Citations

Abstract Introduction Hypoglossal nerve stimulators (HGNS) are used in patients with moderate-to-severe obstructive sleep apnea (OSA) who are unable to tolerate or do not respond to continuous positive airway pressure (CPAP) therapy. However, a subgroup of patients fail to achieve resolution of OSA with HGNS alone. Previous studies have shown that lower BMI, lower nadir oxygenation, decreased sleep latency, and higher VOTE score on drug-induced sleep endoscopy (DISE) predict better treatment outcome. We hypothesize that baseline diagnostic polysomnography (PSG) may further predict which patients will achieve successful therapeutic outcome with HGNS therapy. Methods We conducted a retrospective analysis of all adult patients who underwent HGNS implantation at Mayo Clinic Arizona between 2019-2025 and had a pre-implantation diagnostic PSG available for review. Treatment success was defined by Sher Criteria: >50% reduction in post-treatment apnea hypopnea index (AHI) to a final AHI of < 20/hr. Responders met Sher criteria and non-responders did not meet Sher criteria. Demographics, sleep questionnaire results, PSG variables, and VOTE score on DISE were collected and analyzed using Spearman’s rank correlation of reduction in AHI. Results Twenty-three patients (11M/12F, median age: 69[IQR:64,75] years) met inclusion criteria. Median baseline AHI was 24[IQR:19,37]/hr. Median post-implant AHI was 8 [IQR:3, 14]/hr. Responders (n=15, 65%) and non-responders (n=8, 35%) demonstrated median post-implant AHI of 4.5[IQR:2.3,7.3]/hr and 15.7[IQR:12.3,28.5]/hr, respectively. Treatment response was associated with less time with SpO2 < 88% (T88%) (21min [IQR:3,64] vs. 73[IQR:36,105mins]; p=0.023) and higher central apnea index (CAI) (1[IQR:0.1,3] vs. 0[IQR:0,1], p=0.03) on pre-implantation PSG. Conclusion In this small cohort of OSA patients, less nocturnal hypoxemia as defined by T88% and higher baseline central apnea index were predictors of better treatment response to HGNS therapy as measured by Sher criteria. We hypothesize that greater nocturnal hypoxemia likely reflects more severe airway obstruction during sleep. Our analysis also showed that responders had higher baseline CAI than non-responders, however we believe this association is not clinically significant and likely driven by one outlier (CAI 13/hr). Further analysis in a larger HGNS cohort is needed to confirm these findings. Data enrichment efforts and more sophisticated analyses are underway. Support (if any)

Abstract Introduction Once-nightly sodium oxybate (ON-SXB; LUMRYZ™) is approved to treat excessive daytime sleepiness (EDS) or cataplexy in patients ≥7 years of age with narcolepsy. Findings from 2 studies have demonstrated improvements in objective and subjective EDS with ON-SXB in patients with narcolepsy type 1 (NT1) or 2 (NT2) (NCT02720744, NCT06792708). To evaluate the effect of ON-SXB on EDS in a larger, more diverse narcolepsy patient population, changes in Epworth Sleepiness Scale (ESS) score were analyzed using specialty pharmacy data. Methods Demographic/clinical data were collected from Optum Frontier Therapies pharmacy for adults with NT1 or NT2 with ≥1 filled ON-SXB prescription, ≥1 ON-SXB clinical assessment, and ≥1 follow-up ESS score (6/1/2023-9/30/2024). ESS total scores were assessed at baseline and at each follow-up assessment after ON-SXB initiation. ESS assessment participation was voluntary. Data were analyzed descriptively and stratified by narcolepsy subtype. Results Of 452 patients identified, 195 had ≥1 follow-up ESS score and reported narcolepsy type (NT1, n=123 [63%; mean age, 38.6 years; female, 69%]; NT2, n=72 [37%; mean age, 40.7 years; female, 74%]). More patients with NT1 vs NT2 (72% vs 58%) had any prior oxybate use. Baseline concomitant stimulant/wake-promoting agent use was 58% and 64% for NT1 and NT2, respectively. Mean (SD) ESS total scores at baseline were 12.1 (5.7) and 12.2 (5.3) for patients with NT1 and NT2, respectively; 31% of NT1 and 33% of NT2 had severe EDS. For both subtypes, mean (SD) ESS scores were within the normal EDS range (≤10) by the first follow-up (median time, 52 days; NT1, 10.0 [5.5]; NT2, 9.6 [4.8]). At first follow-up, more than half of patients in the NT1 (55%) and NT2 (54%) subgroups achieved normal levels (ESS total score ≤10) of sleepiness, while 20% of NT1 patients and 10% of NT2 patients had severe EDS. Mean (SD) change from baseline in ESS score was -2.1 (4.3) and -2.6 (5.3) in the NT1 and NT2 subgroups, respectively. Conclusion In this real-world dataset, both NT1 and NT2 patients quickly experienced clinically meaningful improvements in ESS score after initiating ON-SXB. These results support ON-SXB as an effective EDS treatment, regardless of narcolepsy subtype. