleep depth, wakefulness, and upper airway obstruction, especially during treatment with CBT-I, PAP, or both. Insomnia is a disorder of hyperarousal, yet it is unknown whether a low arousal threshold in OSA leads to insomnia or insomnia manifests with a low arousal threshold, or both. The findings of CBT-I reducing OSA severity require validation. When administered with PAP, understanding whether sedative-hypnotics improve OSA severity, sleep quality, and function in those with COMISA is needed. Importantly, whether such use of hypnotics in COMISA is safe in the long-term, especially in vulnerable populations such as the elderly and those on opioid therapy, should be addressed. Finally, data on the efficacy of other treatment combinations such as CBT-I and oral appliance or upper airway stimulation therapy can help to inform the treatment approaches for those who cannot tolerate PAP.

CIRCADIAN MISALIGNMENT IN OBSTRUCTIVE SLEEP APNEA

Circadian rhythms are patterns of behavior and physiology that follow a 24-hour cycle under the control of a self-sustaining molecular oscillator (i.e., circadian clock) that is entrained by external cues such as the solar light-dark cycle and timing of sleep-wake, eating, and exercise.⁸³ Circadian misalignment includes complex conditions that are characterized by mismatches in timing among solar day-night, the central clock, peripheral clocks, and behaviors such as sleep or feeding.⁸³ These misalignment phenomena are common in shift workers, individuals who are forced by social and occupational constraints to adhere to a schedule that does not conform to their natural chronotype (social jet lag), and during travel across time zones.

Epidemiology

To our knowledge, no studies have examined the prevalence of circadian misalignment among individuals with OSA. Recent data do suggest that a bi-directional relationship may exist between circadian misalignment and OSA and contribute to sleep deficiency in individuals who suffer from both.

Pathophysiology

Circadian changes in respiratory control and arousability across the 24-hour period may contribute to sleep apnea pathogenesis. Simulations show that circadian changes can augment sleep-induced periodic breathing, a manifestation of high loop gain, in the evening compared with daytime naps.⁹³ Using a forced desynchrony protocol, Butler and colleagues identified circadian rhythms in the frequency and duration of respiratory events in NREM sleep. At an average clock time of 22:30 (30° from dim light melatonin onset [DLMO]), the AHI was highest, and the duration of apneas and hypopneas was shortest in contrast to the average lowest AHI and longest event duration at an average clock time of 5:30 (135° from DLMO).⁹⁴ These changes may be mediated through an increase in arousal threshold, which increases from the onset to the end of a nocturnal sleep period.⁹⁵

OSA, in contrast, may lead to circadian misalignment. For example, circadian variation of oxygen saturation level that helps to synchronize key components of the molecular clock, including the Period and Clock genes,⁹⁶ is likely to be disrupted by hypoxia caused by OSA. Hypoxia lengthens the period and dampens the amplitude of circadian rhythmicity of the mammalian molecular clock. Hypoxia can also induce misalignment between peripheral clocks and between peripheral and central clock as observed in mice.^97,98 A recent multivariate analysis revealed that hypoxia-inducible factor (HIF-1) levels were associated with evening PER1 levels, suggesting HIF-1 might mediate the relationship between OSA and circadian dysfunction.⁹⁹ Notably, in a small study, treatment with CPAP did not change the expression in Clock genes in those with OSA,¹⁰⁰ suggesting that changes may not be reversible. Above studies provide glimpses of the relationships between circadian rhythms and OSA, and much remains to be elucidated.

Clinical characteristics and consequences of circadian misalignment in OSA

Patients with sleep deficiency owing to circadian misalignment in OSA may present with a delay or advance of their major sleep episode with respect to their desired sleep timing. Extreme difficulty with falling asleep at desired bedtimes and waking up at the required or desired times characterize a delayed rhythm. In contrast, the inability to stay awake during evening hours with an undesirably early wake time characterizes an advanced rhythm. Circadian misalignment can worsen excessive daytime sleepiness and depressive symptoms, common features of OSA that confer a great portion of the disability and lost quality of life associated with the disorder.^101,102 Individuals with delayed phase may also present with insomnia symptoms (inability to fall asleep at conventional evening times) with implications discussed elsewhere in this article. The assessment of circadian timing is, therefore, needed for the success of OSA treatment.

