Association of hypoglossal nerve stimulator response with machine learning identified negative effort dependence patterns.

BACKGROUND: Hypoglossal nerve stimulator (HGNS) is a therapeutic option for moderate to severe obstructive sleep apnea (OSA). Improved patient selection criteria are needed to target those most likely to benefit. We hypothesized that the pattern of negative effort dependence (NED) on inspiratory flow limited waveforms recorded during sleep, which has been correlated with the site of upper airway collapse, would contribute to the prediction of HGNS outcome. We developed a machine learning (ML) algorithm to identify NED patterns in pre-treatment sleep studies. We hypothesized that the predominant NED pattern would differ between HGNS responders and non-responders. METHODS: An ML algorithm to identify NED patterns on the inspiratory portion of the nasal pressure waveform was derived from 5 development set polysomnograms. The algorithm was applied to pre-treatment sleep studies of subjects who underwent HGNS implantation to determine the percentage of each NED pattern. HGNS response was defined by STAR trial criteria for success (apnea-hypopnea index (AHI) reduced by > 50% and < 20/h) as well as by a change in AHI and oxygenation metrics. The predominant NED pattern in HGNS responders and non-responders was determined. Other variables including demographics and oxygenation metrics were also assessed between responders and non-responders. RESULTS: Of 45 subjects, 4 were excluded due to technically inadequate polysomnograms. In the remaining 41 subjects, ML accurately distinguished three NED patterns (minimal, non-discontinuous, and discontinuous). The percentage of NED minimal breaths was significantly greater in responders compared with non-responders (p = 0.01) when the response was defined based on STAR trial criteria, change in AHI, and oxygenation metrics. CONCLUSION: ML can accurately identify NED patterns in pre-treatment sleep studies. There was a statistically significant difference in the predominant NED pattern between HGNS responders and non-responders with a greater NED minimal pattern in responders. Prospective studies incorporating NED patterns into predictive modeling of factors determining HGNS outcomes are needed.

Optimization of Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea With Ultrasound Assessment of Tongue Movement.

BACKGROUND: Hypoglossal nerve stimulation (HGNS) is an Food and Drug Administration-approved therapy for obstructive sleep apnea. Initial programming of HGNS is based on the observation of anterior tongue movement, which may not reflect opening at the retroglossal airway. We developed an ultrasonographic technique to assess the base of tongue movement with HGNS to be used to optimize the initial voltage settings. STUDY QUESTION: This study aimed to investigate the use of ultrasound to assess tongue movement with HGNS and related this measure to the apnea hypopnea index (AHI) on subsequent home sleep apnea testing or in-laboratory polysomnography with therapy. STUDY DESIGN: Seventeen subjects (n = 17) implanted with HGNS were enrolled at least 1 month postimplantation. Ultrasonographic measures were then used to optimize HGNS voltage to produce observable base of tongue protrusion without producing discomfort. Responders were defined as a reduction in AHI > 50% and an AHI of <20 events/h. RESULTS: There were 17 subjects, 11 men and 6 women, with age = 64.6 ± 9.8 years, body mass index = 27.9 ± 2.7 kg/m2, and pretreatment AHI = 36.5 ± 14.4/h, T-90% = 10.7 ± 14.8%. The mean hyoid bone excursion (HBE) in responders = 1.0 ± 0.13 cm versus 0.82 ± 0.12 cm in nonresponders (P = 0.017). HBE was correlated with AHI during HGNS treatment (coef. -0.54, P = 0.03). Best subsets regression analysis using treatment-based AHI as the dependent variable and age, body mass index, baseline AHI, HBE, and HGNS voltage as independent variables showed that HBE (coef. -44.6, P = 0.044) was the only independent predictor of response. Receiver operator curve analysis showed that HBE > 0.85 cm had a sensitivity of 83.3% and specificity of 80.0% with a positive likelihood ratio of 4.17 to predict responder status. CONCLUSION: We demonstrated that ultrasound assessment of HBE during HGNS programming is a useful tool to optimize therapy.

Pedicled nasoseptal flap reconstruction for craniopharyngiomas in pediatric patients.