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Chronic and episodic headaches have a strong bidirectional relationship with insomnia and poor sleep outcomes. AM (morning) headaches are common among chronic pain populations, but additional research is needed to understand their pain experiences and potentially inform targeted interventions. Herein, we investigated whether presence of AM headaches is associated with differences in diary-based sleep parameters and pain ratings in women with pain and sleep complaints. We hypothesize individuals with AM headaches will have more sleep disturbances and fatigue as well as greater pain intensity and unpleasantness. Methods Women (N=293, Mage=39.59, SD 12.65, 65% with morning headaches) reporting insomnia and pain complaints (65% also reporting morning headaches) were recruited in mid-Missouri for an RCT (R01NR017168, ClinicalTrials.gov Identifier: NCT03744156). During baseline assessment, participants completed 2 weeks of daily electronic diaries and reported AM headache presence (Y/N). Independent samples t-tests (SPSS) evaluated differences in sleep parameters and pain ratings in those with and without AM headaches. Participants reporting diagnosed sleep apnea were excluded. Results Morning fatigue was higher among individuals with AM headaches (M=54.72+/-18.25) than those without (M=50.02+/-19.12), t(291)=-2.07, p=.04. Pain intensity was greater in the AM headache group in the morning (M=47.65+/-19.73 vs. M=42.52+/-21.91), t(291)=-2.04, p=.042, and evening, (M=49.62+/-19.10 vs. M=44.23+/-20.66), t(283)=-2.21, p=.028. Evening pain unpleasantness was also rated as higher among those with AM headaches (M=45.90+/-19.55) compared to those without (M=40.82+/-22.52), t(283)=-1.99, p=.048, but morning pain unpleasantness ratings only trended towards significance. Conclusion AM headaches can present as a chronic condition or as a symptom of other sleep disorders. Individuals with AM headaches had minimal sleep differences overall, but morning fatigue, pain intensity (AM and PM), and evening pain unpleasantness ratings were all significantly greater in those with AM headaches. Undiagnosed sleep disorders other than insomnia (i.e., obstructive sleep apnea) or other health concerns, like increased intracranial pressure, may have contributed to pain-related findings. Considering the high prevalence of COMISA in chronic pain populations, further investigation should examine its impact on sleep and headache severity. Support (if any) National Institute of Nursing Research (NR017168; Clinical trial: NCT03744156; PI: McCrae).

Abstract Introduction AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for the treatment of narcolepsy. Long-term efficacy and safety of AXS-12 in participants with narcolepsy with cataplexy (NT1) were previously reported from the Phase 3 ENCORE trial. To better understand the impact of AXS-12 on overall functional burden in NT1, we evaluated changes in cognition and functional outcomes during the ENCORE trial. Methods ENCORE included a 24-week open-label extension (OLE) period, followed by a 3-week double-blind randomized-withdrawal (DBRW) period. During the OLE, participants received AXS-12 (5 mg once-daily for 1 week, twice-daily for 23 weeks). Following this, participants were randomized 1:1 to continue twice-daily AXS-12 for 3 weeks or switch to once-daily AXS-12 plus placebo for 1 week, then placebo twice-daily for 2 weeks. P-values reported are nominal. Results ENCORE enrolled 68 participants; 42 completed the OLE and entered the DBRW (AXS-12, n=22; placebo, n=20). In the OLE, participants treated with AXS-12 reported improvement in the NSAQ Ability to Concentrate item at 1 (54.8%) and 6 (58.5%) months. Participants reported improvement in concentration, assessed by PGI-C, at 1 (66.7%) and 6 (70.0%) months. Narcolepsy overall, assessed by the CGI-C, improved at 1 (90.3%) and 6 (90.2%) months; and improved at 1 (77.8%) and 6 (80.0%) months, assessed by the PGI-C. Functional impairment, assessed by the WPAI, was reduced from 53.0% at baseline to 34.0% at 1 month and 24.3% at 6 months. In the DBRW, a greater proportion of participants switched to placebo experienced worsening on the NSAQ Ability to Concentrate item (52.6% vs 14.3%; P=0.011), and PGI-C for ability to concentrate (57.9% vs 22.2%; P=0.029) at 3 weeks compared with those continuing AXS-12. A greater proportion switched to placebo also reported worsening of their narcolepsy overall (PGI-C) at 3 weeks compared with those continuing AXS-12 (52.6% vs 16.7%; P=0.024). Treatment with AXS-12 was generally well tolerated. Conclusion Long-term, open-label treatment with AXS-12 was associated with improvements in cognitive/functional domains and productivity. Randomized withdrawal to placebo led to worsening cognition and narcolepsy overall. These results further support the long-term therapeutic benefit of AXS-12 for narcolepsy. Support (if any) Axsome Therapeutics Inc.