Diagnosis and Treatment

Melatonin-based measurement of the circadian phase is not practical in a clinical setting. Therefore, actigraphy accompanied by a sleep diary as part of the initial assessment of patients with OSA who present with symptoms suggestive of circadian misalignment is important. These data may help identify individuals who are most likely to benefit from a chronotherapeutic intervention, in addition to CPAP therapy.

Interventions for circadian rhythm disorders include timing of sleep-wake periods, physical activity/exercise, medications, and light therapy (the most effective circadian cue) to phase shift and/or promote sleep or wakefulness. Short amounts (30–60 minutes) of appropriately timed light therapy effectively realigns individuals’ circadian rhythm, with associated improvements in sleep duration, self-reported sleep quality, insomnia symptoms, and fatigue.¹⁰³ Light therapy is also effective in acutely decreasing sleepiness, fatigue, and increasing alertness.^104–108 Benefits of exercise are multifold in patients with OSA who also have obesity. Buxton and colleagues¹¹³ showed that acute bouts of high-intensity exercise after the DLMO can significantly delay the circadian phase. In contrast, early evening exercise before the DLMO can lead to phase advancement.^109,110 Baehr and colleagues¹¹¹ showed that combining bright light therapy and exercise can potentiate their phase-shifting effects.

Future directions

Much of this discussion is based on research in patients without OSA. This is in part due to the lack of readily applied circadian biomarkers. For example, 24-hour blood, urinary, or salivary melatonin level measurements are impractical in most settings. Developing non-invasive measures can help define the type of circadian disturbance among patients with OSA and its impact on treatment efficacy and CPAP adherence. Studies assessing the utility of treating circadian misalignment on patient-centered outcomes, such as daytime sleepiness, insomnia, and quality of life are needed.

PERIODIC LIMB MOVEMENTS OF SLEEP IN OBSTRUCTIVE SLEEP APNEA

PLMS are repetitive movements, typically in the lower extremities involving an extension of the toe and flexion of the ankle, knee, and even the hip. PLMS are often associated with a cortical arousal or an awakening.¹¹² These events can fragment and reduce the duration of sleep already compromised by OSA. Increasing evidence suggests that PLMS are associated with sympathetic activation, inflammation, endothelial dysfunction, and increased cardiovascular risk in those with OSA^113–118 However, the pathophysiology of the relationship between PLMS and OSA and its clinical implications (independent vs. synergistic effects) remain understudied, leaving uncertainty about consequences and management. PLMS often co-exist with restless leg syndrome (RLS). Because RLS is readily identified and treated independently of sleep-disordered breathing, we focus discussion below on sleep deficiency associated with PLMS in OSA.

Epidemiology

The reported prevalence of PLMS in OSA ranges widely (8 – 59%) and depends on cut-offs of AHI and PLM index (PLMI) used to define OSA and PLMS.^119–121 Similarly, the frequency of PLMS in OSA is different in sleep clinic compared to community populations. In a diverse sleep clinical cohort of 849 patients with OSA (AHI ≥ 10/hour) randomized to CPAP or sham (Apnea Positive Pressure Long-term Efficacy Study, APPLES), the prevalence of PLMS (PLMI ≥ 15/hour) was 15%.¹²² The prevalence of PLMS increases markedly with age. Among individuals 65 years or older with OSA (AHI ≥ 15/hour) in community cohorts, PLMS are observed in 52% of women and 60% of men (unpublished data from Study of Osteoporotic Fractures¹²³ and Outcomes of Sleep Disorders in Older Men Study¹²⁴ cohorts). PLMI is underestimated in those with severe OSA because PLMS are not scored when adjacent to respiratory events. Studies in sleep clinic populations show that, in individuals with OSA and PLMS, a PLMI of 15 or more per hour persists in 65 to 76% after adequate CPAP titration.^121,125 Notably, in 9 to 22% of patients with OSA free of limb movements, PLMS emerge after CPAP use,^121,125 suggesting that monitoring for PLMS as a potential cause of residual symptoms may be warranted. Risk factors include low iron stores, chronic lung, heart, and kidney disease, neurologic disorders (e.g., multiple sclerosis, Parkinson’s disease), and psychoactive substances (e.g., caffeine, antidepressants, antihistamines).

