A Deep Learning Framework for Analysis of the Eustachian Tube and the Internal Carotid Artery.

OBJECTIVE: Obtaining automated, objective 3-dimensional (3D) models of the Eustachian tube (ET) and the internal carotid artery (ICA) from computed tomography (CT) scans could provide useful navigational and diagnostic information for ET pathologies and interventions. We aim to develop a deep learning (DL) pipeline to automatically segment the ET and ICA and use these segmentations to compute distances between these structures. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center. METHODS: From a database of 30 CT scans, 60 ET and ICA pairs were manually segmented and used to train an nnU-Net model, a DL segmentation framework. These segmentations were also used to develop a quantitative tool to capture the magnitude and location of the minimum distance point (MDP) between ET and ICA. Performance metrics for the nnU-Net automated segmentations were calculated via the average Hausdorff distance (AHD) and dice similarity coefficient (DSC). RESULTS: The AHD for the ET and ICA were 0.922 and 0.246 mm, respectively. Similarly, the DSC values for the ET and ICA were 0.578 and 0.884. The mean MDP from ET to ICA in the cartilaginous region was 2.6 mm (0.7-5.3 mm) and was located on average 1.9 mm caudal from the bony cartilaginous junction. CONCLUSION: This study describes the first end-to-end DL pipeline for automated ET and ICA segmentation and analyzes distances between these structures. In addition to helping to ensure the safe selection of patients for ET dilation, this method can facilitate large-scale studies exploring the relationship between ET pathologies and the 3D shape of the ET.

Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.

Background: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion: This study shows the importance of examining patient's family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister's unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.

Digenic Congenital Hypogonadotropic Hypogonadism Due to Heterozygous GNRH1 p.R31C and AMHR2 p.G445_L453del Variants.

A 28-year-old man with congenital hypogonadotropic hypogonadism (CHH) was found to be heterozygous for the GNRH1 p.R31C mutation, reported in the literature as pathogenic and dominant. The same mutation was found in his son at birth, but the testing of the infant at 64 days confirmed the hormonal changes associated with minipuberty. This led to further genetic sequencing of the patient and his son, which found a second variant, AMHR2 p.G445_L453del, in the heterozygous form, reported as pathogenic in the patient but not in his son. This suggests a digenic cause of the patient's CHH. Together, these mutations are postulated to contribute to CHH by the lack of anti-Müllerian hormone (AMH) signalling, leading to the impaired migration of gonadotrophin releasing hormone (GnRH) neurons, the lack of the AMH effect on GnRH secretion, and altered GnRH decapeptide with reduced binding to GnRH receptors. This led us to the conclusion that the observed GNRH1 mutation in the heterozygous state is not certain to be dominant or, at least, exhibits incomplete penetrance and variable expressivity. This report also emphasises the opportunity afforded by the time window of minipuberty in assessing the inherited genetic disorders of hypothalamic function.

Vestibular Implantation Can Work Even After More Than 20 Years of Bilateral Vestibular Hypofunction.

OBJECTIVE: To determine whether prosthetic stimulation delivered via a vestibular implant can elicit artificial sensation of head movement despite long (23-yr) duration adult-onset ototoxic bilateral vestibular hypofunction (BVH). STUDY DESIGN: Case report. SETTING: Tertiary care center as part of a first-in-human clinical trial. PATIENTS: One. INTERVENTIONS: Unilateral vestibular implantation with an investigational multichannel vestibular implant in a 55-year-old man with a well-documented 23-year history of aminoglycoside-induced BVH. MAIN OUTCOME MEASURES: Electrically evoked vestibulo-ocular reflexes (eeVOR). RESULTS: Vestibular implant stimulation can drive stimulus-aligned eeVOR and elicit a vestibular percept 23 years after the onset of bilateral vestibulopathy. Prosthetic stimulation targeting individual semicircular canals elicited eye movements that approximately aligned with each targeted canal's axis. The magnitude of the eeVOR response increased with increasing stimulus current amplitude. Response alignment and magnitude were similar to those observed for implant recipients who underwent vestibular implantation less than 10 years after BVH onset. Responses were approximately stable for 18 months of continuous device use (24 h/d except during sleep). CONCLUSIONS: Vestibular implantation and prosthetic electrical stimulation of semicircular canal afferent nerves can drive canal-specific eye movement responses more than 20 years after the onset of ototoxic vestibular hypofunction.

Medical interventions for chronic rhinosinusitis in cystic fibrosis.

