Model-based analysis of implanted hypoglossal nerve stimulation for the treatment of obstructive sleep apnea.

STUDY OBJECTIVES: Individuals with obstructive sleep apnea (OSA), characterized by frequent sleep disruptions from tongue muscle relaxation and airway blockage, are known to benefit from on-demand electrical stimulation of the hypoglossal nerve. Hypoglossal nerve stimulation (HNS) therapy, which activates the protrusor muscles of the tongue during inspiration, has been established in multiple clinical studies as safe and effective, but the mechanistic understanding for why some stimulation parameters work better than others has not been thoroughly investigated. METHODS: In this study, we developed a detailed biophysical model that can predict the spatial recruitment of hypoglossal nerve fascicles and axons within these fascicles during stimulation through nerve cuff electrodes. Using this model, three HNS programming scenarios were investigated including grouped cathode (---), single cathode (o-o), and guarded cathode bipolar (+-+) electrode configurations. RESULTS: Regardless of electrode configuration, nearly all hypoglossal nerve axons circumscribed by the nerve cuff were recruited for stimulation amplitudes <3 V. Within this range, monopolar configurations required lower stimulation amplitudes than the guarded bipolar configuration to elicit action potentials within hypoglossal nerve axons. Further, the spatial distribution of the activated axons was more uniform for monopolar versus guarded bipolar configurations. CONCLUSIONS: The computational models predicted that monopolar HNS provided the lowest threshold and the least sensitivity to rotational angle of the nerve cuff around the hypoglossal nerve; however, this setting also increased the likelihood for current leakage outside the nerve cuff, which could potentially activate axons in unintended branches of the hypoglossal nerve. CLINICAL TRIAL REGISTRATION: NCT01161420.

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.

Endotypic Mechanisms of Successful Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

Rationale: Approximately one-third of patients with obstructive sleep apnea (OSA) treated with hypoglossal nerve stimulation (HGNS) therapy are incomplete responders, despite careful patient selection based on baseline characteristics and drug-induced sleep endoscopy.Objectives: Here we use polysomnographic endotyping to assess the pathophysiological mechanisms underlying favorable versus incomplete responses to HGNS therapy.Methods: Baseline polysomnography data of the STAR (Stimulation Therapy for Apnea Reduction) trial were included. Raw baseline polysomnographic data from 91/126 patients were available for analysis. Traits-loop gain, arousal threshold, collapsibility, and muscle compensation-were calculated from the baseline polysomnography data according to Sands and colleagues (AJRCCM 2018, SLEEP 2018). Logistic regression assessed apnea-hypopnea index (AHI)-adjusted associations between HGNS response (>50% reduction in AHI to <10/h at 1 yr) and OSA traits.Measurements and Main Results: Overall, HGNS treatment reduced AHI from 30.7 (24.9-39.9) to 8.5 (4.0-19.5) events/h (P < 0.0001; median [quartiles 1-3]); N = 53/91 were responders. In adjusted analysis, a favorable response to therapy was independently associated with higher arousal threshold (odds ratio [95% confidence interval]: 6.76 [2.44-23.3], P = 0.001), greater compensation (odds ratio: 4.22 [1.70-12.55] per SD, P = 0.004), and lower loop gain (in milder collapsibility, per significant interaction, P = 0.003). The higher arousal threshold was evident in responders before adjusted analysis. Predicted responders had an approximately fourfold lower treatment AHI versus predicted nonresponders (4.9 [2.7-8.5] vs. 20.7 [10.9-29.7], P < 0.0001; median [quartiles 1-3]); differences remained significant after cross-validation.Conclusions: Favorable responses to HGNS therapy are associated with the pathophysiological traits causing OSA, particularly a higher arousal threshold. Along with established criteria, individuals with favorable traits could potentially be prioritized for precision HGNS therapy.This analysis was a secondary analysis of the STAR trial registered with clinicaltrials.gov (NCT01161420).

Hypoglossal nerve stimulation in a rabbit model of obstructive sleep apnea reduces apneas and improves oxygenation.