Pathophysiology

The pathophysiology of PLMS is discussed in detail elsewhere.¹²⁶ Whether PLMS contribute to the pathogenesis of OSA, are a consequence of respiratory events, or are independent but co-occurring phenomena remains to be understood. Recent studies suggest that a low arousal threshold, a causative trait of OSA, may be a potential mechanism linking PLMS and OSA, whereby the cortical and subcortical arousability observed in PLMS¹²⁷ may manifest as a low arousal threshold. In one study, 59% of individuals with OSA-PLMS exhibited a low arousal threshold compared with 20% among those with OSA alone, findings also observed in another, independent cohort.¹¹⁹In contrast, other work suggests that PLMS may be a consequence of undertreated OSA, with persistent PLMS heralding ongoing airway obstruction (elimination of hypopneas but persistent flow limitation) that improves at higher CPAP pressures.¹¹⁶ Other studies, including secondary analyses of the APPLES trial, show that PLMI after titration or 6 months of therapy did not differ between sham or in-laboratory titrated CPAP arms −4.2 ± 25.4 vs. −4.8 ± 25.0, p = .9).¹²² Similar findings in observational studies showing greater rates of PLMS emergence rather than resolution after CPAP titrations suggest that PLMS and OSA may simply co-occur.^121,125

Clinical Characteristics and Consequences of Periodic Limb Movements of Sleep in Obstructive Sleep Apnea

PLMS may manifest as repeated awakenings, unrefreshing sleep, reports of movements by a bedpartner, as well as fatigue, depression, anxiety, and RLS. Without objective testing (e.g., PSG on PAP or at-home PLMS monitors), however, one is unlikely to detect PLMS, as demographics, baseline sleep study data, and clinical history only have weak predictive value for PLMI of 15 or more per hour.¹²⁸

Evidence is accumulating that PLMS are associated with adverse consequences in OSA. These include impaired sleep quality (prolonged latency, lower efficiency, REM sleep, and sleep duration) before OSA treatment (independently of AHI) and on CPAP, identified in the APPLES study.^122,129 These changes did not translate into increased subjective or objective sleepiness, however. Notably, other daytime symptoms such as insomnia and fatigue associated with PLMS in non-OSA samples¹³⁰ (and common in OSA) were not reported in this study. Both PLMS and OSA are associated with cyclical alternating pattern. EEG subtypes related to arousals increased sympathetic activation,¹²⁶ and heart rate, and blood pressure elevations.^131,132 PLMS may potentiate each of these when associated with respiratory events.^131,132 Small studies also show that inflammation and arterial stiffness are increased in those with PLMS and OSA vs. those with OSA or PLMS alone,^114,115 suggesting synergistic effects.

PLMS are associated with increased risk of prevalent hypertension,¹³³ atrial fibrillation,¹³⁴ and incident CVD, and all-cause mortality, independently of the AHI.^135,136 Few studies, however, have addressed the potential interactive effects of PLMS and OSA. In a cohort of US Veterans, a cluster of patients with predominantly mild OSA and elevated PLMI (median of 64/h) was at an increased risk of incident diabetes (adjusted hazard ratio, 2.26; 95% confidence interval, (1.06 – 4.83)¹¹³ and CVD or death (adjusted hazard ratio of 2.36; 95% confidence interval (1.61 – 3.46)) compared with a mild cluster.¹¹⁸These findings are yet to be replicated, and the impact of therapy for OSA or PLMS on cardiovascular outcomes is unknown.