BACKGROUND: Chronic rhinosinusitis frequently occurs in people with cystic fibrosis. Several medical interventions are available for treating chronic rhinosinusitis in people with cystic fibrosis; for example, different concentrations of nasal saline irrigations, topical or oral corticosteroids, antibiotics - including nebulized antibiotics - dornase alfa and modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) (such as lumacaftor, ivacaftor or tezacaftor). However, the efficacy of these interventions is unclear. This is an update of a previously published review. OBJECTIVES: The objective of this review is to compare the effects of different medical interventions in people diagnosed with cystic fibrosis and chronic rhinosinusitis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search of trials register: 09 September 2021. We also searched ongoing trials databases, other medical databases and the reference lists of relevant articles and reviews. Date of latest additional searches: 22 November 2021. SELECTION CRITERIA: Randomized and quasi-randomized trials of different medical interventions compared to each other or to no intervention or to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials identified for potential inclusion in the review. We planned to conduct data collection and analysis in accordance with Cochrane methods and to independently rate the quality of the evidence for each outcome using the GRADE guidelines. MAIN RESULTS: We identified no trials that met the pre-defined inclusion criteria. The most recent searches identified 44 new references, none of which were eligible for inclusion in the current version of this review; 12 studies are listed as excluded and one as ongoing. AUTHORS' CONCLUSIONS: We identified no eligible trials assessing the medical interventions in people with cystic fibrosis and chronic rhinosinusitis. High-quality trials are needed which should assess the efficacy of different treatment options detailed above for managing chronic rhinosinusitis, preventing pulmonary exacerbations and improving quality of life in people with cystic fibrosis.

Prevalence of Tympanic Membrane Perforations Among Adolescents, Adults, and Older Adults in the United States.

Tympanic membrane (TM) perforations can occur at any age, but limited population-level data are available. Using data from the National Health and Nutrition Examination Survey, we performed a cross-sectional analysis of the prevalence and population estimates for TM perforations among individuals ≥12 years old in the United States. Overall, TM perforations have a prevalence of 2.1% (95% CI, 1.7%-2.6%), corresponding to 5.8 million Americans. Across the life course, older adults have the highest prevalence of TM perforations at 6.1% (95% CI, 4.7%-7.6%), corresponding to nearly 3 million Americans, as opposed to a prevalence of 0.6% (95% CI, 0.3%-0.9%) in adolescents, which equates to 0.2 million Americans. Males and females have a similar prevalence at 2.3% (95% CI, 1.6%-3.0%) among males and 2.0% (95% CI, 1.4%-2.6%) among females. These prevalence and population estimates provide the first US-based population estimates of the burden of TM perforations over the life course.

Predictive value of the Eustachian Tube Dysfunction Questionnaire-7 for identifying obstructive Eustachian tube dysfunction: A systematic review.

OBJECTIVE: To perform a systematic review to determine if a total score of ≥14.5 (mean score ≥ 2.1) on the ETDQ-7 accurately identifies patients with obstructive Eustachian tube dysfunction (OETD) on impedance tympanometry (peak compliance <0.2 mL or middle ear pressure of -100 daPa) or other objective measures of OETD. METHODS: A systematic review without a meta-analysis was performed of studies in four electronic databases (Pubmed, Embase, Web of Science, and Scopus) that used the ETDQ-7 and at least one objective measure of OETD. RESULTS: Six-hundred and fifty-two studies were identified in the initial literature search. Abstracts from 337 studies were screened, followed by full-text review of 61 studies, and qualitative synthesis of 12 studies. Tympanometry was used as an objective measure in ten studies. Eight of the 12 included studies had patient cohort selection bias. Eight studies administered the ETDQ-7 in cohorts of patients with or without OETD, already confirmed on tympanometry, and found a sensitivity of 91%-100% and specificity of 67%-100%. Four studies administered the ETDQ-7 to patients who had not previously undergone objective testing and found a sensitivity of 49%-80% and specificity of 24%-78%. CONCLUSIONS: The ETDQ-7 is an important patient-reported outcome measure. However, based upon existing literature, the ETDQ-7 appears limited as a diagnostic tool for OETD or as an objective measure of Eustachian tube function.

MRI With Gadolinium as a Measure of Blood-Labyrinth Barrier Integrity in Patients With Inner Ear Symptoms: A Scoping Review.

