Oral appliance therapy and hypoglossal nerve stimulation as non-positive airway pressure treatment alternatives for obstructive sleep apnea: a narrative expert review.

This perspective on alternatives to positive airway pressure (PAP) therapy for the treatment of obstructive sleep apnea (OSA) summarizes the proceedings of a focus group that was conducted by the Sleep Research Society Foundation. This perspective is from a multidisciplinary panel of experts from sleep medicine, dental sleep medicine, and otolaryngology that aims to identify the current role of oral appliance therapy and hypoglossal nerve stimulation for the treatment of OSA with emphasis on the US practice arena. A secondary aim is to identify-from an implementation science standpoint-the various barriers and facilitators for adoption of non-PAP treatment that includes access to care, multidisciplinary expertise, reimbursement, regulatory aspects, current treatment guidelines, health policies, and other factors related to the delivery of care. The panel has contextualized the review with recent events-such as a large-scale PAP device recall compounded by supply chain woes of the pandemic-and emerging science in the field of OSA and offers solutions for multidisciplinary approaches while identifying knowledge gaps and future research opportunities.

The stability of slow-wave sleep and EEG oscillations across two consecutive nights of laboratory polysomnography in cognitively normal older adults.

Laboratory polysomnography provides gold-standard measures of sleep physiology, but multi-night investigations are resource intensive. We assessed the night-to-night stability via reproducibility metrics for sleep macrostructure and electroencephalography oscillations in a group of cognitively normal adults attending two consecutive polysomnographies. Electroencephalographies were analysed using an automatic algorithm for detection of slow-wave activity, spindle and K-complex densities. Average differences between nights for sleep macrostructure, electroencephalography oscillations and sleep apnea severity were assessed, and test-retest reliability was determined using two-way intraclass correlations. Agreement was calculated using the smallest real differences between nights for all measures. Night 2 polysomnographies showed significantly greater time in bed, total sleep time (6.3 hr versus 6.8 hr, p < 0.001) and percentage of rapid eye movement sleep (17.5 versus 19.7, p < 0.001). Intraclass correlations were low for total sleep time, percentage of rapid eye movement sleep and sleep efficiency, moderate for percentage of slow-wave sleep and percentage of non-rapid eye movement 2 sleep, good for slow-wave activity and K-complex densities, and excellent for spindles and apnea-hypopnea index with hypopneas defined according to 4% oxygen desaturation criteria only. The smallest real difference values were proportionally high for most sleep macrostructure measures, indicating moderate agreement, and proportionally lower for most electroencephalography microstructure variables. Slow waves, K-complexes, spindles and apnea severity indices are highly reproducible across two consecutive nights of polysomnography. In contrast, sleep macrostructure measures all demonstrated poor reproducibility as indicated by low intraclass correlation values and moderate agreement. Although there were average differences in percentage of rapid eye movement sleep and total sleep time, these were numerically small and perhaps functionally or clinically less significant. One night of in-laboratory polysomnography is enough to provide stable, reproducible estimates of an individual's sleep concerning measures of slow-wave activity, spindles, K-complex densities and apnea severity.

Lack of association of impaired upper airway sensation with the presence or absence of obstructive sleep apnoea or chronic rhinosinusitis in World Trade Center responders.

OBJECTIVE: Examine sensory function of the upper airway in four groups of subjects recruited from the World Trade Centre General Responder Cohort (WTCGRC), with/without obstructive sleep apnoea (OSA), and with/without chronic rhinosinusitis (CRS). METHODS: Upper airway sensory function was determined using 2-point discrimination (2-PD) and vibration threshold (VT) in 163 WTCGRC subjects with both OSA and CRS (cases), OSA or CRS alone and without OSA or CRS (controls). Presence of OSA was determined from clinical sleep studies or home sleep testing. Presence of CRS was determined by nasal symptom questionnaire. The relationship between the presence of OSA and CRS and upper airway sensory impairment was assessed using linear regression analysis with each of 2PD and VT sensory threshold values as the dependent variable; OSA, CRS and their interaction were the independent variables. Age, gender and body mass index were covariates in the statistical model. The primary analysis was comparison of OSA+CRS versus controls (no OSA and no CRS) evaluated by linear contrasts. RESULTS: There were no differences in 2-PD or VT in those with OSA+CRS, OSA and CRS alone or controls. However, both 2-PD and VT were significantly higher in the WTCGRC controls compared with values seen in historical controls using the same methodology (median 2-PD 13.0; CI (11.0 to 13.5) vs 10.5; CI (8 to 11); VT: mean±SEM (9.3±0.6 vs 2.2±0.1)). CONCLUSION: While no differences were found in upper airway sensation between cases of OSA and CRS versus controls in the WTGRC population, there was evidence of impaired upper airway sensation in the WTGRC overall.

