Delayed Facial Nerve Dysfunction Following CyberKnife® Radiosurgery for Vestibular Schwannoma.

OBJECTIVE: The incidence and risk factors for facial nerve dysfunction (FND) following CyberKnife® therapy for vestibular schwannoma (VS) remain poorly understood. This study investigates whether differential radiation doses to vulnerable segments of the facial nerve may be associated with FND outcomes. METHODS: Patients were identified who underwent CyberKnife® radiosurgery for VS at a single institution. Basic demographics, tumor characteristics, and facial nerve function were collected. Total radiation doses to tumor, internal auditory canal (IAC), and labyrinthine segment of facial nerve (LSFN) were evaluated. RESULTS: Six out of 64 patients experienced FND following CyberKnife® treatment for VS (9.38%, 6/64). Patients with FND were compared to those without FND (control). Of the 64 patients, complete radiation records were obtained for 30 patients (6 FND vs. 24 control). There were no significant differences in demographic or tumor characteristics between control and FND cohorts. More severe FND (HB ≥ 4) had significantly larger tumors (3.74 vs. 1.27 cm3, p = 0.037) with directionally decreased time to FND (3.50 vs. 33.5 months, p = 0.106) than patients with HB < 4, respectively. There were directionally, nonsignificant differences between maximum radiation doses to the LSFN (2492.4 vs. 2557.0 cGy, p = 0.121) and IAC (2877.3 vs. 2895.5 cGy, p = 0.824) between the control and FND cohorts, respectively. CONCLUSIONS: FND may represent an underrecognized sequelae of CyberKnife® radiosurgery for VS that can occur many months following treatment. Further studies are needed to elucidate the effect of differential radiation exposure to the facial nerve with FND following treatment. LEVEL OF EVIDENCE: III (Retrospective Cohort Study) Laryngoscope, 2024.

Variability in Perioperative Steroid Therapy Regimen for Cochlear Implantation as It Relates to Hearing Preservation.

HYPOTHESIS: We aimed to identify practice trends and association between physician training and administration of perioperative steroids for cochlear implantation (CI) as it relates to hearing preservation. BACKGROUND: Perioperative steroid therapy regimens are postulated to protect residual hearing and improve hearing preservation outcomes in CI. METHODS: A 27-question online survey was developed by the senior authors using the Qualtrics Survey Tool, then distributed via email from September to November 2022 to otolaryngologists specializing in otology or neurotology and who practice in the United States or Canada. RESULTS: The survey was sent to 463 physicians, 162 (35.0%) of whom completed the survey. One hundred forty-four (31.1%) responses underwent analysis. All physicians administering preoperative steroids (n = 31) prefer preoperative oral prednisone. Of 143 physicians administering intraoperative steroids, 54.5% prefer intraoperative intravenous dexamethasone. More than half (77.6%) of 85 physicians administering postoperative steroids prefer postoperative oral prednisone. Postoperative steroid administration (p < 0.006) and taper utilization (p < 0.041) were greater among physicians who complete greater than 40 CIs annually (n = 47 [71.2%]; n = 30 [49.2%]) than physicians who complete up to 40 CIs annually (n = 37 [48.7%]; n = 20 [31.3%]), respectively. Physicians practicing for 5 to 20 years after residency are more prevalent in using postoperative steroid tapers than physicians practicing for fewer than 5 years after and more than 20 years after residency (n = 37 [51.4%] versus n = 14 [25.5%], p < 0.001). CONCLUSION: Consensus is needed about the optimal steroid treatment for CI patients. LEVEL OF EVIDENCE: 4.

Emerging Mechanisms in the Pathogenesis of Menière's Disease: Evidence for the Involvement of Ion Homeostatic or Blood-Labyrinthine Barrier Dysfunction in Human Temporal Bones.

