Enlarged Vestibular Aqueduct and Associated Inner Ear Malformations: Hearing Loss Prognostic Factors and Data Modeling from an International Cohort.

ACKGROUND: There is a need to operationalize existing clinical data to support precision medicine in progressive hearing loss (HL). By utilizing enlarged vestibular aqueduct (EVA) and its associated inner ear abnormalities as an exemplar, we model data from a large international cohort, confirm prognostic factors for HL, and explore the potential to generate a prediction model to optimize current management paradigms. METHODS: An international retrospective cohort study. Regression analyses were utilized to model frequency-specific HL and identify prognostic factors for baseline average HL severity and progression. Elastic-net regression and machine learning (ML) techniques were utilized to predict future average HL progression based upon routinely measurable clinical, genetic, and radiological data. RESULTS: Higher frequencies of hearing were lost more severely. Prognostic factors for HL were the presence of incomplete partition type 2 (coefficient 12.95 dB, P=.011, 95% CI 3.0-22 dB) and presence of sac signal heterogeneity (P=.009, 95% CI 0.062-0.429) on magnetic resonance imaging. Elastic-net regression outperformed the ML algorithms (R2 0.32, mean absolute error 11.05 dB) with coefficients for baseline average hearing level and the presence of sac heterogeneity contributing the most to prediction outcomes. CONCLUSION: Incomplete partition type 2 and endolymphatic sac signal heterogeneity phenotypes should be monitored closely for hearing deterioration and need for early audiological rehabilitation/cochlear implant. Preliminary prediction models have been generated using routinely collected health data in EVA. This study showcases how international collaborative research can use exemplar techniques to improve precision medicine in relatively rare disease entities.

Cochlear Implantation in Children with Enlarged Vestibular Aqueduct: A Systematic Review of Surgical Implications and Outcomes.

OBJECTIVES: This study investigated age at implantation, improvement in hearing and speech perception outcomes, as well as surgical complications in pediatric cochlear implant recipients with Pendred Syndrome (PS) or non-syndromic enlarged vestibular aqueduct (NSEVA). DESIGN: A systematic review of the literature between 1984 and 2021 was performed. Two independent reviewers performed abstract and full-text screening using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The inclusion criteria were: English language, cochlear implant, age at implantation available, age <18 years, PS, Mondini malformation, and enlarged vestibular aqueduct. Full-text analysis was completed using the National Institute of Health assessment tool for case series and case-control studies. Studies were also graded according to the Oxford Centre for Evidence-Based Medicine grading system. RESULTS: In total, 198 studies were identified and screened, and 55 studies were included for analysis. Audiological outcomes were available in 46 studies, and the four-frequency pure-tone audiogram average improved by 60 to 78 dB HL due to cochlear implantation. Auditory performance and speech intelligibility scores increased by 44%. The overall average implantation age was 60 months. The implantation age was 21 months lower in the studies where individuals were implanted after the year 2000 compared with those implanted before the year 2000. Perilymph gusher/oozing was the most common surgical incident reported, occurring in 187 of 1572 implantations. CONCLUSIONS: In children with PS/NSEVA, cochlear implantation improves pure-tone average by 60 to 78 dB HL and capacity of auditory performance/speech intelligibility by 44%. The implantation age for these children has decreased during the last two decades but is still somewhat higher than reported for unselected pediatric cochlear implantation. Perilymph gusher/oozing is the most common surgical complication.

Receptive language acquisition in a pediatric population with Pendred syndrome and non-syndromic enlarged vestibular aqueduct.

Background: Children with Pendred syndrome (PS) and non-syndromic enlarged vestibular aqueduct (NSEVA) represent a group of pre-lingual hearing-impaired individuals with rehabilitation challenges.Objective: To evaluate receptive language capabilities in a pediatric cohort with PS and NSEVA.Materials and methods: Twenty-four (24) children diagnosed with either PS or NSEVA, were examined using the Peabody Picture Vocabulary Test (PPVT) and compared to a cohort of 55 Danish children with normal hearing, as well as to a mixed group of 29 children with hearing impairment of congenital and hereditary non-syndromal type. In addition, test results were compared to normative data (PPVT-4 US standard scores).Results: PS/NSEVA children's PPVT-4 test scores fall within the normative data for the PPVT-4 (US) but proved to be significantly lower statistically, when compared to Danish children with normal hearing (p<.0001) or to children with mixed non-syndromic hereditary hearing impairment (p=.006). Implantation age was significantly later for the PS/NSEVA group (median = 43 months), compared to the mixed non-syndromic hereditary congenial hearing impairment group (median = 11 months).Conclusions and significance: Children with PS/NSEVA perform below age equivalent for receptive vocabulary outcome when compared to both children with normal hearing, and children with non-syndromic mixed hereditary congenital hearing impairment who receive cochlear implants earlier.