Nasal resistance and inflammation: mechanisms for obstructive sleep apnea from chronic rhinosinusitis.

STUDY OBJECTIVES: We have previously estimated that the prevalence of obstructive sleep apnea (OSA) among World Trade Center (WTC) rescue and recovery workers is 75% and identified that having symptoms of chronic rhinosinusitis (CRS) is an independent risk factor for OSA in this population. Nasal inflammation and/or elevated awake nasal resistance that carried over into sleep could explain this association. To understand the mechanism(s) for the elevated risk of OSA observed in WTC responders with chronic rhinosinusitis (CRS) symptoms we examined if elevated awake supine nasal resistance was associated with OSA, CRS and/or nasal inflammatory biomarkers. METHODS: 601 individuals (83% male, average age 53 years, BMI=29.9 ± 5.5 kg/m2) enrolled in the WTC Health Program and without significant pre-9/11 snoring, underwent two nights of home sleep apnea testing, measurements of anterior rhinomanometry in the supine position, and nasal lavage. RESULTS: Awake supine nasal resistance was not associated with OSA; 74.8% and 74.4% of the participants with low and high nasal resistance respectively, had OSA (P=NS). Patients with CRS had elevated nasal inflammatory markers (IL6, IL8, ECP and Neut) but did not have high nasal resistance. Nasal inflammatory markers were not correlated with nasal resistance. CONCLUSIONS: As awake nasal resistance did not explain the relationship of CRS to OSA in this large and well characterized dataset, our findings suggest that either "sleep" nasal resistance or other factors such as increased supraglottic inflammation, perhaps through impairing upper airway reflex mechanisms, or systemic inflammation are involved in the pathophysiology of OSA in the WTC population.

Sleep-wake body temperature regulates tau secretion in mice and correlates with CSF and plasma tau in humans.

The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP2 and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.

Ventilatory Burden as a Measure of Obstructive Sleep Apnea Severity Is Predictive of Cardiovascular and All-Cause Mortality.

Rationale: The apnea-hypopnea index (AHI), used for the diagnosis of obstructive sleep apnea, captures only the frequency of respiratory events and has demonstrable limitations. Objectives: We propose a novel automated measure, termed "ventilatory burden" (VB), that represents the proportion of overnight breaths with less than 50% normalized amplitude, and we show its ability to overcome limitations of AHI. Methods: Data from two epidemiological cohorts (EPISONO [Sao Paolo Epidemiological Study] and SHHS [Sleep Heart Health Study]) and two retrospective clinical cohorts (DAYFUN; New York University Center for Brain Health) were used in this study to 1) derive the normative range of VB, 2) assess the relationship between degree of upper airway obstruction and VB, and 3) assess the relationship between VB and all-cause and cardiovascular disease (CVD) mortality with and without hypoxic burden that was derived using an in-house automated algorithm. Measurements and Main Results: The 95th percentiles of VB in asymptomatic healthy subjects across the EPISONO and the DAYFUN cohorts were 25.2% and 26.7%, respectively (median [interquartile range], VBEPISONO, 5.5 [3.5-9.7]%; VBDAYFUN, 9.8 [6.4-15.6]%). VB was associated with the degree of upper airway obstruction in a dose-response manner (VBuntreated, 31.6 [27.1]%; VBtreated, 7.2 [4.7]%; VBsuboptimally treated, 17.6 [18.7]%; VBoff-treatment, 41.6 [18.1]%) and exhibited low night-to-night variability (intraclass correlation coefficient [2,1], 0.89). VB was predictive of all-cause and CVD mortality in the SHHS cohort before and after adjusting for covariates including hypoxic burden. Although AHI was predictive of all-cause mortality, it was not associated with CVD mortality in the SHHS cohort. Conclusions: Automated VB can effectively assess obstructive sleep apnea severity, is predictive of all-cause and CVD mortality, and may be a viable alternative to the AHI.

Night-to-night reliability and agreement of obstructive sleep apnea pathophysiologic mechanisms estimated with phenotyping using polysomnography in cognitively normal elderly participants.