Objective: Capillaries within the inner ear form a semi-permeable barrier called the blood-labyrinth barrier that is less permeable than capillary barriers elsewhere within the human body. Dysfunction of the blood-labyrinth barrier has been proposed as a mechanism for several audio-vestibular disorders. There has been interest in using magnetic resonance imaging (MRI) with intravenous gadolinium-based contrast agents (GBCA) as a marker for the integrity of the blood labyrinth barrier in research and clinical settings. This scoping review evaluates the evidence for using intravenous gadolinium-enhanced MRI to assess the permeability of the blood-labyrinth barrier in healthy and diseased ears. Methods: A systematic search was conducted of three databases: PubMed, EMBASE, CINAHL PLUS. Studies were included that used GBCA to study the inner ear and permeability of the blood-labyrinth barrier. Data was collected on MRI protocols used and inner ear enhancement patterns of healthy and diseased ears in both human and animal studies. Results: The search yielded 14 studies in animals and 53 studies in humans. In healthy animal and human inner ears, contrast-enhanced MRI demonstrated gradual increase in inner ear signal intensity over time that was limited to the perilymph. Signal intensity peaked at 100 min in rodents and 4 h in humans. Compared to controls, patients with idiopathic sudden sensorineural hearing loss and otosclerosis had increased signal intensity both before and shortly after GBCA injection. In patients with Ménière's disease and vestibular schwannoma, studies reported increased signal at 4 h, compared to controls. Quality assessment of included studies determined that all the studies lacked sample size justification and many lacked adequate control groups or blinded assessors of MRI. Conclusions: The included studies provided convincing evidence that gadolinium crosses the blood-labyrinth barrier in healthy ears and more rapidly in some diseased ears. The timing of increased signal differs by disease. There was a lack of evidence that these findings indicate general permeability of the blood-labyrinth barrier. Future studies with consistent and rigorous methods are needed to investigate the relationship between gadolinium uptake and assessments of inner ear function and to better determine whether signal enhancement indicates permeability for molecules other than gadolinium.

Reducing the risk of cerebrospinal fluid rhinorrhea following translabyrinthine surgery of the posterior fossa.

OBJECTIVE: To describe the procedure and results of an adapted closure and reconstruction technique for translabyrinthine surgery that focuses on identifying and managing potential pathways for CSF egress to the middle ear and Eustachian tube. METHODS: Retrospective review of a cohort of translabyrinthine acoustic neuroma cases that were reconstructed using this technique. RESULTS: In addition to meticulous packing of potential conduits using soft tissue, hydroxyapatite cement is used to seal opened air cell tracts prior to obliteration of the mastoid defect using adipose tissue. Early results of a small patient cohort using this technique are encouraging and there were no wound infections. There was a single case of CSF rhinorrhea associated with incomplete sealing of opened petrous apex cells, with no recurrence after appropriate implementation of the described protocol during revision surgery. CONCLUSION: Proactive management of potential conduits of CSF egress including opened air cell tracts has a high likelihood of reducing rates of rhinorrhea and need for revision surgery after the translabyrinthine approach to the posterior fossa.

Sudden Sensorineural Hearing and Vestibular Loss in a Case of Relapsing Polychondritis.

OBJECTIVES: To report a case of profound bilateral sensorineural hearing and vestibular loss from relapsing polychondritis and hearing outcomes after cochlear implantation. METHODS: Case report and literature review. RESULTS: A 43 year-old woman developed sudden loss of hearing and balance that progressed over several weeks to bilateral, profound hearing and vestibular loss. Steroid treatments were ineffective. She underwent vestibular physical therapy and left cochlear implantation. About 10 months after her initial presentation, she developed erythema, warmth, swelling, and pain of the left auricle sparing the lobule, flattening of the bridge of her nose, and right ankle swelling, warmth, and skin erythema. A biopsy of the left auricle revealed histopathologic findings consistent with relapsing polychondritis. She was treated with high dose prednisolone. The ear inflammation resolved, however, despite excellent auditory response to pure tone thresholds, the patient reported no improvement in speech perception after cochlear implantation. CONCLUSIONS: Relapsing polychondritis can present with rapidly progressive, profound loss of hearing and vestibular function. Hearing outcomes after cochlear implantation can include poor speech discrimination despite good pure tone detection thresholds.

Familial Dysalbuminemic Hyperthyroxinemia as a Cause for Discordant Thyroid Function Tests.