Abstract Introduction The remedē System® Therapy Study (reST) is a real world evaluation using transvenous phrenic nerve stimulation (TPNS) to treat adults with moderate-to-severe central sleep apnea (CSA). Based on previous clinical trials, it was expected that most patients with CSA would have heart failure (HF). However, recent CSA prevalence publications demonstrated the opposite. We present the baseline characteristics of patients with CSA treated with TPNS. Methods Adult subjects determined eligible for a commercial TPNS device implant by routine clinical PSGs were consented to participate in the trial. Baseline assessments were performed and medical history collected. Patients will be followed for ≥1 year following therapy activation; follow-up is ongoing. This report describes the baseline characteristics of the patient population. Results Twenty-nine sites enrolled a total of 197 subjects (171 United States & 26 the Netherlands) between July 2019 and March 2025. Median [Q1-Q3] age was 70 [61-76] years, 82% were male, and 97% white race. Body mass index was 28.7 [25.8-31.6] kg/m2, with neck size 41 [28-44] cm. Patients had moderate-to-severe CSA with site-reported apnea-hypopnea index of 46/hour [30-64], including central apnea index of 24/hour [13-38]. Despite a range of comorbidities among patients, HF was documented in just 23%. Other cardiovascular conditions were more prevalent, including hypertension (70%), hyperlipidemia (65%), coronary artery disease (37%), atrial fibrillation (34%), and prior stroke (14%). Non-cardiac issues such as depression (27%), diabetes (26%), and renal disease (18%) were also present. Additionally, 22% of patients used narcotics, and 89% had previously failed another CSA therapy, most often CPAP (79%), Bi-PAP (39%), or ASV (32%). Lastly, almost 20% were from high altitude locations (>5,000 feet). Conclusion Patients implanted with TPNS had significant co-morbidities. However, HF was much less common than anticipated. This finding could be due to CSA being present in clinical practice with a wider range of underlying causes beyond HF, or undiagnosed early-stage HF. Alternatively, it may reflect referral bias for this specific therapy, with patients selected because of prior treatment failures or other comorbidities. These possibilities highlight the importance of recognizing CSA in a diverse patient population and underscore the need for multidisciplinary team management. Support (if any) ZOLL Respicardia, Inc.