Diagnosis and Treatment

Objective monitoring is required to diagnose PLMS, and scoring criteria are defined in the American Academy of Sleep Medicine manual.¹³⁷ Other approaches to define PLMS and respiratory-related limb movements that may be more relevant in OSA have been proposed.^138–140 The ICSD defines PLMD as a PLMI of more than 15/h and the lack of another explanation for clinical or functional disturbance being observed. Current guidelines suggest treatment of PLMS in those with OSA should only be considered if they persist after treatment. This approach, however, is challenged by recent findings that in over 60% of patients with OSA and PLMS, the movements persist after adequate CPAP titration,^121,125 CPAP does not decrease PLMS severity over 6 months, and that movements are associated with impaired sleep quality.¹²² Similarly, in another study, PLMS persisted in 76% of patients with OSA and PLMS treated with CPAP (111/145), and new PLMS emerged in 11% of those with OSA on CPAP who did not have PLMS at baseline (79/716).¹⁴¹ These observations raise the question of whether PLMS and OSA should be treated in parallel, or at least monitoring for PLMS be done in those with impaired sleep quality or residual daytime symptoms after OSA therapy.

Approaches to therapy for PLMS are analogous to those for RLS. Addressing modifiable factors (e.g., insufficient sleep opportunity, iron storage deficiency, antihistamine, and caffeine use) is important before instituting pharmacotherapy (e.g., alpha-2-delta calcium channel ligands, dopamine agonists). Although it is conceptually appealing to use these therapies to improve sleep quality, to our knowledge, no study has assessed whether treatment of PLMS improves sleep or cardiovascular outcomes in OSA.

Future Directions

The key unknowns in those with OSA and PLMS include establishing causal relationships (or lack thereof) between limb movement and respiratory events. This factor is likely to be addressed by signal analysis studies examining the timing and consequences (e.g., autonomics, cortical arousability) of both events and randomized interventional trials targeting PLMS in those with OSA. Moreover, although these data suggest potential synergy between PLMS and OSA in risk of intermediate outcomes and CVD, studies aiming to establish whether the risk in OSA is modified by PLMS and in which groups (e.g., elderly, without prevalent CVD) are needed. Finally, assessing whether PLMS specific therapies improve patient-centered outcomes in OSA is a domain ripe for exploration.

SUMMARY

Sleep deficiency in patients with OSA can be captured under the domains of short sleep duration, poor quality sleep, circadian misalignment, and influenced by other sleep-related disorders. Conditions including chronic insomnia, circadian misalignment, and PLMS should be considered when evaluating sleep deficiency in patients with OSA.

KEY POINTS.

• Sleep deficiency in patients with obstructive sleep apnea includes abnormal quality, timing, and duration of sleep, and the presence of other sleep disorders.

• Obstructive sleep apnea occurring alongside insomnia is termed comorbid insomnia and obstructive sleep apnea and affects about one-third of patients with obstructive sleep apnea.

• Cognitive behavioral therapy for insomnia concurrent with the treatment of upper airway obstruction improves patient-centered outcomes in comorbid insomnia and obstructive sleep apnea.

• Despite their potential impact, the relationship between obstructive sleep apnea and circadian misalignment (pathogenesis, patient symptoms, and function) is understudied.

• Periodic limb movements of sleep are common in obstructive sleep apnea and are associated with poor sleep quality in those with obstructive sleep apnea that does not improve with positive airway pressure.

Synopsis:

Obstructive sleep apnea (OSA) is a very common disorder which is related to sleep pattern which is affecting the general population. OSA is also related to many health problems, including psychiatric, metabolic, and cardiovascular diseases such as diabetes, depression, hypertension, and stroke. It is important to note that OSA leads to daytime functioning imbalance which is due to sleep deprivation, encompassing improper duration of sleep, circadian alignment, sleep quality, and other related disorders.

CLINICS CARE POINTS.

• Patients with OSA should be assessed for symptoms of insomnia.

• Co-occurrence of OSA and insomnia (COMISA) is associated with greater daytime impairments, poorer physical, and mental health outcomes.

• Treating insomnia concurrently with OSA in patients with COMISA improves patient-centered outcomes (CPAP adherence and daytime function).

• Clinical trials examining concurrent treatment of periodic limb movements or circadian misalignment in patients with OSA do not exist. However, addressing these sources of sleep deficiency, independently of OSA, may help ameliorate sleep deficiency in OSA patients.