Progressive Sensorineural Hearing Loss Research Articles

Human blood-labyrinth barrier model to study the effects of cytokines and inflammation.

Hearing loss is one of the 10 leading causes of disability worldwide. No drug therapies are currently available to protect or restore hearing. Inner ear auditory hair cells and the blood-labyrinth barrier (BLB) are critical for normal hearing, and the BLB between the systemic circulation and stria vascularis is crucial for maintaining cochlear and vestibular homeostasis. BLB defects are associated with inner ear diseases that lead to hearing loss, including vascular malformations, inflammation, and Meniere's disease (MD). Antibodies against proteins in the inner ear and cytokines in the cochlea, including IL-1α, TNF-α, and NF-kβ, are detected in the blood of more than half of MD patients. There is also emerging evidence of inner ear inflammation in some diseases, including MD, progressive sensorineural hearing loss, otosclerosis, and sudden deafness. Here, we examined the effects of TNF-α, IL6, and LPS on human stria vascularis-derived primary endothelial cells cultured together with pericytes in a Transwell system. By measuring trans-endothelial electrical resistance, we found that TNF-α causes the most significant disruption of the endothelial barrier. IL6 had a moderate influence on the barrier, whereas LPS had a minimal impact on barrier integrity. The prominent effect of TNF-α on the barrier was confirmed in the expression of the major junctional genes responsible for forming the tight endothelial monolayer, the decreased expression of ZO1 and OCL. We further tested permeability using 2 μg of daptomycin (1,619 Da), which does not pass the BLB under normal conditions, by measuring its passage through the barrier by HPLC. Treatment with TNF-α resulted in higher permeability in treated samples compared to controls. LPS-treated cells behaved similarly to the untreated cells and did not show differences in permeability compared to control. The endothelial damage caused by TNF-α was confirmed by decreased expression of an essential endothelial proteoglycan, syndecan1. These results allowed us to create an inflammatory environment model that increased BLB permeability in culture and mimicked an inflammatory state within the stria vascularis.

Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.

Genetic hearing loss is the most common hereditary sensorial disorder. Though more than 120 genes associated with deafness have been identified, unveiled causative genes and variants of diverse types of hearing loss remain. Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration. CEP250 encodes C-Nap1 protein belonging to the CEP protein family, comprising 30 proteins that play roles in centrosome aggregation and cell cycle progression. The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol. In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response. In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice.

Evaluation of hearing levels and vestibular function and the impact on cognitive performance in (pre)-symptomatic patients with DFNA9: protocol for a prospective longitudinal study (Rosetta study)

IntroductionUntreated hearing loss is the largest potentially modifiable risk factor for dementia. Additionally, vestibular dysfunction has been put forward as a potential risk factor for accelerated cognitive decline. Patients with...

Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease.

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.

Bilateral Sensorineural Hearing Loss Related to a Skull Base Spontaneous Cerebrospinal Fluid Leak: A Case Report and Literature Review.

Spontaneous intracranial hypotension (SIH) is a rare condition characterized by orthostatic headache, pulsatile tinnitus, vertigo, nausea, and fluctuating hearing loss; this latter seems to be due to the development of cochlear endolymphatic hydrops following negative cerebrospinal fluid (CSF) pressure transmitted to the perilymphatic space through a patent cochlear aqueduct. We here describe a case of bilateral progressive sensorineural hearing loss (SNHL) due to intracranial hypotension caused by an undiagnosed spontaneous CSF leak from a skull base defect in a middle-aged woman. To the best of our knowledge, this is the first report describing a SNHL in a patient affected by SIH secondary to sphenoidal CSF leak.

Intracochlear schwannoma: about a case

Vestibular schwannoma is a benign tumor that originates from Schwann cells. It is most often found in the internal auditory meatus or cerebellopontine angle. Less frequently, intralabyrinthine localization (IL) can be found. These benign lesions usually present with progressive sensorineural hearing loss, tinnitus, and vertigo. Magnetic resonance imaging (MRI) allows a precise diagnosis of these tumors, also defining their exact location within the labyrinth. Currently, the treatment of IL may require radiosurgery, tumor removal surgery, and tumor follow-up with MRI. We will present a clinical case of a patient with intracochlear schwannoma (ICS) of the left ear.

Dominant Optic Atrophy With Varied Phenotype in a Family of Eastern India: A Case Report of a Rare Mutation

Background: Autosomal dominant optic atrophy (ADOA) can present with a varied phenotype in the form of pure ADOA, ADOA with sensorineural hearing loss, or the extended spectrum of DOA plus syndrome. Multiple genes have been identified over the years and majority of the cases are attributed to OPA1 gene mutation. Here we present an index case of DOA plus syndrome with affection of multiple family members across 2 generations with a rare mutation detection. Case Presentation: A middle-aged female presented with onset of bilateral progressive visual blurring in the first decade followed by progressive sensorineural hearing loss since the second decade and onset of lower limb predominant cerebellar ataxia since the third decade. Routine parameters, imaging and electrophysiological studies were negative. Next generation clinical exome sequencing (NGCES) revealed an unique OPA1 gene mutation with worldwide evidence of only 3 such cases in database. Conclusion: DOA suspicion should be made in early onset visual defects with multiaxial involvement with a significant family history.

The Importance of Extended High Frequencies in Hearing Evaluation of Pediatric Patients with Type 1 Diabetes.