Association of SLC26A4 mutations, morphology, and hearing in pendred syndrome and NSEVA.

OBJECTIVE: To investigate the relations of monoallelic (M1), biallelic (M2), or the absence of mutations (M0) in SLC26A4 to inner ear morphology and hearing levels in individuals with Pendred syndrome (PS) or nonsyndromic enlarged vestibular aqueduct (NSEVA) associated with hearing loss. METHODS: In a cohort of 139 PS/NSEVA individuals, 115 persons from 95 unrelated families had full genetic sequencing of SLC26A4, and 113 had retrievable images for re-assessment of inner ear morphology. The association between the number of mutant alleles in SLC26A4, inner ear morphology (including endolymphatic sac size and protein content on magnetic resonance imaging), and hearing level (pure tone average) was explored. RESULTS: Biallelic SLC26A4 mutations (M2) occurred in three-quarters of the cohort and was invariably associated with poor hearing; in 87%, it was associated with incomplete partition type II of the cochlea as well as enlarged endolymphatic sac and vestibular aqueduct. M1 or M0 individuals exhibited a greater variability in inner ear morphology. Endolymphatic sac size and presence of "high-protein" sac contents were significantly higher in M2 individuals compared to M1 and M0 individuals. CONCLUSION: The number of SLC26A4 mutations is associated with severity and variability of inner ear morphology and hearing level in individuals with PS or NSEVA. M2 individuals have poorer hearing and present largely incomplete partition type II of the cochleas with enlarged endolymphatic sacs, whereas individuals with M1 and no detectable SLC26A4 mutations have less severe hearing loss and more diverse inner ear morphology. LEVEL OF EVIDENCE: 4. Laryngoscope, 129:2574-2579, 2019.

The Natural History of Hearing Loss in Pendred Syndrome and Non-Syndromic Enlarged Vestibular Aqueduct.

INTRODUCTION: The aim was to investigate the progress of hearing loss over time in a cohort of pendred syndrome and non-syndromic enlarged vestibular aqueduct (PS/NSEVA) with one or two confirmed pathogenic variations in SLC26A4. STUDY DESIGN: Retrospective cohort study. SUBJECTS AND METHODS: At our tertiary referral center, a retrospective search of all patients with enlarged vestibular aqueduct, hearing loss and SLC26A4 mutations yielded 103 individuals by March 2017, 96 of whom had records of hearing levels; both an early audiometry and the latest between 3 and 668 months follow-up. Pure-tone average (PTA; average of thresholds at 0.5, 1, 2 and 4 kHz) was calculated for both ears at time 1 and time 2. Neonatal screening results were retrieved. RESULTS: Eighty-seven (87) individuals had biallelic (M2) and 16 had monoallelic alterations (M1) in their SLC26A4. On average, the PTA progressed to 80 dB HL by the age of 6 years for the entire cohort, and 3.2 years for the biallelic (M2) affected individuals. 25% of the cohort was screened in the neonatal screening program; of these 42% had "passed" at least monaurally. Audiometric profiles related to age show faster deterioration in high frequencies than in low frequencies. CONCLUSION: In patients with PS/NSEVA and SLC26A4 mutations, the average hearing loss progresses to 80 dB HL by the age of 6 years. For biallelic (M2) affected individuals it was 3.2 years. Although hearing levels reached severe to profound during childhood, almost 1/2 had passed neonatal hearing screening, at least monaurally, emphasizing the need for close follow-up.

Cochlear implantation in a 10-year old boy with Pendred syndrome and extremely enlarged endolymphatic sacs.