PURPOSE: Though the use of the pedicled nasoseptal flap (NSF), a reconstructive technique used after endoscopic endonasal approaches (EEA) for resection of craniopharyngiomas, has been shown to reduce the occurrence of post-operative cerebrospinal fluid (CSF) leaks in adults, less is known about its use in pediatric populations, specifically in children under the age of 7. The goal of this retrospective cohort study is to determine the viability of the pedicled NSF for pediatric patients. METHODS: Retrospective review of 12 pediatric patients (ages 2-16) undergoing 13 NSF reconstructions after resection of craniopharyngiomas. Radioanatomic analysis of computed tomography (CT) scans was utilized to classify the pneumatization of the sphenoid sinus depending on the thickness of the sphenoid bone margin. Intercarotid distances were measured from magnetic resonance imaging (MRI) scans to assess the feasibility of this reconstruction technique in pediatric patients. RESULTS: At the time of surgery, all patients were noted to have adequate NSF length and width. No post-operative high-flow CSF leaks were found within the group. Lack of pneumatization of the sphenoid sinus and narrow intercarotid distances in the youngest of patients did not lead to negative clinical outcomes. CONCLUSIONS: Based on our results and experience, the pedicled nasoseptal flap is a viable reconstructive option after EEA in the pediatric population, including even the youngest of patients. In these patients, a narrowed window between the intercarotid arteries and the lack of pneumatization of the sphenoid sinus present a challenge that can be overcome by using stereotactic navigation and advanced endoscopic techniques.

Space invader: pleural penetration of a hypoglossal nerve stimulator sensor lead.

The mainstay of treatment for obstructive sleep apnea is positive airway pressure therapy, which may be difficult for some patients to tolerate leading to compromised adherence and requiring alternative therapies. Hypoglossal nerve stimulation has become an option for those who meet implantation criteria. Implantation of the device is an ambulatory surgical procedure and is generally well-tolerated, though rare adverse events have been reported. We report an unusual complication of hypoglossal nerve stimulation in a patient who had initial success with this therapy. After 3 years of treatment, the sensor lead penetrated into the pleural space. Components of the hypoglossal nerve stimulation were explanted, and a new sensor lead and generator were reimplanted. The new device was activated, and therapy was successfully resumed. This case demonstrates that there is a potential for a delayed complication of sensor lead penetration into the pleural space, which has only rarely been reported. CITATION: Lou B, Hahn S, Korotun M, Quintero L, Shikowitz M, Greenberg H. Space invader: pleural penetration of a hypoglossal nerve stimulator sensor lead. J Clin Sleep Med. 2021;17(11):2329-2332.

Epidermal growth factor-induced cyclooxygenase-2 expression is mediated through phosphatidylinositol-3 kinase, not mitogen-activated protein/extracellular signal-regulated kinase kinase, in recurrent respiratory papillomas.

PURPOSE: Recurrent respiratory papillomas, caused by human papillomaviruses, are premalignant tumors that overexpress the epidermal growth factor receptor (EGFR). The goals of this study were as follows: (a) to evaluate the expression of cyclooxygenase-2 (COX-2) in papillomas, (b) to investigate the role of EGFR signaling in COX-2 expression, and (c) to determine whether COX-2 activity is important for the growth of papilloma cells. EXPERIMENTAL DESIGN: Immunohistochemistry, Western blotting, and real-time PCR were used to determine levels of COX-2 in papilloma and normal laryngeal tissue. Explant cultures of both normal laryngeal and papilloma cells were used to define the signaling pathways that regulate COX-2 expression and investigate the potential of targeting COX-2 as a strategy to suppress papilloma growth. RESULTS: COX-2 levels were markedly increased in papillomas. In vitro studies suggested that overexpression in papillomas reflected activation of EGFR-->phosphatidylinositol 3-kinase signaling. Treatment with prostaglandin E2 (PGE2) induced COX-2, whereas celecoxib, a selective COX-2 inhibitor, suppressed levels of COX-2, suggesting a positive feedback loop. Moreover, treatment with PGE2 stimulated papilloma cell growth, whereas celecoxib suppressed proliferation and induced apoptosis. CONCLUSIONS: Overexpression of COX-2 in papillomas seems to be a consequence of enhanced EGFR-->phosphatidylinositol 3-kinase signaling. We propose a positive feedback loop for COX-2 expression, with induction of COX-2 resulting in enhanced PGE2 synthesis and further expression of COX-2 that contributes to the growth of papillomas in vivo. These data strengthen the rationale for evaluating whether nonsteroidal anti-inflammatory drugs, prototypic COX inhibitors, will be useful in the management of respiratory papillomas.