Abstract Introduction Once-nightly sodium oxybate (ON-SXB [LUMRYZ™]) is approved to treat excessive daytime sleepiness (EDS) or cataplexy in patients ≥7 years of age with narcolepsy. Real-world demographic/clinical characteristics and treatment adherence in patients with narcolepsy who received ON-SXB from a specialty pharmacy were assessed. Methods Baseline demographic/clinical data were collected from Optum Frontier Therapies pharmacy for patients with ≥1 filled ON-SXB prescription, ≥1 ON-SXB-related clinical assessment, and baseline Epworth Sleepiness Scale (ESS) score from 6/1/2023-9/30/2024. Adherence (≥80% of days covered) was assessed for patients with ≥3 months of ON-SXB use. Data were stratified by narcolepsy subtype (narcolepsy type 1 [NT1] and 2 [NT2] when available) and prior oxybate use (transitioned from prior oxybate therapy to ON-SXB ≤30 days of index [switch]/were oxybate-naive or discontinued oxybate >30 days before index [not-on-oxybate]). Data were analyzed descriptively. Results 452 patients were identified (NT1, 55%; NT2, 37%; NT unknown, 9%; switch, 40%; not-on-oxybate, 60% [oxybate-naive, n=147/271]). Mean (range) age was 38.9 (16.0-88.0) years. Most patients were female (68%) and had commercial insurance (78%). Overall, 67% of patients had prior oxybate use (NT1, 72% [n=179/247]; NT2, 59% [n=98/166]; switch, 100%; not-on-oxybate, 46% [n=124/271]); for these patients, the most common oxybate (65%) was mixed-salt oxybates (NT1, 61%; NT2, 70%; switch, 61%; not-on-oxybate, 70%). Overall, 64% of patients used stimulants/wake-promoting agents (WPAs) (NT1, 64%; NT2, 65%; switch, 60%; not-on-oxybate, 67%). Overall, the mean (SD) baseline ESS score was 12.0 ([5.5]; NT1, 11.7 [5.5]; NT2, 12.5 [5.3]; switch, 11.0 [5.7]; not-on-oxybate, 12.7 [5.3]). At baseline, 29% of patients experienced severe EDS (ESS score ≥16: NT1, 26%; NT2, 30%; switch, 20%; not-on-oxybate, 34%). Of 269 patients with ON-SXB use ≥3 months, 84% (NT1, 84%; NT2, 89%; switch, 94%; not-on-oxybate, 76%) demonstrated adherence. Conclusion Patients not on an oxybate had the highest baseline ESS scores and proportion with severe EDS, despite greater stimulant/WPA utilization. Patients with NT1 used oxybates more frequently than those with NT2 despite those with NT2 having higher baseline ESS scores and a greater proportion having severe EDS, suggesting oxybates merit earlier consideration in patients with NT2. Most patients demonstrated ON-SXB adherence, indicating they would likely receive full therapeutic benefit. Support (if any) Avadel Pharmaceuticals

OBJECTIVE Adamantinomatous craniopharyngioma (ACP) is a rare type of brain tumor that affects a wide age range, from children to older adults. Due to the rarity of the disease, existing studies are predominantly limited to single-center or single-surgeon experiences, often lacking statistical power and generalizability. The aim of this study was to address this gap by providing a comprehensive analysis of ACP outcomes based on a large multicenter cohort from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). METHODS This multicenter retrospective cohort study was conducted via the RAPID consortium and assessed patients with histologically confirmed ACP treated surgically between August 2000 and November 2024 at high-volume pituitary centers across the United States. RESULTS Among the 359 patients (206 male, median age at primary surgery of 47 years) included in the analysis, 76% underwent endoscopic transsphenoidal surgery and 22% underwent craniotomy. Gross-total resection was achieved in 45% and subtotal resection in 47%. Notably, 120 of 311 patients (39%) presented with preoperative hypothalamic-pituitary axis dysfunction. Following all treatments, permanent hypothyroidism was reported in 40% of patients, adrenal insufficiency in 33%, and arginine vasopressin deficiency in 19%. Of 263 patients who underwent primary surgery, radiation therapy was administered in 84 (32%). Progression-free survival (PFS) declined from 66% at 1 year to 31% at 6 years. In the multivariable analysis, independent predictors of worse PFS included subtotal resection (HR 0.22, 95% CI 0.11–0.42; p = 0.001), partial resection (HR 0.11, 95% CI 0.04–0.28, p = 0.001), larger tumor size (HR 0.77, 95% CI 0.64–0.94; p = 0.009), and tumor extension beyond the sella and suprasellar regions (HR 0.21, 95% CI 0.06–0.74; p = 0.016). Primary surgery and salvage surgery groups showed comparable PFS. CONCLUSIONS In this large multicenter cohort study, gross-total resection was achieved in fewer than half of patients and was independently associated with improved PFS. Approximately one-third of patients underwent radiation therapy after primary surgery. These findings provide robust evidence supporting the prognostic value of extent of resection and inform contemporary treatment algorithms for ACP. The high incidence of postoperative endocrinopathy underscores the need for individualized multidisciplinary long-term care. While the retrospective design is a limitation, the multicenter approach enhances the generalizability of these results.

