Association of Hypoglossal Nerve Stimulation With Improvements in Long-term, Patient-Reported Outcomes and Comparison With Positive Airway Pressure for Patients With Obstructive Sleep Apnea.

Importance: Hypoglossal nerve stimulation (HNS) and positive airway pressure (PAP) have been shown to improve patient-reported outcomes (PROs) in obstructive sleep apnea (OSA). However, to our knowledge, there are no data that compare change in PROs between HNS and PAP or that indicate whether HNS improves comorbid insomnia or depression in the long term. Objectives: To determine whether HNS is associated with improvements in patient-reported sleepiness, insomnia, and depression in the long term and to compare the respective associations of HNS and PAP with improved PROs. Design, Setting, and Participants: This retrospective cohort study used data from patients treated at the Cleveland Clinic for OSA. Participants received either HNS (referred sample) from November 1, 2015, to September 31, 2018, or PAP (previous cohort) from January 1, 2010, to December 31, 2014, for OSA. Patients were matched 3:1 for PAP:HNS based on age, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), sex, and apnea hypopnea index (AHI). Data were collected at baseline and at prespecified follow-up points. Data were analyzed from March 26, 2020, to September 9, 2021. Exposures: Treatment with HNS vs PAP. Main Outcomes and Measures: Data collected included AHI and Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), Insomnia Severity Index (ISI), and Patient Health Questionnaire-9 (PHQ-9; depression) scores. Results: Among 85 patients receiving HNS (mean [SD] age, 62.8 [9.5] years; 59 men [69.4%]; 77 White patients [90.6%]; mean [SD] BMI, 28.8 [3.1]), compared with 217 matched patients receiving PAP (mean [SD] age, 62.1 [9.9] years; 157 men [72.4%]; 173 White patients [81.2%]; mean [SD] BMI, 29.5 [3.1]) included in the analysis, significant improvements were seen in PHQ-9 scores for HNS vs PAP (least square means, -4.06 [95% CI, -5.34 to -2.79] vs -2.58 [95% CI, -3.35 to -1.82]; mean difference, -1.48 [95% CI, -2.78 to -0.19]) with comparable improvements in ESS, FOSQ, and ISI scores. Clinically meaningful differences were observed in 42 of 65 HNS group patients (64.6%) vs 118 PAP group patients (54.5%) for ESS scores, 29 of 49 HNS group patients (59.2%) vs 67 of 217 PAP group patients (30.9%) for FOSQ scores, 14 of 48 HNS group patients (29.2%) vs 53 of 217 PAP group patients (24.4%) for PHQ-9 scores, and 23 of 49 HNS group patients (46.9%) vs 79 of 217 PAP group patients (36.4%) for ISI scores. At the 1-year post-HNS assessment, meaningful improvements were seen in 17 of 28 patients (60.7%) for ESS scores, 11 of 20 patients (55.0%) for FOSQ scores, 7 of 23 patients (30.4%) for PHQ-9 scores, and 11 of 25 patients (44.0%) for ISI scores. Conclusions and Relevance: In this cohort study of patients with OSA, sustained improvements in PROs were observed 1 year after HNS and were comparable to those for PAP at 3 months. These findings suggest that HNS is a viable treatment for improving insomnia and depression in patients with OSA.

Evaluation of Surgical Learning Curve Effect on Obstructive Sleep Apnea Outcomes in Upper Airway Stimulation.

OBJECTIVE: An increasing number of facilities offer Upper Airway Stimulation (UAS) with varying levels of experience. The goal was to quantify whether a surgical learning curve exists in operative or sleep outcomes in UAS. METHODS: International multi-center retrospective review of the ADHERE registry, a prospective international multi-center study collecting UAS outcomes. ADHERE registry centers with at least 20 implants and outcomes data through at least 6-month follow-up were reviewed. Cases were divided into two groups based on implant order (the first 10 or second 10 consecutive implants at a given site). Group differences were assessed using Mann-Whitney U-tests, Chi-squared tests, or Fisher's Exact tests, as appropriate. A Mann-Kendall trend test was used to detect if there was a monotonic trend in operative time. Sleep outcome equivalence between experience groups was assessed using the two one-sided tests approach. RESULTS: Thirteen facilities met inclusion criteria, contributing 260 patients. Complication rates did not significantly differ between groups (P = .808). Operative time exhibited a significant downward trend (P < .001), with the median operative time dropping from 150 minutes for the first 10 implants to 134 minutes for the subsequent 10 implants. The decrease in AHI from baseline to 12-month follow-up was equivalent between the first and second ten (22.8 vs 21.2 events/hour, respectively, P < .001). Similarly, the first and second ten groups had equivalent ESS decreases at 6 months (2.0 vs 2.0, respectively, P < .001). ESS outcomes remained equivalent for those with data through 12-months. CONCLUSIONS: Across the centers' first 20 implants, an approximately 11% reduction operative time was identified, however, no learning curve effect was seen for 6-month or 12-month AHI or ESS over the first twenty implants. Ongoing monitoring through the ADHERE registry will help measure the impact of evolving provider and patient specific characteristics as the number of implant centers increases.