STUDY OBJECTIVES: Phenotyping using polysomnography (PUP) is an algorithmic method to quantify physiologic mechanisms underlying obstructive sleep apnea (OSA): loop gain (LG1), arousal threshold (ArTH), and upper airway collapsibility (Vpassive) and muscular compensation (Vcomp). The consecutive-night test-retest reliability and agreement of PUP-derived estimates are unknown. From a cohort of elderly (age ≥55 years), largely non-sleepy, community-dwelling volunteers who underwent in-lab polysomnography (PSG) on 2 consecutive nights, we determined the test-retest reliability and agreement of PUP-estimated physiologic factors. METHODS: Participants who had an apnea-hypopnea index (AHI3A) of at least 15 events per hour on the first night were included. PUP analyses were performed on each of the two PSGs from each participant. Physiologic factor estimates were derived from NREM sleep and compared across nights using intraclass correlation coefficients for reliability and smallest real differences (SRD) for agreement. RESULTS: Two PSGs from each of 43 participants (86 total) were analyzed. A first-night effect was evident with increased sleep time and stability and decreased OSA severity on the second night. LG1, ArTH, and Vpassive demonstrated good reliability (ICC > 0.80). Vcomp had modest reliability (ICC = 0.67). For all physiologic factors, SRD values were approximately 20% or more of the observed ranges, suggesting limited agreement of longitudinal measurements for a given individual. CONCLUSIONS: For NREM sleep in cognitively normal elderly individuals with OSA, PUP-estimated LG1, ArTH, and Vpassive demonstrated consistent relative ranking of individuals (good reliability) on short-term repeat measurement. For all physiologic factors, longitudinal measurements demonstrated substantial intraindividual variability across nights (limited agreement).

Distinguishing central from obstructive hypopneas on a clinical polysomnogram.

Among sleep-related disordered breathing events, hypopneas are the most frequent. Like obstructive and central apneas, hypopneas may be obstructive or central (reduced drive) in origin. Nevertheless, unlike apneas, categorizing hypopneas as either "obstructive" or "central" is often difficult or ambiguous. It has been suggested that hypopneas could be categorized as obstructive when associated with snoring, inspiratory flow limitation, or paradoxical thoraco-abdominal excursions. This approach, however, has not been extensively tested and misclassification of hypopneas is unavoidable. Yet, much rides on the accurate distinction of these events to guide therapy with medical devices or pharmacological therapy in each patient. Additionally, accurate hypopnea classification is critical for design of clinical trials, because therapeutic responses differ depending on the subtype of hypopnea. Correctly classifying hypopneas can also allay concerns about obtaining coverage for therapies that specifically target either central or obstructive sleep-disordered breathing events. The present paper expands on the current criteria for differentiating obstructive from central hypopneas and provides illustrative tracings that can help classify these events. CITATION: Javaheri S, Rapoport DM, Schwartz AR. Distinguishing central from obstructive hypopneas on a clinical polysomnogram. J Clin Sleep Med. 2023;19(4):823-834.

Association between lower body temperature and increased tau pathology in cognitively normal older adults.

BACKGROUND: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. METHODS: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. RESULTS: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). CONCLUSIONS: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. CLINICAL TRIAL NUMBER: NCT03053908.

Sleep apnoea in the elderly: a great challenge for the future.

Due in part to overall improvements in health, the population of elderly individuals is increasing rapidly. Similarly, obstructive sleep apnoea (OSA) is both gaining increased recognition and also increasing due to the worldwide obesity epidemic. The overlap of OSA and ageing is large, but there is strong plausibility for causation in both directions: OSA is associated with pathological processes that may accelerate ageing and ageing-related processes; ageing may cause physical and neurological changes that predispose to obstructive (and central) apnoea. In addition, the common symptoms (e.g. excessive daytime sleepiness, and defects in memory and cognition), possible physiological consequences of OSA (e.g. accelerated cardiovascular and cerebrovascular atherosclerosis), and changes in metabolic and inflammatory markers overlap with the symptoms and associated conditions seen in ageing. There is also the possibility of synergy in the effects of these symptoms and conditions on quality of life, as well as a need to separate treatable consequences of OSA from age-related complaints. Taken together, the aforementioned considerations make it essential to review the interaction of OSA and ageing, both proven and suspected. The present review examines some aspects of what is known and points to the need for further investigation of the relationships, given the large number of potentially affected subjects.

Immediate Physiological Responses to Inspiratory Flow Limited Events in Mild Obstructive Sleep Apnea.