Based on a prior anesthetized model, we developed an unanesthetized model to evaluate the effects of hypoglossal nerve stimulation (HNS) during sleep. We prepared three rabbits with injections of hyaluronic acid in the base of tongue to produce upper airway obstruction followed by HNS implant. Two rabbits were saline controls, and one, a passive control. Measures were sleep, airflow, effort, oxygen saturation, and heart rate. HNS with electrodes around the right hypoglossal nerve were adjusted to a level without behaviorally disturbing the animal. During HNS stimulation in the tongue-base injected rabbits, obstructive apneas and hypopneas of intermediate (3 to 7 cycles of respiratory effort) or longer (≥8 cycles) duration were largely eliminated while less clinically relevant shorter events (<3) were unaffected, and oxygen saturation was improved. Control animals exhibited no intermediate or long events. In this model HNS can relieve induced sleep apnea, without disturbing the animal: however, despite being non-canine and of substantial size, the model has its challenges.NEW & NOTEWORTHY This report describes a rabbit model for testing the impact of hypoglossal nerve stimulation (HNS) on obstructive apneas. Obstructive sleep apnea (OSA) is induced by injecting hyaluronic acid (as a filler) into the base of the tongue. HNS reduced the length and rate of obstructions and improved oxygenation during sleep. Our efforts with this model advanced understanding of the complexities of this OSA preclinical model for neurostimulation reversal of sleep-disordered breathing.

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.

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.

Post-approval upper airway stimulation predictors of treatment effectiveness in the ADHERE registry.

Upper airway stimulation (UAS) has been shown to reduce severity of obstructive sleep apnoea. The aim of this study was to identify predictors of UAS therapy response in an international multicentre registry.Patients who underwent UAS implantation in the United States and Germany were enrolled in an observational registry. Data collected included patient characteristics, apnoea/hypopnoea index (AHI), Epworth sleepiness scale (ESS), objective adherence, adverse events and patient satisfaction measures. Post hoc univariate and multiple logistic regression were performed to evaluate factors associated with treatment success.Between October 2016 and January 2018, 508 participants were enrolled from 14 centres. Median AHI was reduced from 34 to 7 events·h-1, median ESS reduced from 12 to 7 from baseline to final visit at 12-month post-implant. In post hoc analyses, for each 1-year increase in age, there was a 4% increase in odds of treatment success. For each 1-unit increase in body mass index (BMI), there was 9% reduced odds of treatment success. In the multivariable model, age persisted in serving as statistically significant predictor of treatment success.In a large multicentre international registry, UAS is an effective treatment option with high patient satisfaction and low adverse events. Increasing age and reduced BMI are predictors of treatment response.

Upper Airway Stimulation for Obstructive Sleep Apnea: Results from the ADHERE Registry.

Objective Upper airway stimulation (UAS) is an alternative treatment option for patients unable to tolerate continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnea (OSA). Studies support the safety and efficacy of this therapy. The aim of this registry is to collect retrospective and prospective objective and subjective outcome measures across multiple institutions in the United States and Germany. To date, it represents the largest cohort of patients studied with this therapy. Study Design Retrospective and prospective registry study. Setting Ten tertiary care hospitals in the United States and Germany. Subjects and Methods Patients were included who had moderate to severe OSA, were intolerant to CPAP, and were undergoing UAS implantation. Baseline demographic and sleep study data were collected. Objective and subjective treatment outcomes, adverse events, and patient and physician satisfaction were reviewed. Results The registry enrolled 301 patients between October 2016 and September 2017. Mean ± SD AHI decreased from 35.6 ± 15.3 to 10.2 ± 12.9 events per hour ( P < .0001), and Epworth Sleepiness Scale scores decreased from 11.9 ± 5.5 to 7.5 ± 4.7 ( P < .0001) from baseline to the posttitration visit. Patients utilized therapy for 6.5 hours per night. There were low rates of procedure- and device-related complications. Clinical global impression scores demonstrated that the majority of physicians (94%) saw improvement in their patients' symptoms with therapy. The majority of patients (90%) were more satisfied with UAS than CPAP. Conclusions Across a multi-institutional registry, UAS therapy demonstrates significant improvement in subjective and objective OSA outcomes, good therapy adherence, and high patient satisfaction.

Upper Airway Stimulation for Obstructive Sleep Apnea: 5-Year Outcomes.