OBJECTIVE Communicating hydrocephalus may occur following stereotactic radiosurgery (SRS) for vestibular schwannomas (VSs), yet identifying individual patient risk factors associated with this post-SRS complication remains a challenge. This study examined predictors of nonobstructive ventricular enlargement and symptomatic communicating hydrocephalus following primary SRS treatment for VS via a single-center institutional cohort review and meta-analysis of the literature. METHODS A retrospective single-institution cohort study and systematic literature review and meta-analysis examining post-SRS communicating hydrocephalus in VS was performed. RESULTS The institutional cohort consisted of 634 patients who received primary SRS as treatment for VS. The cohort was 51.6% female, with a median age of 64 (range 18–89) years. Following SRS treatment, 364 patients (57.4%) experienced tumor shrinkage, 218 (34.4%) had no change in the size of their lesion, and 52 (8.2%) experienced tumor growth. Nonobstructive ventricular enlargement was observed in 23 patients (3.6%) following SRS treatment, of whom 9 (39.1%) remained asymptomatic and 14 (60.9%) required placement of a ventriculoperitoneal (VP) shunt, with a median time to shunt placement of 8 months. In the multivariate analysis, patients ≥ 65 years old (p = 0.038), SRS target volume ≥ 5 cm 3 (p < 0.001), maximum SRS dose ≥ 26 Gy (p = 0.015), and tumor growth at the most recent follow-up (p = 0.002) were associated with an increased risk of post-SRS ventricular enlargement. Similarly, patients with older age (p = 0.049), increased SRS target volume (p = 0.002), and tumor growth (p = 0.016) were at an increased risk of symptomatic communicating hydrocephalus requiring VP shunt placement. Twenty-nine studies, including the cohort in this study, met inclusion criteria in the meta-analysis. Of the pooled 7825 patients, the overall incidence of hydrocephalus following SRS was 5%, and a subanalysis of 7081 patients demonstrated the incidence of symptomatic hydrocephalus requiring a VP shunt to be 4%. In this subanalysis, the overall shunting rate in patients who experienced post-SRS ventriculomegaly was 92%. Among individual studies in the literature, increased tumor size was most commonly found to be a statistically significant risk factor for post-SRS hydrocephalus. CONCLUSIONS Approximately 5% of patients may experience nonobstructive ventricular enlargement following primary SRS treatment for VS. However, not all patients may be symptomatic and require shunting. Patients who are older (≥ 65 years), those with larger tumor volumes, and those with post-SRS tumor growth may be at increased risk of communicating hydrocephalus and may benefit from closer clinical monitoring.

Background: Premedications used to prevent paclitaxel-associated infusion hypersensitivity reactions (iHSRs) can cause undesirable toxicities, such as sleep disturbance and weight gain. Although phase II data suggest that discontinuing premedications after paclitaxel-associated iHSRs may be safe and feasible in select patients without prior iHSRs, no prospective randomized trials have evaluated this approach. Patients and Methods: This randomized clinical trial enrolled patients with breast cancer receiving paclitaxel chemotherapy. Those who experienced no iHSRs with the first 2 doses of paclitaxel were randomized to either continue standard premedications (control arm) or to discontinue all premedications (investigational arm). Both arms were followed longitudinally for any subsequent iHSRs requiring parenteral rescue medications. Additionally, changes in weight, drug-related side effects, and quality of life were assessed. Results: A total of 98 patients were randomized; 89 were evaluable (46 in the control arm and 43 in the investigational arm). Only 1 (2.3%) patient in the investigational arm experienced an iHSR, which resolved with rescue medications. No iHSRs occurred in the control arm. The estimated proportion of subjects who experienced a hypersensitivity reaction (exact binomial 95% CI) was 2.3% (95% CI, 0.1%–12.3%) in the investigational arm and 0.0% (95% CI, 0.0%–7.7%) in the control arm. Patients in the investigational arm reported significantly less sleep disruption (0.5 vs 1.7; P =.002) and unwanted appetite increases (1.0 vs 2.5; P =.0018). Conclusions: Discontinuation of premedications after 2 uneventful paclitaxel doses was not associated with a high rate of subsequent iHSRs and resulted in fewer steroid-related side effects. This strategy may reduce unnecessary medication exposure, improve patient experience, and streamline clinical workflows. For patients who do not experience iHSRs during the first 2 paclitaxel treatments, discontinuing premedications appears safe and may improve tolerability.