HYPOTHESIS: Analysis of human temporal bone specimens of patients with Menière's disease (MD) may demonstrate altered expression of gene products related to barrier formation and ionic homeostasis within cochlear structures compared with control specimens. BACKGROUND: MD represents a challenging otologic disorder for investigation. Despite attempts to define the pathogenesis of MD, there remain many gaps in our understanding, including differences in protein expression within the inner ear. Understanding these changes may facilitate the identification of more targeted therapies for MD. METHODS: Human temporal bones from patients with MD (n = 8) and age-matched control patients (n = 8) were processed with immunohistochemistry stains to detect known protein expression related to ionic homeostasis and barrier function in the cochlea, including CLDN11, CLU, KCNJ10, and SLC12A2. Immunofluorescence intensity analysis was performed to quantify protein expression in the stria vascularis, organ of Corti, and spiral ganglion neuron (SGN). RESULTS: Expression of KCNJ10 was significantly reduced in all cochlear regions, including the stria vascularis (9.23 vs 17.52, p = 0.011), OC (14.93 vs 29.16, p = 0.014), and SGN (7.69 vs 18.85, p = 0.0048) in human temporal bone specimens from patients with MD compared with control, respectively. CLDN11 (7.40 vs 10.88, p = 0.049) and CLU (7.80 vs 17.51, p = 0.0051) expression was significantly reduced in the SGN. CONCLUSION: The results of this study support that there may be differences in the expression of proteins related to ionic homeostasis and barrier function within the cochlea, potentially supporting the role of targeted therapies to treat MD.

Dissection of Adult Mouse Stria Vascularis for Single-Nucleus Sequencing or Immunostaining.

Endocochlear potential, which is generated by the stria vascularis, is essential to maintain an environment conducive to appropriate hair cell mechanotransduction and ultimately hearing. Pathologies of the stria vascularis can result in a decreased hearing. Dissection of the adult stria vascularis allows for focused single-nucleus capture and subsequent single-nucleus sequencing and immunostaining. These techniques are used to study stria vascularis pathophysiology at the single-cell level. Single-nucleus sequencing can be used in the setting of transcriptional analysis of the stria vascularis. Meanwhile, immunostaining continues to be useful in identifying specific populations of cells. Both methods require proper stria vascularis dissection as a prerequisite, which can prove to be technically challenging.

The role of the stria vascularis in neglected otologic disease.

The stria vascularis (SV) has been shown to play a critical role in the pathogenesis of many diseases associated with sensorineural hearing loss (SNHL), including age-related hearing loss (ARHL), noise-induced hearing loss (NIHL), hereditary hearing loss (HHL), and drug-induced hearing loss (DIHL), among others. There are a number of other disorders of hearing loss that may be relatively neglected due to being underrecognized, poorly understood, lacking robust diagnostic criteria or effective treatments. A few examples of these diseases include autoimmune inner ear disease (AIED) and/or autoinflammatory inner ear disease (AID), Meniere's disease (MD), sudden sensorineural hearing loss (SSNHL), and cytomegalovirus (CMV)-related hearing loss (CRHL). Although these diseases may often differ in etiology, there have been recent studies that support the involvement of the SV in the pathogenesis of many of these disorders. We strive to highlight a few prominent examples of these frequently neglected otologic diseases and illustrate the relevance of understanding SV composition, structure and function with regards to these disease processes. In this study, we review the physiology of the SV, lay out the importance of these neglected otologic diseases, highlight the current literature regarding the role of the SV in these disorders, and discuss the current strategies, both approved and investigational, for management of these disorders.

Retained tracheostomy stay suture with migration into the glottic airway: A case report.

The stay-suture technique (SST) helps ensure safe replacement of the tracheostomy tube after accidental decannulation. We describe a patient found to have a retained stay suture in the glottis 2 weeks post-decannulation. It is important to appreciate the possible complications associated with SST, including airway compromise, infection, and laryngospasm.

Poly (acetyl, arginyl) glucosamine disrupts Pseudomonas aeruginosa biofilms and enhances bacterial clearance in a rat lung infection model.