Upper Airway Stimulation versus Untreated Comparators in Positive Airway Pressure Treatment-Refractory Obstructive Sleep Apnea.

Rationale: Understand the impact of insurance coverage on sleep apnea outcomes for patients awaiting upper airway stimulation.Objectives: Examine the natural history of impact of upper airway stimulation treatment versus insurance denial (comparators) on sleep apnea outcomes.Methods: A parallel-arm experimental study design was used to compare objective sleep apnea measures and patient-reported outcomes in those who received upper airway stimulation approval versus denial in a multinational prospective study (NCT02907398). Wilcoxon rank-sum test and logistic regression models were used to assess for differences of objective and subjective outcome changes in those who underwent upper airway stimulation versus no treatment comparators.Results: A greater reduction in apnea-hypopnea index was observed in those who underwent upper airway stimulation (n = 230, follow-up: 360 ± 171 d) versus no treatment (n = 100, follow-up: 272 ± 278 d), that is, -19.1 ± 15.8 versus -8.1 ± 20.9, respectively, P < 0.001, with consistent findings observed with nocturnal hypoxia measures. Concordantly, a greater improvement noted with subjective measures of dozing propensity was observed in patients undergoing upper airway stimulation versus comparators (Epworth Score, -5.1 ± 5.5 vs. 1.8 ± 3.7, respectively, P < 0.001) and overall sleep-related patient-reported outcomes. Women and those with previous oral appliance use had a lower odds of insurance approval (odds ratio [OR], 0.40; 95% confidence interval [95% CI], 0.22-0.71 and OR, 0.35; 95% CI, 0.18-0.69, respectively).Conclusions: Objective and subjective sleep apnea burden was more improved in those receiving upper airway stimulation versus not. Results underscore the need to optimize clinical care pathways focused on effective treatment of patients with obstructive sleep apnea who are not upper airway stimulation-insurance eligible and prioritize public health policy initiatives to address insurance-based sex-specific disparities.

Upper Airway Stimulation vs Positive Airway Pressure Impact on BP and Sleepiness Symptoms in OSA.

BACKGROUND: Positive airway pressure (PAP) and upper airway stimulation (UAS) are approved OSA treatment options. Although the effect of PAP on improvement in BP and daytime sleepiness (defined according to the Epworth Sleepiness Scale [ESS]) has been established, the impact of UAS on BP remains unclear. This study hypothesized that PAP and UAS will confer improvements in BP and daytime sleepiness. METHODS: Clinic-based BP and ESS scores were compared between 517 patients with OSA (apnea-hypopnea index, 15-65) and BMI ≤ 35 kg/m2 initiating PAP therapy (2010-2014) at the Cleveland Clinic and 320 patients with UAS implantation (2015-2017) via an international registry with 2- to 6-month follow-up. Mixed effect models were used to compare outcomes in 201 patients in each arm following propensity matching. RESULTS: PAP showed greater improvement in diastolic BP (mean difference of change between groups, 3.7 mm Hg; P < .001) and mean arterial pressure (mean difference of change between groups, 2.8 mm Hg; P = .008) compared with UAS. UAS showed greater improvement in ESS scores vs PAP (mean difference of change between PAP and UAS groups, -0.8; P = .046). UAS therapy usage was 6.2 h/week greater than PAP-treated patients (95% CI, 3.3-9.0). Results were consistent following adjustment for therapy adherence. CONCLUSIONS: PAP showed greater improvement in BP, potentially reflecting an enhanced ability of PAP to exert beneficial mechanical intrathoracic cardiac and vascular influences. BP measurement error in the UAS group may also have accounted for findings. Greater improvement in sleepiness symptoms was noted with UAS compared with PAP.

Results of the ADHERE upper airway stimulation registry and predictors of therapy efficacy.