Rationale: Inspiratory flow limitation (IFL), characterized by flattening of individual breaths on the airflow/time tracing, is a noninvasive indicator of elevated upper airway resistance. An IFL "event" in isolation has not been defined, nor has the ability to reproducibly identify event occurrence been tested. IFL events and their association with immediate physiological responses-as well as the impact of characteristics such as age, sex, sleep stage, sleepiness, and event duration on their association with such outcomes-have not been studied. Symptomatic patients with a normal to mildly abnormal apnea-hypopnea index who have predominant IFL on their polysomnography may benefit from treatment. Objectives: To test the reproducibility of identifying IFL events and their termination and to determine the frequency of the immediate physiological response to their occurrence, including desaturation, electroencephalography (EEG) arousal, and increased heart rate (HR). Methods: Fifty-eight patients with obstructive sleep apnea (OSA) underwent full diagnostic polysomnography. IFL events and their termination were identified manually using predefined rules from the unscored nasal cannula flow channel alone and were evaluated for responses such as EEG arousal, oxygen desaturation of ⩾3%, and HR increase. Results: Interscorer reliability was acceptable, with an average percent agreement for occurrence of 82% ± 3%. Of all IFL events, 24% (regardless of the definition) were not associated with an EEG arousal, an increase in HR, or O2 desaturation. Of all IFL events scored, 25% caused O2 desaturation, 40% were associated with an EEG arousal, and 55% were associated with an increase in HR; 67% caused either an EEG arousal and/or an increase in HR. Responses were observed to occur either in isolation or in combination. IFL events that terminated with at least two non-IFL breaths, one of which had a 200% increase in amplitude, were significantly associated with O2 desaturation, EEG arousal, and increase in HR compared with events that ended in one non-IFL breath. IFL events that had a >50% reduction in flow amplitude compared with baseline were significantly associated with O2 desaturation compared with events that had a 30% reduction or less. Conclusions: Most IFL events resulted in immediate physiological responses, and no single consequence reliably occurred after every event. We propose a framework that can incorporate the scoring of IFL events into assessing the diagnosis and severity of OSA and suggest that no single consequence be used to define IFL as a respiratory event. The relationship of IFL events to OSA outcomes remains to be tested.

Selective Continuous Positive Airway Pressure Withdrawal With Supplemental Oxygen During Slow-Wave Sleep as a Method of Dissociating Sleep Fragmentation and Intermittent Hypoxemia-Related Sleep Disruption in Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is considered to impair memory processing and increase the expression of amyloid-ß (Aß) and risk for Alzheimer's disease (AD). Given the evidence that slow-wave sleep (SWS) is important in both memory and Aß metabolism, a better understanding of the mechanisms by which OSA impacts memory and risk for AD can stem from evaluating the role of disruption of SWS specifically and, when such disruption occurs through OSA, from evaluating the individual contributions of sleep fragmentation (SF) and intermittent hypoxemia (IH). In this study, we used continuous positive airway pressure (CPAP) withdrawal to recapitulate SWS-specific OSA during polysomnography (PSG), creating conditions of both SF and IH in SWS only. During separate PSGs, we created the conditions of SWS fragmentation but used oxygen to attenuate IH. We studied 24 patients (average age of 55 years, 29% female) with moderate-to-severe OSA [Apnea-Hypopnea Index (AHI); AHI4% > 20/h], who were treated and adherent to CPAP. Participants spent three separate nights in the laboratory under three conditions as follows: (1) consolidated sleep with CPAP held at therapeutic pressure (CPAP); (2) CPAP withdrawn exclusively in SWS (OSA SWS ) breathing room air; and (3) CPAP withdrawn exclusively in SWS with the addition of oxygen during pressure withdrawal (OSA SWS + O 2). Multiple measures of SF (e.g., arousal index) and IH (e.g., hypoxic burden), during SWS, were compared according to condition. Arousal index in SWS during CPAP withdrawal was significantly greater compared to CPAP but not significantly different with and without oxygen (CPAP = 1.1/h, OSA SWS + O2 = 10.7/h, OSA SWS = 10.6/h). However, hypoxic burden during SWS was significantly reduced with oxygen compared to without oxygen [OSA SWS + O 2 = 23 (%min)/h, OSA SWS = 37 (%min)/h]. No significant OSA was observed in non-rapid eye movement (REM) stage 1 (NREM 1), non-REM stage 2 (NREM 2), or REM sleep (e.g., non-SWS) in any condition. The SWS-specific CPAP withdrawal induces OSA with SF and IH. The addition of oxygen during CPAP withdrawal results in SF with significantly less severe hypoxemia during the induced respiratory events in SWS. This model of SWS-specific CPAP withdrawal disrupts SWS with a physiologically relevant stimulus and facilitates the differentiation of SF and IH in OSA.