A 10-year-old boy with fluctuating sensorineural hearing loss (SNHL) and biallelic mutations in the SLC26A4 gene and with inner ear anomalies received a cochlear implantation. SLC26A4 mutations are associated with variable degrees of SNHL and enlarged vestibular aqueducts (EVA), identified either as non-syndromic EVA or classic Pendred syndrome; the latter also associated with thyroid dysfunction. The inner ear malformations in this group of patients have been considered a relative contraindication against cochlear implantation because of the potential per- and postoperative complications such as peroperative cerebrospinal fluid leak or postoperative vestibular symptoms. In the current case there were no surgical or postoperative complications, indicating that extremely enlarged endolymphatic sacs are not as such a contraindication for cochlear implantation. This case also illustrates the management dilemma of an appropriate timing for cochlear implantation.

Cochlear implantation in Pendred syndrome and non-syndromic enlarged vestibular aqueduct - clinical challenges, surgical results, and complications.

OBJECTIVE: To explore specific clinical issues, surgical results, and complications of 80 cochlear implantations (CI) in 55 patients with Pendred syndrome (PS) or non-syndromic enlarged vestibular aqueduct (NSEVA). BACKGROUND: Previous studies have focused either on unselected case series or on populations with mixed cochlear malformations. PS/NSEVA accounts for up to 10% of congenital SNHL, rendering this a large group of cochlear implant candidates. The abnormal inner ear anatomy of these patients may be associated with a lower surgical success rate and a higher rate of complications. STUDY DESIGN: Retrospective review of patients' medical records and CT/MRI. SETTING: Tertiary referral center. MATERIALS AND METHODS: The medical records and CT/MRI images of 55 PS/NSEVA patients receiving 80 cochlear implantations from 1982-2014 were reviewed. Demographic data, surgical results, intra-operative incidents, and post-operative complications were retrieved. RESULTS: Complications occurred in 36% of implantations; 5% hereof major complications. Gushing/oozing from the cochleostoma occurred in 10% of implantations and was related to transient, but not prolonged post-operative vertigo. CONCLUSION: Intra-operative risks of gushing/oozing and post-operative vertigo are the primary clinical issues in PS/NSEVA patients regarding CI. Nonetheless, the surgical success rate is high and the major complication rate is low; similar to studies of unselected series of CI recipients.

The true malignancy rate in 135 patients with preoperative diagnosis of a lateral neck cyst.

OBJECTIVE: In this study, the true malignancy rate in 135 patients with a preoperative tentative diagnosis of a lateral neck cyst (LNC) was assessed. Furthermore, the sensitivity and specificity of fine needle aspiration of suspected LNC were evaluated and the diagnostic delay was analyzed. STUDY DESIGN: This study was retrospective in design and included all patients who had undergone surgery for a suspected LNC in four secondary hospitals in the eastern regions of Denmark during the period of 2009 to 2012. METHODS: One hundred thirty-five patients were identified and included by means of a search strategy for NOMECO surgical procedure codes KENB40A+B in the electronic surgical booking systems. Because the procedure codes also include median neck cysts and fistulas, the latter were excluded manually. RESULTS: Of the 135 patients preoperatively diagnosed with LNC, a malignant postoperative histopathological diagnosis was revealed in 19 patients (14.4%). Of these, three individuals were between 35 to 40 years of age. In 17 cases, preoperative fine-needle aspiration biopsy showed benign cytology, whereas histopathology postoperatively proved to be malignant. This renders a sensitivity of 88.8% and a specificity of 60.0% for fine needle aspiration biopsy with regard to LNC diagnostics. CONCLUSION: This study suggests that, for patients older than 35 years, a cystic lateral neck mass should be considered potentially malignant; by contrast, LNC is a diagnosis of exclusion. Any delay in treatment should be avoided until final histopathological diagnosis has been obtained. Arguably, all patients older than 35 years with a cystic lesion laterally on the neck should be included in the fast-track cancer referral program. LEVEL OF EVIDENCE: 2b.

Isolated oedema of the uvula induced by intense snoring and ACE inhibitor.

A case of snoring-induced angioedema of uvula is described in a patient who was treated with ACE inhibitor. The patient partially responded to complement C1-inhibitor concentrate and did not suffer any recurrences after the medication was withdrawn. When encountering a patient suffering from swellings of the orofacial area it should be considered whether the mechanism is mast-cell associated or not, as classical antiallergic treatment is ineffective in non-mast-cell-associated disease (ie, bradykinin-mediated angioedema). Other causes of uvular oedema are also discussed.

Vocal cord paralysis associated with Ramsay Hunt syndrome: looking back 50 years.