INTRODUCTION: Discordant thyroid function tests are routinely encountered in clinical practice. Differential diagnoses include acute thyroxine (T4) ingestion, laboratory interference from heterophilic antibodies, thyroid hormone resistance, thyroid-stimulating hormone (TSH)-secreting pituitary adenomas, and T4 protein binding abnormalities. The impact of abnormal binding proteins may be less recognized since widespread use of free T4 (FT4) assays compared to older total T4 assays. CASE REPORT: A 69-year-old female was referred for assessment of discordant thyroid function tests. Biochemistry since July 2015 showed persistently elevated FT4 levels by immunoassay ranging between 25 to 34 pmol/L with normal or slightly decreased TSH ranging between 0.05 to 2.74 mU/L. The patient was clinically euthyroid on 100 mcg daily of levothyroxine for Hashimoto's thyroiditis. FT4 measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was 19.5 pmol/L. Exome sequencing (confirmed by Sanger sequencing) detected a guanine to adenine substitution at residue 725 of the ALB gene previously associated with dysalbuminemic hyperthyroxinemia. The patient's daughter had similar thyroid function tests and the same genetic variant. FT4 results from 3 different automated immunoassays showed the Roche Cobas and Siemens Centaur platforms to be most affected by the variant, and Abbott Architect had the best agreement with LC-MS/MS. CONCLUSION: Familial dysalbuminemic hyperthyroxinemia is a potential cause of discordant thyroid function tests. Clinicians suspecting protein-binding abnormalities may further investigate using reference methods such as LC-MS/MS and equilibrium dialysis if available. The increasing accessibility of exome sequencing offers a cost-effective method of diagnosing genetic variants that cause discordant thyroid function tests.

A Historical Perspective on Surgical Manipulation of the Membranous Labyrinth for Treatment of Meniere's Disease.

Meniere's disease is an inner ear disorder without a known cause. Endolymphatic hydrops is a swelling of the endolymph spaces that has been observed consistently on post-mortem histology in patients with a history of Meniere's disease but can occur in asymptomatic individuals and in association with other diseases. Since its discovery, Meniere's disease has been a disorder managed primarily by otolaryngologists. Surgical treatments, therefore, have accompanied attempts at medical management. Inspired by patients' sensations of ear fullness and later by the histologic findings of hydrops, surgeons began manipulating the membranous labyrinth to relieve episodes of vertigo while attempting to preserve hearing. This review highlights this history of manipulation of the membranous labyrinth. These procedures indicate a rich history of innovation that parallels developments in otologic surgery. The studies involving patients are uniformly retrospective, with some procedures performed first in animal models of endolymphatic hydrops. Many approaches were endorsed by eminent otologic surgeons. Surgeries on the endolymphatic sac are performed by some surgeons today; however, procedures on the membranous labyrinth resulted in similar symptomatic relief through a minimally invasive technique, in many cases performed using only local anesthetic. Episodic vertigo in patients with Meniere's disease is a distressing symptom, yet spontaneous remissions are common. The reports of procedures on the membranous labyrinth reviewed here consistently indicated fewer vertigo episodes. Variable degrees of hearing loss were common following these procedures, and many were abandoned. Additional innovative surgeries are inevitable, but we must understand better the relationships among endolymphatic hydrops, Meniere's disease pathophysiology, and patient symptoms.

Transmastoid Trans-facial canal approach to facial nerve tumors.

Facial nerve tumors within the temporal bone present several surgical challenges due to the tortuous course of the facial nerve and the nerve's close relationship to other important structures. Surgical approaches often have either sacrificed hearing/vestibular function or involved brain retraction. We present a case of a patient who was diagnosed with a facial nerve schwannoma (House-Brackmann IV/VI). Magnetic resonance imaging (MRI) showed the tumor was limited to the middle ear. The patient had already undergone facial reanimation procedures and elected to have the tumor removed. A transmastoid trans-facial canal surgical approach was used to remove the tumor without disturbing the ossicular chain. The patient's hearing and vestibular function remained intact. Operating from within the facial canal provides the surgeon additional room to dissect facial nerve tumors from the middle ear to the geniculate ganglion when using a transmastoid approach. This surgical approach is similar to the previously described transmastoid/supralabyrinthine approach to excise facial nerve tumors within the temporal bone but modified to keep the ossicles intact. While the described approach has a limited application, in certain cases of facial nerve tumors within the temporal bone when surgery is warranted, a transmastoid trans-facial canal approach may have advantages over previously-described approaches.

Continuous vestibular implant stimulation partially restores eye-stabilizing reflexes.