Pseudomonas aeruginosa is a common opportunistic pathogen that can cause chronic infections in multiple disease states, including respiratory infections in patients with cystic fibrosis (CF) and non-CF bronchiectasis. Like many opportunists, P. aeruginosa forms multicellular biofilm communities that are widely thought to be an important determinant of bacterial persistence and resistance to antimicrobials and host immune effectors during chronic/recurrent infections. Poly (acetyl, arginyl) glucosamine (PAAG) is a glycopolymer that has antimicrobial activity against a broad range of bacterial species, and also has mucolytic activity, which can normalize the rheological properties of cystic fibrosis mucus. In this study, we sought to evaluate the effect of PAAG on P. aeruginosa bacteria within biofilms in vitro, and in the context of experimental pulmonary infection in a rodent infection model. PAAG treatment caused significant bactericidal activity against P. aeruginosa biofilms, and a reduction in the total biomass of preformed P. aeruginosa biofilms on abiotic surfaces, as well as on the surface of immortalized cystic fibrosis human bronchial epithelial cells. Studies of membrane integrity indicated that PAAG causes changes to P. aeruginosa cell morphology and dysregulates membrane polarity. PAAG treatment reduced infection and consequent tissue inflammation in experimental P. aeruginosa rat infections. Based on these findings we conclude that PAAG represents a novel means to combat P. aeruginosa infection, and may warrant further evaluation as a therapeutic.

Utilizing Single Cell RNA-Sequencing to Implicate Cell Types and Therapeutic Targets for SSNHL in the Adult Cochlea.

OBJECTIVE: To identify genes implicated in sudden sensorineural hearing loss (SSNHL) and localize their expression in the cochlea to further explore potential pathogenic mechanisms and therapeutic targets. STUDY DESIGN: Systematic literature review and bioinformatics analysis. DATA SOURCES: The following sources were searched from inception through July 2, 2020: PubMed-NCBI, MEDLINE, Embase, CINAHL, Cochrane Library, ClinicalTrials.gov, OpenGrey, GreyNet, GreyLiterature Report, and European Union Clinical Trials Registry. PubMed-NCBI and MEDLINE were additionally searched for human temporal bone histopathologic studies related to SSNHL. METHODS: Literature review of candidate SSNHL genes was conducted according to PRISMA guidelines. Existing temporal bone studies from SSNHL patients were analyzed to identify the most commonly affected inner ear structures. Previously published single-cell and single-nucleus RNA-Seq datasets of the adult mouse stria vascularis, as well as postnatal day 7 and 15 mouse cochlear hair cells and supporting cells, were utilized for localization of the SSNHL-related genes curated through literature review. CONCLUSIONS: We report 92 unique single nucleotide polymorphisms (SNPs) in 76 different genes that have been investigated in relation to SSNHL in the literature. We demonstrate that a subset of these genes are expressed by cell types in the adult mouse stria vascularis and organ of Corti, consistent with findings from temporal bone studies in human subjects with SSNHL. We highlight several potential genetic targets relevant to current and possible future SSNHL treatments.

Hearing restoration and the stria vascularis: evidence for the role of the immune system in hearing restoration.

PURPOSE OF REVIEW: This article reviews the current literature regarding the pathogenesis of immune-mediated sensorineural hearing loss, utilizes previously published single-nucleus transcriptional profiles to characterize cytokine and cytokine receptor expression in the adult stria vascularis cell types to support immune system interaction with the stria vascularis and reviews the current literature on immunomodulatory agents currently being used for hearing-restoration treatment. RECENT FINDINGS: The literature review highlights recent studies that elucidate many cytokines and immune markers, which have been linked to various immune-mediated disease processes that have been observed with sensorineural hearing loss within the stria vascularis and highlights recent publications studying therapeutic targets for these pathways. SUMMARY: This review highlights the current literature regarding the pathogenesis of immune-mediated hearing loss. The role of cochlear structures in human temporal bones from patients with immune-mediated sensorineural hearing loss are highlighted, and we review cytokine signalling pathways relevant to immune-mediated sensorineural hearing loss and localize genes encoding both cytokine and cytokine receptors involved in these pathways. Finally, we review immunomodulatory therapeutics in light of these findings and point to opportunities for the application of novel therapeutics by targeting these signalling pathways.