OBJECTIVE/HYPOTHESIS: The ADHERE Registry is a multicenter prospective observational study following outcomes of upper airway stimulation (UAS) therapy in patients who have failed continuous positive airway pressure therapy for obstructive sleep apnea (OSA). The aim of this registry and purpose of this article were to examine the outcomes of patients receiving UAS for treatment of OSA. STUDY DESIGN: Cohort Study. METHODS: Demographic and sleep study data collection occurred at baseline, implantation visit, post-titration (6 months), and final visit (12 months). Patient and physician reported outcomes were also collected. Post hoc univariate and multivariate analysis was used to identify predictors of therapy response, defined as ≥50% decrease in Apnea-Hypopnea Index (AHI) and AHI ≤20 at the 12-month visit. RESULTS: The registry has enrolled 1,017 patients from October 2016 through February 2019. Thus far, 640 patients have completed their 6-month follow-up and 382 have completed the 12-month follow-up. After 12 months, median AHI was reduced from 32.8 (interquartile range [IQR], 23.6-45.0) to 9.5 (IQR, 4.0-18.5); mean, 35.8 ± 15.4 to 14.2 ± 15.0, P < .0001. Epworth Sleepiness Scale was similarly improved from 11.0 (IQR, 7-16) to 7.0 (IQR, 4-11); mean, 11.4 ± 5.6 to 7.2 ± 4.8, P < .0001. Therapy usage was 5.6 ± 2.1 hours per night after 12 months. In a multivariate model, only female sex and lower baseline body mass index remained as significant predictors of therapy response. CONCLUSIONS: Across a multi-institutional study, UAS therapy continues to show significant improvement in subjective and objective OSA outcomes. This analysis shows that the therapy effect is durable and adherence is high. LEVEL OF EVIDENCE: 2 Laryngoscope, 130:1333-1338, 2020.

Alternative interventions for obstructive sleep apnea.

Positive airway pressure (PAP) therapy is the gold standard treatment for patients with obstructive sleep apnea (OSA) and has been shown to positively impact quality of life and cardiovascular outcomes. However, not all patients with OSA can use or tolerate PAP therapy. Alternative interventions to PAP include lifestyle measures, surgical interventions, hypoglossal nerve stimulation, oral appliance therapy, and expiratory PAP devices for OSA. While these alternative interventions may benefit patients and have demonstrated improvements in OSA and quality-of-life measures, the cardiovascular impact of these interventions is uncertain as data are limited.

Clinical neurophysiology of apnea.

Understanding the clinical neurophysiology of apnea generation encompasses discussion of the neuroanatomic aspects of central respiratory rhythm and pattern generation, including the central respiratory control networks, central and peripheral chemoreceptors, mechanisms of respiratory muscles, and sleep state dependent differences. Anatomical and functional links to apnea also involve central respiratory motor output recruited from the hypoglossal nerve, which has led to novel treatments for obstructive sleep apnea. Autonomic fluctuations occur in relation to sleep-wake and sleep states (i.e., REM vs NREM sleep), with both parasympathetic and sympathetic contributions. Finally, our understanding of the pathophysiology of obstructive sleep apnea now includes concepts of critical closing pressure of the upper airway, increased loop gain as reflected by high responsiveness to external perturbations, inadequate responsiveness of upper airway muscle recruitment, and reductions in arousal threshold leading to ventilatory instability. In turn, these concepts have led to the development of novel therapies such as hypoglossal nerve stimulation and targeting key culprit physiologic mechanisms specific to the individual.

Previous Surgery and Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

OBJECTIVE: To examine whether previous palate or hypopharyngeal surgery was associated with efficacy of treatment of obstructive sleep apnea with hypoglossal nerve stimulation. STUDY DESIGN: Cohort (retrospective and prospective). SETTING: Eleven academic medical centers. SUBJECTS AND METHODS: Adults treated with hypoglossal nerve stimulation were enrolled in the ADHERE Registry. Outcomes were defined by the apnea-hypopnea index (AHI), in 3 ways: change in the AHI and 2 definitions of therapy response requiring ≥50% reduction in the AHI to a level <20 events/h (Response20) or 15 events/h (Response15). Previous palate and hypopharyngeal (tongue, epiglottis, or maxillofacial) procedures were documented. Linear and logistic regression examined the association between previous palate or hypopharyngeal surgery and outcomes, with adjustment for age, sex, and body mass index. RESULTS: The majority (73%, 217 of 299) had no previous palate or hypopharyngeal surgery, while 25% and 9% had previous palate or hypopharyngeal surgery, respectively, including 6% with previous palate and hypopharyngeal surgery. Baseline AHI (36.0 ± 15.6 events/h) decreased to 12.0 ± 13.3 at therapy titration (P < .001) and 11.4 ± 12.6 at final follow-up (P < .001). Any previous surgery, previous palate surgery, and previous hypopharyngeal surgery were not clearly associated with treatment response; for example, any previous surgery was associated with a 0.69 (95% CI: 0.37, 1.27) odds of response (Response20 measure) at therapy titration and a 0.55 (95% CI: 0.22, 1.34) odds of response (Response20 measure) at final follow-up. CONCLUSION: Previous upper airway surgery was not clearly associated with efficacy of hypoglossal nerve stimulation.