BACKGROUNDBilateral loss of vestibular (inner ear inertial) sensation causes chronically blurred vision during head movement, postural instability, and increased fall risk. Individuals who fail to compensate despite rehabilitation therapy have no adequate treatment options. Analogous to hearing restoration via cochlear implants, prosthetic electrical stimulation of vestibular nerve branches to encode head motion has garnered interest as a potential treatment, but prior studies in humans have not included continuous long-term stimulation or 3D binocular vestibulo-ocular reflex (VOR) oculography, without which one cannot determine whether an implant selectively stimulates the implanted ear's 3 semicircular canals.METHODSWe report binocular 3D VOR responses of 4 human subjects with ototoxic bilateral vestibular loss unilaterally implanted with a Labyrinth Devices Multichannel Vestibular Implant System vestibular implant, which provides continuous, long-term, motion-modulated prosthetic stimulation via electrodes in 3 semicircular canals.RESULTSInitiation of prosthetic stimulation evoked nystagmus that decayed within 30 minutes. Stimulation targeting 1 canal produced 3D VOR responses approximately aligned with that canal's anatomic axis. Targeting multiple canals yielded responses aligned with a vector sum of individual responses. Over 350-812 days of continuous 24 h/d use, modulated electrical stimulation produced stable VOR responses that grew with stimulus intensity and aligned approximately with any specified 3D head rotation axis.CONCLUSIONThese results demonstrate that a vestibular implant can selectively, continuously, and chronically provide artificial sensory input to all 3 implanted semicircular canals in individuals disabled by bilateral vestibular loss, driving reflexive VOR eye movements that approximately align in 3D with the head motion axis encoded by the implant.TRIAL REGISTRATIONClinicalTrials.gov: NCT02725463.FUNDINGNIH/National Institute on Deafness and Other Communication Disorders: R01DC013536 and 2T32DC000023; Labyrinth Devices, LLC; and Med-El GmbH.

Medical interventions for chronic rhinosinusitis in cystic fibrosis.

BACKGROUND: Chronic rhinosinusitis frequently occurs in people with cystic fibrosis. Several medical interventions are available for treating chronic rhinosinusitis in people with cystic fibrosis; for example, different concentrations of nasal saline irrigations, topical or oral corticosteroids, antibiotics - including nebulized antibiotics, dornase alfa and modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) (such as lumacaftor, ivacaftor or tezacaftor). However, the efficacy of these interventions is unclear. OBJECTIVES: The objective of this review is to compare the effects of different medical interventions in people diagnosed with cystic fibrosis and chronic rhinosinusitis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search of trials register: 22 May 2019.We also searched ongoing trials databases, other medical databases and the reference lists of relevant articles and reviews. Date of latest additional searches: 20 May 2019. SELECTION CRITERIA: Randomized and quasi-randomized trials of different medical interventions compared to each other or to no intervention or to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials identified for potential inclusion in the review. We planned to conduct data collection and analysis in accordance with Cochrane methods and to independently rate the quality of the evidence for each outcome using the GRADE guidelines. MAIN RESULTS: We identified no trials that met the pre-defined inclusion criteria. The searches identified 47 trials, none of which were eligible for inclusion in the current version of this review. AUTHORS' CONCLUSIONS: We identified no eligible trials assessing the medical interventions in people with cystic fibrosis and chronic rhinosinusitis. High-quality trials are needed which should assess the efficacy of different treatment options detailed above for managing chronic rhinosinusitis, preventing pulmonary exacerbations and improving quality of life in people with cystic fibrosis.

Pressure Transmission to the Inner Ear by Mastoid Palpation After Transmastoid Surgery for Superior Canal Dehiscence.

OBJECTIVE: To discuss an effect of transmastoid repair of superior semicircular canal dehiscence and its resolution using a mastoid titanium mesh plate. PATIENTS: A 53-year-old woman with a history of superior canal dehiscence syndrome (SCDS) and subsequent transmastoid repair experienced dizziness and a loud, drum-like sound in her repaired ear when touching the ear. Palpating the skin over the mastoid defect reproduced the symptoms and could be observed on binocular microscopy as tympanic membrane deformation synchronous with mastoid palpation. INTERVENTION (S): Surgery to place a titanium mesh cranioplasty plate over the mastoid cavity. MAIN OUTCOME MEASURE (S): Reduction in dizziness and auditory symptoms when palpating the mastoid. RESULTS: In follow-up 2 months after surgery, palpation of the left mastoid no longer results in vertigo or hearing a loud sound. Hearing and vestibular function remained unchanged. CONCLUSIONS: Despite resolution of SCDS symptoms after transmastoid plugging and resurfacing of the superior semicircular canal involving mastoidectomy, patients can be bothered by dizziness and vertigo when pressing on the mastoid soft tissue envelope. This acts like a balloon that, when compressed, changes middle ear pressure and moves the tympanic membrane and can even cause alternobaric vertigo. This can be avoided or resolved by rigidly reconstructing the defect in the mastoid bone.