In silico Single-Cell Analysis of Steroid-Responsive Gene Targets in the Mammalian Cochlea.

BACKGROUND: Treatment of many types of hearing instability in humans, including sudden sensorineural hearing loss, Meniere's disease, and autoimmune inner ear disease, rely heavily on the utilization of corticosteroids delivered both by oral and transtympanic routes. Despite this use, there is heterogeneity in the response to treatment with corticosteroids in humans with these diseases. The mechanisms by which corticosteroids exert their effect and the cell types in which they exert their effects in the inner ear remain poorly characterized. In this study, we localize steroid-responsive genes to cochlear cell types using previously published transcriptome datasets from the mammalian cochlea. METHODS: Steroid-responsive genes were localized to specific cochlear cell types using existing transcriptome datasets from wild-type mammalian cochlea exposed to systemic and transtympanic steroids, as well as previously published single-cell and single-nucleus RNA-sequencing datasets from the mammalian cochlea. Gene ontology (GO) analysis of differentially expressed genes (DEGs) was performed using PANTHER to investigate cellular processes implicated in transtympanic vs. systemic steroid action in the cochlea. RESULTS: Steroid-responsive genes were localized to specific cell types and regions in the cochlea including the stria vascularis, organ of Corti, and spiral ganglion neurons (SGN). Analyses demonstrate differential prevalence of steroid-responsive genes. GO analysis demonstrated steroid-responsive DEGs in the SGN to be associated with angiogenesis, apoptosis, and cytokine-mediated anti-inflammatory pathways. CONCLUSIONS: Single-cell and single-nucleus transcriptome datasets localize steroid-responsive genes to specific regions in the cochlea. Further study of these regionally-specific steroid-responsive genes may provide insight into the mechanisms of and clinical response to corticosteroids in diseases of hearing instability.

Cochlear Implantation and Perioperative Management in Autoimmune Inner Ear Disease: A Systematic Review and Meta-Analysis.

Objective: To assess outcomes in autoimmune inner ear disease (AIED) after cochlear implantation (CI) through systematic review and meta-analysis. Databases Reviewed: PubMed, MedLine, Embase, and CINAHL. Methods: Databases were queried for inclusion of AIED patients who underwent CI with outcomes recorded ≥3 months postoperatively. We examined demographics, pure-tone average (PTA), speech perception, preoperative imaging, intraoperative management, and postoperative complications. Results: Twenty-six articles encompassing 124 patients met inclusion criteria. Mean implantation age was 26.2 years (range 4-65 years) with average length of follow-up at 28.2 months (range 3-120 months). Meta-analysis demonstrated significant improvement in speech perception following CI. There was a statistically significant improvement in speech recognition score (SRS) (standard mean difference [SMD] = 6.5, 95% confidence interval [CI], 4.8-8.0, P < 0.0001) as well as word recognition score (WRS) (SMD = 5.5, 95% CI, 4.2-6.8, P < 0.0001) after CI. Anomalous preoperative radiologic manifestations were reported by 57.7% (15/26) studies. Disease activity-related intraoperative adjustment was noted in 57.7% (15/26) studies; common consequences were cochlear drill-out (53.3%), difficult round window insertion (26.7%), and scala vestibuli insertion (26.7%). Frequent postoperative complications noted in 26.9% (7/26) studies included systemic AIED flares (71.4%) and wound healing delay (42.9%). Conclusion: Findings of this systematic review of AIED cochlear implant literature demonstrate a lack of consistent reporting standards for PTA and speech perception as well as a lack of long-term follow-up. Despite these findings, meta-analysis suggests that CI is a viable treatment for improving speech perception in AIED patients.

Novel Therapy of Bicarbonate, Glutathione, and Ascorbic Acid Improves Cystic Fibrosis Mucus Transport.