Clinical trial of photodynamic therapy with meso-tetra (hydroxyphenyl) chlorin for respiratory papillomatosis.

OBJECTIVE: To determine the efficacy of photodynamic therapy (PDT) with meso-tetra (hydroxyphenyl) chlorin (m-THPC) photosensitizer for recurrent respiratory papillomatosis. DESIGN: Parallel-arm, randomized trial of patients requiring surgery at least 3 times yearly with single PDT 6 or 18 months after enrollment and 12-month follow-up. Disease extent was scored and papillomas were removed during direct endoscopy every 3 months after enrollment. SETTING: Tertiary medical centers. PATIENTS: Of 23 patients aged 4 to 60 years enrolled in the study, 15 patients, plus 2 in the late group without PDT owing to airway risk, completed the study. Six patients withdrew voluntarily after PDT. INTERVENTION: Intravenous administration of m-THPC 6 days before direct endoscopic PDT with 80 to 100 J of light for adults and 60 to 80 J for children. MAIN OUTCOME MEASURES: Difference in severity scores between the early and late groups and between pre- and post-PDT scores for all patients. Secondary measures were the associations between baseline characteristics and response and changes in immune response and the prevalence of latent viral DNA. RESULTS: There were significant differences between groups, with marked improvement in laryngeal disease across time after PDT (P = .006). Five of 15 patients were in remission 12 to 15 months after treatment, but there was recurrence of disease after 3 to 5 years. Tracheal disease was not responsive to PDT. No change occurred in the prevalence of latent human papillomavirus DNA. The immune response to virus improved with clinical response. CONCLUSIONS: Use of m-THPC PDT reduces the severity of laryngeal papillomas, possibly through an improved immune response. Failure to maintain remission with time suggests that this is not an optimal treatment.

Patient selection in congenital pyriform aperture stenosis repair - 14 year experience and systematic review of literature.

PURPOSE: Congenital nasal pyriform aperture stenosis (CNPAS) is a rare cause of respiratory distress in neonates that may necessitate early surgical intervention. Restenosis and granulation are postoperative concerns that may prompt a return to the operating room. Reoperation places children at increased risk of perioperative complications and prolonged hospital stays. We are presenting a review of our institutional experience of 16 patients treated for CNPAS over a 14 year period and a systematic review with pooled data analysis to determine the effect of craniofacial and neurologic anomalies on surgical success. METHODS: Retrospective chart review of all cases of CNPAS treated at our tertiary children's hospital between 1999 and 2013. Systematic review of English language literature was conducted adhering to the PRISMA statement to determine the effect of neurologic anomalies and craniofacial dysmorphism (CFD) on surgical failure for CNPAS treatment. Univariate and exact multiple logistic regression were used for analysis of an individual patient data analysis. RESULTS: 10 patients had surgery and 6 were treated medically. Average pyriform apertures were 5.71±1.72mm for the surgical group and 4.83±1.26mm for the medical group (p=0.38). 31% had neurological impairments. 31% had craniofacial dysmorphisms (CFD). 2 patients developed restenosis and 1 required tracheotomy. Both of these patients had other CFDs. Literature review captured 63 surgical patients and 9 failures in 6 series of CNPAS. 4.6% of patients without CFD and 36.8% of patients with CFD required surgical revision (p=0.023, OR13.8). CONCLUSION: When repairing CNPAS, co-morbidities must be considered. Impaired respiration, central neurologic deficits and extensive craniofacial anomalies may require additional surgeries or an alternative approach.

HLA alleles, IFN-gamma responses to HPV-11 E6, and disease severity in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) remains an immunologic enigma. Human papillomavirus (HPV) types 6 and 11 are the predominant HPV viruses that cause papilloma development. However, it is unclear why only a very small fraction of HPV-exposed individuals develop RRP. We performed high-resolution HLA class I and II genotyping on 70 randomly selected patients (56 Caucasians and 14 African-Americans) with RRP. We report, for the first time, an increased frequency of HLA-DRB1*0102 in Caucasian patients with RRP, suggesting that this allele predisposes individuals to RRP. Additionally, HLA-DRB1*0301, DQB1*0201, and DQB1*0202 alleles were selectively enriched in Caucasians with severe disease, suggesting that these alleles may regulate disease severity. In contrast, HLA-DQB1*0602 was more frequent in controls than in Caucasians with severe disease, suggesting a severity-sparing effect of this allele. Furthermore, both DQB1*0201 and DQB1*0202 were enriched, whereas DQB1*0602 was absent, in African-Americans. Interestingly, HLA-DRB1*0301 and DQB1*0201 correlated with reduced interferon-gamma expression in patients with RRP. Larger studies are needed to identify other class II major histocompatibility complex alleles that may influence disease predisposition, disease severity, or both, especially in African-American patients, to ultimately illuminate the regulatory effects of these alleles in the predisposition and severity of RRP.