Objective To present 5-year outcomes from a prospective cohort of patients with obstructive sleep apnea (OSA) who were treated with upper airway stimulation (UAS) via a unilateral hypoglossal nerve implant. Study Design A multicenter prospective cohort study. Setting Industry-supported multicenter academic and clinical trial. Methods From a cohort of 126 patients, 97 completed protocol, and 71 consented to a voluntary polysomnogram. Those having continuous positive airway pressure failure with moderate to severe OSA, body mass index <32 kg/m2, and no unfavorable collapse on drug-induced sleep endoscopy were enrolled in a phase 3 trial. Prospective outcomes included apnea-hypopnea index (AHI), oxygen desaturation index, and adverse events, as well as measures of sleepiness, quality of life, and snoring. Results Patients who did and did not complete the protocol differed in baseline AHI, oxygen desaturation index, and Functional Outcomes of Sleep Questionnaire scores but not in any other demographics or treatment response measures. Improvement in sleepiness (Epworth Sleepiness Scale) and quality of life was observed, with normalization of scores increasing from 33% to 78% and 15% to 67%, respectively. AHI response rate (AHI <20 events per hour and >50% reduction) was 75% (n = 71). When a last observation carried forward analysis was applied, the responder rate was 63% at 5 years. Serious device-related events all related to lead/device adjustments were reported in 6% of patients. Conclusions Improvements in sleepiness, quality of life, and respiratory outcomes are observed with 5 years of UAS. Serious adverse events are uncommon. UAS is a nonanatomic surgical treatment with long-term benefit for individuals with moderate to severe OSA who have failed nasal continuous positive airway pressure.

Proteomic profiling of the hypothalamus in two mouse models of narcolepsy.

Narcolepsy is a disabling neurological disorder of sleepiness linked to the loss of neurons producing orexin neuropeptides in the hypothalamus. Two well-characterized phenotypic mouse models of narcolepsy, loss-of-function (orexin-knockout), and progressive loss of orexin (orexin/ataxin-3) exist. The open question is whether the proteomics signatures of the hypothalamus would be different between the two models. To address this gap, we utilized a label-free proteomics approach and conducted a hypothalamic proteome analysis by comparing each disease model to that of wild type. Following data processing and statistical analysis, 14 484 peptides mapping to 2282 nonredundant proteins were identified, of which 39 proteins showed significant differences in protein expression across groups. Altered proteins in both models showed commonalties in pathways for mitochondrial dysfunction and neuronal degeneration, as well as altered proteins related to inflammatory demyelination, insulin resistance, metabolic responses, and the dopaminergic and monoaminergic systems. Model-specific alterations in insulin degraded enzyme (IDE) and synaptosomal-associated protein-25 were unique to orexin-KO and orexin/ataxin-3, respectively. For both models, proteomics not only identified clinically suspected consequences of orexin loss on energy homeostasis and neurotransmitter systems, but also identified commonalities in inflammation and degeneration despite the entirely different genetic basis of the two mouse models.

Upper Airway Stimulation for Obstructive Sleep Apnea: Patient-Reported Outcomes after 48 Months of Follow-up.

Objective To assess patient-based outcomes of participants in a large cohort study-the STAR trial (Stimulation Therapy for Apnea Reduction)-48 months after implantation with an upper airway stimulation system for moderate to severe obstructive sleep apnea. Study Design A multicenter prospective cohort study. Setting Industry-supported multicenter academic and clinical setting. Subjects Participants (n = 91) at 48 months from a cohort of 126 implanted participants. Methods A total of 126 participants received an implanted upper airway stimulation system in a prospective phase III trial. Patient-reported outcomes at 48 months, including Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), and snoring level, were compared with preimplantation baseline. Results A total of 91 subjects completed the 48-month visit. Daytime sleepiness as measured by ESS was significantly reduced ( P = .01), and sleep-related quality of life as measured by FOSQ significantly improved ( P = .01) when compared with baseline. Soft to no snoring was reported by 85% of bed partners. Two patients required additional surgery without complication for lead malfunction. Conclusion Upper airway stimulation maintained a sustained benefit on patient-reported outcomes (ESS, FOSQ, snoring) at 48 months in select patients with moderate to severe obstructive sleep apnea.

Sonographic evaluation of tongue motions during upper airway stimulation for obstructive sleep apnea-a pilot study.