Defective airway mucus clearance is a defining characteristic of cystic fibrosis lung disease, and improvements to current mucolytic strategies are needed. Novel approaches targeting a range of contributing mechanisms are in various stages of preclinical and clinical development. ARINA-1 is a new nebulized product comprised of ascorbic acid, glutathione, and bicarbonate. Using microoptical coherence tomography, we tested the effect of ARINA-1 on central features of mucociliary clearance in F508del/F508del primary human bronchial epithelial cells to assess its potential as a mucoactive therapy in cystic fibrosis. We found that ARINA-1 significantly augmented mucociliary transport rates, both alone and with CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy, whereas airway hydration and ciliary beating were largely unchanged compared with PBS vehicle control. Analysis of mucus reflectivity and particle-tracking microrheology indicated that ARINA-1 restores mucus clearance by principally reducing mucus layer viscosity. The combination of bicarbonate and glutathione elicited increases in mucociliary transport rate comparable to those seen with ARINA-1, indicating the importance of this interaction to the impact of ARINA-1 on mucus transport; this effect was not recapitulated with bicarbonate alone or bicarbonate combined with ascorbic acid. Assessment of CFTR chloride transport revealed an increase in CFTR-mediated chloride secretion in response to ARINA-1 in CFBE41o- cells expressing wild-type CFTR, driven by CFTR activity stimulation by ascorbate. This response was absent in CFBE41o- F508del cells treated with VX-809 and primary human bronchial epithelial cells, implicating CFTR-independent mechanisms for the effect of ARINA-1 on cystic fibrosis mucus. Together, these studies indicate that ARINA-1 is a novel potential therapy for the treatment of impaired mucus clearance in cystic fibrosis.

The effect of CFTR modulators on a cystic fibrosis patient presenting with recurrent pancreatitis in the absence of respiratory symptoms: a case report.

BACKGROUND: Cystic fibrosis (CF) is a genetic disorder of the epithelial CFTR apical chloride channel resulting in multi-organ manifestations, including pancreatic exocrine secretion. In the pancreas, CFTR abnormality results in abnormally viscous secretions that obstruct proximal ducts leading to fibrotic injury and ultimately pancreatic insufficiency in 85% of the CF population. CFTR modulators, including the potentiator ivacaftor, augment channel gating to restore 30-50% of CFTR-mediated anion transport. While CFTR modulation has been shown to alkalinize the pH of the alimentary tract and potentially augment pancreatic enzyme activity, the effect of ivacaftor on recurrent pancreatitis is emerging. Here we describe a case of a patient with CF (R117H/7 T/F508del) who presented with recurrent pancreatitis who was effectively treated with ivacaftor in the absence of respiratory symptoms. CASE PRESENTATION: A 24-year-old white male with past medical history of recurrent acute pancreatitis presented for evaluation following a referral from an outside hospital. The patient reported a lifetime of gastrointestinal symptoms requiring over 20 hospitalizations for pancreatitis in the last 10 years. Prior U/S and CT imaging for pancreatitis ruled out gallstones or anatomical etiologies. Family history included a brother with CF carrier status who suffered from recurrent acute pancreatitis. Sweat chloride testing was suggestive of CFTR dysfunction (57 mmol/L). Genetic testing demonstrated disease causing CFTR mutations: R1117H/7 T/F508del. Patient was prescribed pancrelipase, however, he reported worsened gas and diarrhea symptoms. Pancrelipase was discontinued and the patient was prescribed ivacaftor 150 mg BID. After 6 weeks of ivacaftor treatment, patient reported improved gastrointestinal symptoms. For an additional 19 months, patient reported no episodes of pancreatitis until he discontinued ivacaftor. Over the next 3 weeks, patient experienced progressive nausea and sharp epigastric pain and laboratory studies confirmed pancreatitis. Patient was subsequently lost to follow up. CONCLUSIONS: These findings support a possible relationship between the use of CFTR modulators, such as ivacaftor, in the management of recurrent pancreatitis in the setting of patients with cystic fibrosis and a CFTR mutation with residual CFTR activity or otherwise known to be responsive in vitro. Ivacaftor may be useful for recurrent pancreatitis, even in the absence of respiratory morbidity.