The effect of upper airway surgery on voice.

OBJECTIVE: Our goal was to assess patient perception and acoustic characteristics of voice before and after upper airway surgery. STUDY DESIGN AND SETTING: We conducted a prospective assessment of 44 surgical patients preoperatively and postoperatively at a tertiary care, academic hospital. Operations included septoplasty and turbinectomy (n = 28) and septoplasty, turbinectomy, uvulopalatopharyngoplasty, and tonsillectomy (n = 16). Patient opinion measures included Voice Handicap Index score, perception of vocal resonance, and change in voice. Acoustic measures included assessment of the relative amplitude of selected formants (resonances) of the vocal tract. RESULTS: Mean Voice Handicap Index scores were unchanged after surgery. Nine patients (20%) perceived their voice to be improved after surgery. None perceived the voice to be worse. Postoperative changes in relative formant amplitudes were statistically significant. These changes caused the acoustic features to become more representative of normative data than the preoperative values. CONCLUSION: Upper airway oeprations can affect acoustics and perception of voice. SIGNIFICANCE: Patients are unlikely to perceive a change in voice as a result of upper airway surgeries, but in those cases where a difference is perceived, it is likely to be a positive change.

Congenital nasal pyriform aperture stenosis: diagnosis and treatment.

Congenital nasal pyriform aperture stenosis is a rare and an unusual cause of airway obstruction in infants. It has been described as a clinical entity only since 1989. Presenting symptoms in infants include cyclical cyanosis, feeding difficulty or sudden total obstruction. Embryologically, an overgrowth of maxillary ossification at the area of the nasal process of the maxilla may be responsible for this deformity. Definitive surgical management may be accomplished via a sublabial approach with magnification, drilling and post-operative stenting of the airway. Two new cases are presented. The diagnosis, embryology and technique of surgical correction are discussed.

Failure of gamma interferon but not interleukin-10 expression in response to human papillomavirus type 11 E6 protein in respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a chronic, debilitating disease of the upper airway caused by human papillomavirus type 6 (HPV-6) or HPV-11. We describe responses of peripheral blood mononuclear cells (PBMC) and T cells from RRP patients and controls to the HPV-11 early proteins E6 and E7. PBMC were exposed in vitro to purified E6 or E7 proteins or transduced with fusion proteins containing the first 11 amino acids of the human immunodeficiency virus type 1 protein tat fused to E6 or E7 (tat-E6/tat-E7). T(H)1-like (interleukin-2 [IL-2], gamma interferon [IFN-gamma], IL-12, and IL-18), and T(H)2-like (IL-4 and IL-10) cytokine mRNAs were identified by reverse transcription-PCR, and IFN-gamma and IL-10 cytokine-producing cells were identified by enzyme-linked immunospot assay. These studies show that HPV-11 E6 skews IL-10-IFN-gamma expression by patients with RRP toward greater expression of IL-10 than of IFN-gamma. In addition, there is a general cytokine hyporesponsiveness to E6 that is more prominent for T(H)1-like cytokine expression by patients with severe disease. Patients showed persistent IL-10 cytokine expression by the nonadherent fraction of PBMC when challenged with E6 and tat-E6, and, in contrast to controls, both T cells and non-T cells from patients expressed IL-10. However, E7/tat-E7 cytokine responses in patients with RRP were similar to those of the controls. In contrast, E6 inhibited IL-2 and IL-18 mRNA expression that would further contribute to a cytokine microenvironment unfavorable to HPV-specific, T-cell responses that should control persistent HPV infection. In summary, E6 is the dominant inducer of cytokine expression in RRP, and it induces a skewed expression of IL-10 compared to the expression of IFN-gamma.