Interactive Associations of Neuropsychiatry Inventory-Questionnaire Assessed Sleep Disturbance and Vascular Risk on Alzheimer's Disease Stage Progression in Clinically Normal Older Adults.

Background: To determine whether sleep disturbance (SD) and vascular-risk interact to promote Alzheimer's disease (AD) stage-progression in normal, community-dwelling older adults and evaluate their combined risk beyond that of established AD biomarkers. Methods: Longitudinal data from the National Alzheimer's Coordinating Center Uniform-Dataset. SD data (i.e., SD+ vs. SD-), as characterized by the Neuropsychiatric Inventory-Questionnaire, were derived from 10,600 participants at baseline, with at-least one follow-up visit. A subset (n = 361) had baseline cerebrospinal fluid (CSF) biomarkers and MRI data. The Framingham heart study general cardiovascular disease (FHS-CVD) risk-score was used to quantify vascular risk. Amnestic mild cognitive impairment (aMCI) diagnosis during follow-up characterized AD stage-progression. Logistic mixed-effects models with random intercept and slope examined the interaction of SD and vascular risk on prospective aMCI diagnosis. Results: Of the 10,600 participants, 1,017 (9.6%) reported SD and 6,572 (62%) were female. The overall mean (SD) age was 70.5 (6.5), and follow-up time was 5.1 (2.7) years. SD and the FHS-CVD risk-score were each associated with incident aMCI (aOR: 1.42 and aOR: 2.11, p < 0.01 for both). The interaction of SD and FHS-CVD risk-score with time was significant (aOR: 2.87, p < 0.01), suggesting a synergistic effect. SD and FHS-CVD risk-score estimates remained significantly associated with incident aMCI even after adjusting for CSF (Aß, T-tau, P-tau) and hippocampal volume (n = 361) (aOR: 2.55, p < 0.01), and approximated risk-estimates of each biomarker in the sample where data was available. Conclusions: Clinical measures of sleep and vascular risk may complement current AD biomarkers in assessing risk of cognitive decline in older adults.

Quantification of airway conductance from noninvasive ventilatory drive in patients with sleep apnea.

Upper airway conductance, the ratio of inspiratory airflow to inspiratory effort, quantifies the degree of airway obstruction in hypopneas observed in sleep apnea. We evaluated the ratio of ventilation to noninvasive ventilatory drive as a surrogate of conductance. Furthermore, we developed and tested a refinement of noninvasive drive to incorporate the interactions of inspiratory flow, pressure, and drive to better estimate conductance. Hypopneas were compiled from existing polysomnography studies with esophageal catheterization in 18 patients with known or suspected sleep apnea, totaling 1,517 hypopneas during NREM sleep. For each hypopnea, reference standard conductance was calculated as the ratio of peak inspiratory flow to esophageal pressure change during inspiration. Ventilatory drive was calculated using the algorithm developed by Terrill et al. and then mathematically modified according to the presence or absence of flow limitation to noninvasively estimate esophageal pressure. The ratio of ventilation to ventilatory drive and the ratio of peak inspiratory flow to estimated esophageal pressure were each compared with the reference standard for all hypopneas and for median values from individual patients. Hypopnea ventilation to drive ratios were of limited correlation with the reference standard (R2 = 0.17, individual hypopneas; R2 = 0.03, median patient values). Modification of drive to estimated pressure yielded estimated conductance, which strongly correlated with reference standard conductance (R2 = 0.49, individual hypopneas; R2 = 0.77, median patient values). We conclude that the severity of airway obstruction during hypopneas may be estimated from noninvasive drive by accounting for mechanical effects of flow on pressure. NEW & NOTEWORTHY Classification of hypopneas as obstructive (decreased upper airway conductance) or central (decreased inspiratory flow commensurate with decreased effort) is complicated by the requirement of invasive methods, such as esophageal manometry. Here, we demonstrate that using a few esophageal pressure measurements to account for the interactions between inspiratory flow, pressure, and noninvasive ventilatory drive allows estimation of upper airway conductance. Further studies may use these findings to quantify airway obstruction completely noninvasively.