Uvulopalatopharyngoplasty vs CN XII stimulation for treatment of obstructive sleep apnea: A single institution experience.

OBJECTIVES: Hypoglossal nerve stimulation (HNS) therapy is an emerging surgical treatment for select patients with obstructive sleep apnea (OSA). This study aims to compare outcomes in patients with moderate to severe OSA who underwent HNS surgery (Inspire Medical Systems) and those who underwent traditional airway reconstructive surgery, specifically uvulopalatopharyngoplasty (UPPP). METHODS: Patients who underwent HNS implantation (n = 20), all with moderate to severe OSA, inability to adhere to positive pressure therapy, and compliant with previously published inclusion criteria, were compared to a historical cohort that were intolerant of CPAP with similar inclusion criteria who all underwent UPPP (n = 20) with some also undergoing additional procedures such as septoplasty/turbinate reduction. Data including body mass index (BMI), pre- and post-implant apnea-hypopnea index (AHI) were assessed. RESULTS: For patients who underwent HNS, mean preoperative BMI was 28.0. Mean AHI decreased significantly from 38.9 ±â€¯12.5 to 4.5 ±â€¯4.8. All patients achieved an AHI < 20 post implant with 65% (13/20) with an AHI ≤ 5. For patients who underwent traditional airway surgery, mean preoperative BMI was 27.5; mean AHI decreased from 40.3 ±â€¯12.4 to 28.8 ±â€¯25.4. CONCLUSION: While both traditional surgery and HNS are effective treatments for patients with moderate to severe OSA with CPAP intolerance, our study demonstrates that HNS is "curative" in normalizing the AHI to <5 in the majority of patients. For select patients, HNS therapy provides excellent objective improvement in outcome measures.

Sleep-Disordered Breathing.

PURPOSE OF REVIEW: Sleep-disordered breathing encompasses a broad spectrum of sleep-related breathing disorders, including obstructive sleep apnea (OSA), central sleep apnea, as well as sleep-related hypoventilation and hypoxemia. Diagnostic criteria have been updated in the International Classification of Sleep Disorders, Third Edition and the American Academy of Sleep Medicine Manual for Scoring Sleep and Associated Events. Neurologic providers should have basic knowledge and skills to identify at-risk patients, as these disorders are associated with substantial morbidity, the treatment of which is largely reversible. RECENT FINDINGS: OSA is the most common form of sleep-disordered breathing and is highly prevalent and grossly underdiagnosed. Recent studies suggest that prevalence rates in patients with neurologic disorders including epilepsy and stroke exceed general population estimates. The physiologic changes that occur in OSA are vast and involve complex mechanisms that play a role in the pathogenesis of cardiovascular and metabolic disorders and, although largely unproven, likely impact brain health and disease progression in neurologic patients. A tailored sleep history and examination as well as validated screening instruments are effective in identifying patients with sleep-disordered breathing, although sleep testing is necessary for diagnostic confirmation. While continuous positive airway pressure therapy and other forms of noninvasive positive pressure ventilation remain gold standard treatments, newer therapies, including mandibular advancement, oral appliance devices, and hypoglossal nerve stimulation, have become available. Emerging evidence of the beneficial effects of treatment of sleep-disordered breathing on neurologic outcomes underscores the importance of sleep education and awareness for neurologic providers. SUMMARY: Sleep-disordered breathing is highly prevalent and grossly underrecognized. The adverse medical and psychosocial consequences of OSA and other sleep-related breathing disorders are considerable. The impact of sleep therapies on highly prevalent neurologic disorders associated with substantial morbidity and health care costs is becoming increasingly recognized.