INTRODUCTION: The objective was to evaluate the feasibility of sonographic evaluation of functional tongue motion as a tool to evaluate postoperative outcomes in human subjects using breathing-synchronized stimulation of the hypoglossal nerve-a novel therapy option for patients with obstructive sleep apnea (OSA). MATERIAL AND METHODS: Sixteen patients with OSA (n = 16, age 60.4 ± 10.2, BMI 28.7 ± 2.4, AHI 35.0 ± 11.8) underwent sonographic evaluation of tongue motion after initiation of therapy with the Inspire II Upper Airway Stimulation system. Sonographic examination was performed in four different planes (A = floor of the mouth frontal, B = base of the tongue horizontal, C = floor of the mouth parallel to mandible, and D = floor of the mouth median sagittal) in an attempt to visualize tongue surface, tongue and hyoid motion, and the distance of protrusion. RESULTS: Identification of the tongue surface was achieved in all cases in planes B, C, and D and 81 % of patients in plane A. Tongue motion was evident on the right (implant) side in 63 % in plane A and 75 % in plane B. Distance of protrusion was measured in plane B at 1.04 cm (±0.51), in plane C at 1.08 cm (±0.47), and in plane D at 0.96 cm (±0.45). Hyoid protrusion was measured in plane C or D and was 0.57 cm (±0.39). Significant correlations among the three planes were observed, but there was no correlation to the reduction of apnea-hypopnea index. CONCLUSION: The results indicate feasibility of sonography to identify tongue and hyoid motions during upper airway stimulation. Useful sonographic planes and landmarks, which allow visualization of dynamic effects of upper airway stimulation, could be established. The evaluation of the tongue in a horizontal (B) and in a sagittal plane (D) appears to be superior to the other investigated planes. The approximate tongue protrusion needed to generate a significant reduction of AHI and ODI was 1 cm.

High-altitude Pulmonary Hypertension: an Update on Disease Pathogenesis and Management.

High-altitude pulmonary hypertension (HAPH) affects individuals residing at altitudes of 2,500 meters and higher. Numerous pathogenic variables play a role in disease inception and progression and include low oxygen concentration in inspired air, vasculopathy, and metabolic abnormalities. Since HAPH affects only some people living at high altitude genetic factors play a significant role in its pathogenesis. The clinical presentation of HAPH is nonspecific and includes fatigue, shortness of breath, cognitive deficits, cough, and in advanced cases hepatosplenomegaly and overt right-sided heart failure. A thorough history is important and should include a search for additional risk factors for lung disease and pulmonary hypertension (PH) such as smoking, indoor air pollution, left-sided cardiac disease and sleep disordered breathing. Twelve-lead electrocardiogram, chest X-ray and echocardiography can be used as screening tools. A definitive diagnosis should be made with right-sided heart catheterization using a modified mean pulmonary artery pressure of at least 30 mm Hg, differing from the 25 mm Hg used for other types of PH. Treatment of HAPH includes descent to a lower altitude whenever possible, oxygen therapy and the use of medications such as endothelin receptor antagonists, phosphodiesterase 5 blockers, fasudil and acetazolamide. Some recent evidence suggests that iron supplementation may also be beneficial. However, it is important to note that the scientific literature lacks long-term randomized controlled data on the pharmacologic treatment of HAPH. Thus, an individualized approach to treatment and informing the patients regarding the benefits and risks of the selected treatment regimen are essential.

Upper Airway Stimulation for Obstructive Sleep Apnea: Self-Reported Outcomes at 24 Months.

OBJECTIVES: To evaluate the long-term (24-mo) effect of cranial nerve upper airway stimulation (UAS) therapy on patient-centered obstructive sleep apnea (OSA) outcome measures. METHODS: Prospective, multicenter, cohort study of 126 patients with moderate to severe OSA who had difficulty adhering to positive pressure therapy and received the surgically implanted UAS system. Outcomes were measured at baseline and postoperatively at 12 mo and 24 mo, and included self- and bedpartner-report of snoring intensity, Epworth Sleepiness Scale (ESS), and Functional Outcomes of Sleep Questionnaire (FOSQ). Additional analysis included FOSQ subscales, FOSQ-10, and treatment effect size. RESULTS: Significant improvement in mean FOSQ score was observed from baseline (14.3) to 12 mo (17.3), and the effect was maintained at 24 mo (17.2). Similar improvements and maintenance of effect were seen with all FOSQ subscales and FOSQ-10. Subjective daytime sleepiness, as measured by mean ESS, improved significantly from baseline (11.6) to 12 mo (7.0) and 24 mo (7.1). Self-reported snoring severity showed increased percentage of "no" or "soft" snoring from 22% at baseline to 88% at 12 mo and 91% at 24 mo. UAS demonstrated large effect size (> 0.8) at 12 and 24 mo for overall ESS and FOSQ measures, and the effect size compared favorably to previously published effect size with other sleep apnea treatments. CONCLUSIONS: In a selected group of patients with moderate to severe OSA and body mass index ≤ 32 kg/m2, hypoglossal cranial nerve stimulation therapy can provide significant improvement in important sleep related quality-of-life outcome measures and the effect is maintained across a 2-y follow-up period.