Ramsay Hunt syndrome is defined by herpes zoster oticus and peripheral facial nerve palsy which is often associated with otalgia. The syndrome is, in rare cases, associated with other cranial nerve paralyses including the vagal nerve causing unilateral vocal cord paralysis. Vocal cord paralysis is more often seen as a symptom of various other diseases, that is, malignant tumours, neurodegenerative illness, cerebrovascular assaults, inflammatory processes or as a result of intubation or surgical procedures. The symptoms of unilateral vocal cord paralysis are mainly hoarseness, dyspnoea and dysphagia. We present a case of Ramsay Hunt syndrome combined with unilateral hearing loss and left vocal cord paralysis. The patient underwent MRI, CT and a lumbar puncture causing anxiety in the patient and delaying the initiation of antiviral and anti-inflammatory treatment, which is only efficient when initiated within 72 h. We hope to raise the awareness of this disease.

Angiotensin-converting enzyme inhibitor-induced angioedema--a dangerous new epidemic.

Angioedema is a sudden localised and often asymmetric swelling of the skin or mucous membranes caused by transient increased endothelial permeability causing plasma extravasation. In the last decades the incidence of severe angioedema involving the upper airways and even fatal outcome due to asphyxia has increased. This is mainly due to pharmaceuticals such as angiotensin converting enzyme-inhibitors, which are extensively used worldwide. Some aspects of the pathophysiology have been elucidated and the vasoactive molecule bradykinin is shown to be one of the main causative agents. The diagnosis is often delayed and traditional treatment usually ineffective. Complement C1 inhibitor concentrate and bradykinin receptor antagonists, normally used to treat patients with hereditary angioedema, have shown good results when used in patients with bradykinin-mediated angioedema. This review discusses the disease, prognosis and treatment options.

[Laryngeal fractures due to blunt trauma]. / Larynxfrakturer opstået ved stump vold.

INTRODUCTION: Laryngeal fractures due to blunt trauma are rare. Consensus on diagnosis and treatment is therefore needed. MATERIALS AND METHODS: A retrospective search of patient records in the period 2000-2007. Data were obtained on sex, age, time from trauma to first medical visit, time from trauma to operation, result of laryngeal computertomography, pre- and postoperative videostroboscopy, pre- and postoperative evaluation of voice quality, method of operation and status at last follow-up. RESULTS: Seven patients, six males aged 24-54 and one female aged 24. All had moderate to severe laryngeal trauma, and all except one needed surgical intervention. Three had the fracture stabilized with titanium net/miniplates. The postoperative voice was evaluated as good/acceptable in four patients, one had a recurrent nerve palsy and was lost to follow-up; one is still undergoing voice therapy. CONCLUSION: Patients must be examined for hoarseness, laryngeal pain, aphonia, asymmetry, bleeding and subcutaneous emphysema located in or around the larynx. Based on a computertomography, dislocated fractures should be operated (preferably within 48 hours). It is necessary to obtain stable fractures. The use of titanium nets or miniplates is recommended.

Histomorphometric estimation of air cell development in experimental otitis media.

OBJECTIVES: The objectives of this study were to examine the effect of acute otitis media on the bony development of the growing middle ear air cell system with a reliable and concise stereologic histomorphometric method and to generate a standard baseline growth plot for the middle ear of the rat. STUDY DESIGN: The authors conducted a histomorphometric analysis of bullar volume during the entire growth period after early induction of unilateral otitis media. METHODS: The authors conducted undecalcified processing of 27 rat skulls sectioned horizontally at various ages from 20 to 83 days after unilateral transtympanic injection of Streptococcus pneumoniae at 19 days postpartum. Stereologic estimation of bullar volume was performed in the experimental and the control ear with Cavalieri's principle. Body mass and air cell volume were plotted as functions of subject age using standard developmental equations on the experimental results. RESULTS: Volumes of the middle ear air cell system were consistently smaller in the otitis ears. Bullar growth was completed at 60 days regardless of otitis history, but body mass was increasing throughout the experimental period. CONCLUSIONS: A single incident of otitis media introduced early in life is sufficient to significantly reduce the final volume of the bulla in rats. This finding may mimic the effect of otitis media contracted in early childhood on the development of the mastoid air cells. The standard growth plot provides a timeframe for studies of signaling molecules responsible for bone modeling in pneumatization.