Three-Year Outcomes of Cranial Nerve Stimulation for Obstructive Sleep Apnea: The STAR Trial.

OBJECTIVE: To describe the 36-month clinical and polysomnography (PSG) outcomes in an obstructive sleep apnea (OSA) cohort treated with hypoglossal cranial nerve upper airway stimulation (UAS). STUDY DESIGN: A multicenter prospective cohort study. SETTING: Industry-supported multicenter academic and clinical setting. SUBJECTS: Participants (n = 116) at 36 months from a cohort of 126 implanted participants. METHODS: Participants were enrolled in a prospective phase III trial evaluating the efficacy of UAS for moderated to severe OSA. Prospective outcomes included apnea-hypopnea index, oxygen desaturation index, other PSG measures, self-reported measures of sleepiness, sleep-related quality of life, and snoring. RESULTS: Of 126 enrolled participants, 116 (92%) completed 36-month follow-up evaluation per protocol; 98 participants additionally agreed to a voluntary 36-month PSG. Self-report daily device usage was 81%. In the PSG group, 74% met the a priori definition of success with the primary outcomes of apnea-hypopnea index, reduced from the median value of 28.2 events per hour at baseline to 8.7 and 6.2 at 12 and 36 months, respectively. Similarly, self-reported outcomes improved from baseline to 12 months and were maintained at 36 months. Soft or no snoring reported by bed partner increased from 17% at baseline to 80% at 36 months. Serious device-related adverse events were rare, with 1 elective device explantation from 12 to 36 months. CONCLUSION: Long-term 3-year improvements in objective respiratory and subjective quality-of-life outcome measures are maintained. Adverse events are uncommon. UAS is a successful and appropriate long-term treatment for individuals with moderate to severe OSA.

Hypoglossal nerve stimulation rescue surgery after multiple multilevel procedures for obstructive sleep apnea.

Hypoglossal nerve stimulation (HNS) is a new procedure offered for the treatment of moderate-to-severe obstructive sleep apnea (OSA) that has been shown to decrease the severity and symptoms of OSA in select patients. We report on a case of a patient with persistent symptoms and findings of OSA despite a history of multiple multilevel procedures, including an uvulopalatopharyngoplasty (UPPP) with revision, a genioglossus advancement, and a maxillomandibular advancement. The patient then underwent HNS with significant improvement of his symptoms and severity. The success of this patient's HNS surgery demonstrates that we need to examine where HNS fits into the approach to surgery for OSA. There could be benefit to considering cranial nerve stimulation earlier than conventional approaches for select patients.

Randomized controlled withdrawal study of upper airway stimulation on OSA: short- and long-term effect.

OBJECTIVE: To assess the efficacy and durability of upper airway stimulation via the hypoglossal nerve on obstructive sleep apnea (OSA) severity including objective and subjective clinical outcome measures. STUDY DESIGN: A randomized controlled therapy withdrawal study. SETTING: Industry-supported multicenter academic and clinical setting. SUBJECTS: A consecutive cohort of 46 responders at 12 months from a prospective phase III trial of 126 implanted participants. METHODS: Participants were randomized to either therapy maintenance ("ON") group or therapy withdrawal ("OFF") group for a minimum of 1 week. Short-term withdrawal effect as well as durability at 18 months of primary (apnea hypopnea index and oxygen desaturation index) and secondary outcomes (arousal index, oxygen desaturation metrics, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, snoring, and blood pressure) were assessed. RESULTS: Both therapy withdrawal group and maintenance group demonstrated significant improvements in outcomes at 12 months compared to study baseline. In the randomized assessment, therapy withdrawal group returned to baseline, and therapy maintenance group demonstrated no change. At 18 months with therapy on in both groups, all objective respiratory and subjective outcome measures showed sustained improvement similar to those observed at 12 months. CONCLUSION: Withdrawal of therapeutic upper airway stimulation results in worsening of both objective and subjective measures of sleep and breathing, which when resumed results in sustained effect at 18 months. Reduction of obstructive sleep apnea severity and improvement of quality of life were attributed directly to the effects of the electrical stimulation of the hypoglossal nerve.