Type 1 diabetes (T1D), one of the most common childhood diseases worldwide, can cause hearing loss through its systemic effects. Diabetes-induced hearing loss is considered a progressive sensorineural hearing loss with a gradual onset typically occurring at high frequencies. We investigated extended high-frequency (EHF) hearing sensitivity in children with T1D who did not complain of hearing loss as an early marker for hearing loss at the standard/conventional frequency range of hearing. We evaluated 42 children (21 with T1D and 21 healthy controls) in a case-control design. Conventional and EHF (14,000, 16,000, and 18,000 Hz) audiometry were performed. The diabetes group underwent routine blood biochemistry and glycated hemoglobin (HbA1c) measurements. The data were analyzed by the Student t-test, Mann-Whitney U test, chi-square test, and logistic regression analysis. The mean hearing thresholds were significantly higher (p < 0.05) in the diabetes group than in controls at 500, 2,000, 4,000, and 8,000 Hz (all < 15 decibel hearing level [dB HL]). The number of ears with thresholds > 15 dB HL at 14,000-18,000 Hz but ≤ 15 dB HL at 500-4,000 Hz was significantly higher in the diabetes group than in the control group (p = 0.049). Children with diabetes showed normal hearing thresholds within the conventional audiometric frequency range; however, they presented higher hearing thresholds during EHF audiometry when they were compared with controls. Audiometry in these children should be performed using frequencies above 8,000 Hz combined with the conventional frequency range. EHF audiometry could be an effective method for identifying subclinical hearing loss in children with diabetes. Thus, diabetic children with an EHF mean hearing threshold above 15 dB HL should be monitored more closely in terms of blood glucose regulation to prevent diabetes-related hearing loss at the conventional frequency range.

A Case of MELAS Syndrome Involving Diabetes Mellitus, Cerebellar Ataxia and Progressive Sensorineural Hearing Loss

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder. MELAS syndrome manifests different clinical symptoms due to mitochondrial heteroplasmy and individual susceptibility and tends to be aggravated by metabolic events. It presents various clinical manifestations including hearing impairment, diabetes mellitus, and stroke like episodes. However, to date, only a few cases of MELAS syndrome accompanied with cerebellar ataxia have been reported in Korea. We hereby present an unusual case of a patient diagnosed with MELAS syndrome involving diabetes mellitus, cerebellar ataxia and sensorineural hearing loss, which were aggravated by metabolic stresses such as pregnancy and hypoglycemic shock.

Dysregulation of fetal-derived cochlear resident tissue macrophages mediates CMV-associated sensorineural hearing loss

Abstract Cytomegalovirus (CMV) is the most common congenital viral infection in the developed world and the leading cause of non-genetic sensorineural hearing loss (SNHL) in children. Congenital CMV causes progressive SNHL long after acute infection has resolved, suggesting a lasting effect on the developing host immune response in the cochlea. Using fate-mapping models, we investigated the contribution of fetal-derived resident tissue macrophages (RTMs) to normal cochlear development and function, and their role in mediating CMV-associated SNHL. We uncovered dual contribution of fetal-derived cochlear RTMs (F4/80 hiCD11b lo) from yolk sac (YS) and fetal liver (FL) hematopoiesis at birth. YS-derived RTMs naturally recede postnatally after cochlea development, but remain in key tissues, such as the spiral ligament and stria vascularis, through adulthood. Depletion of fetal-derived RTMs by anti-CSF1R blocking Ab led to SNHL and impairments to cochlear architecture. Similarly, embryonic deletion of YS-derived RTMs by induced deletion of CSF1R leads to SNHL at high frequencies. During acute CMV infection, RTMs expand and become transcriptionally dysregulated in developmental programs, including tissue remodeling, chemorepulsion, otic vesicle morphogenesis, and FGF signaling. Importantly, analysis of CSF1R-Cre labeling suggests YS-derived RTMs retract in response to CMV infection, suggesting RTM expansion is caused by infiltration of BM-derived macrophages. Ongoing work examines spatial distribution of fetal-derived cochlear RTMs, transcriptional differences between YS, FL, and BM-derived RTMs in response to CMV, and how replacement of fetal-derived RTMs with BM-derived RTMs affects tissue function and response to CMV. Supported by grants from NIAID (T32 5T32AI138945) and University of Utah molecular medicine and immunology, inflammation and infectious disease (3i) initiative

Unusual manifestation of cerebellopontine angle medulloblastoma with tinnitus and sensorineural hearing loss

Abstract BACKGROUND. Medulloblastoma is the most common central nervous system embryonal tumor in children. In adults, this tumor is extremely rare, accounting for nearly 1% of primary brain tumors. Raised intracranial pressure signs are common manifestations of posterior fossa tumors, but tinnitus and/or sensorineural hearing loss are very uncommon presenting symptoms. MATERIAL AND METHODS. Starting from a very rare case of a 39-year-old male with left tinnitus and progressive left sensorineural hearing loss as isolated symptoms of a medulloblastoma, we performed a literature survey using the PubMed, ProQuest, Web of Science, Science Direct, Wiley Online search engines for patients with medulloblastoma and tinnitus and/or sensorineural hearing loss. RESULTS. All patients found in the relevant literature with auditory dysfunctions presented sensorineural hearing loss. Other frequent manifestations were: ataxia, facial numbness, vertigo, headache, nystagmus. Two patients were found with tinnitus and sensorineural hearing loss as isolated symptoms of medulloblastoma, as in our case, and in two other cases the sensorineural hearing loss was the unique symptom. With refers to the onset of medulloblastoma, just 3 patients had the first symptoms sensorineural hearing loss and tinnitus. Concerning the tumor location, in patients manifested with isolated tinnitus and sensorineural hearing loss, like our patient, the tumor arised from the internal auditory meatus, extended to the cerebellopontine angle or involved the vestibulocochlear nerve. With regards to treatment, surgery in association with radiotherapy and chemotherapy was elected in most cases (38%). CONCLUSION. It is important to pay attention at patients with isolated auditory dysfunction that may mimic significant posterior fossa tumors, such as a medulloblastoma.

Deep Brain Stimulation for the Management of AIFM1-Related Disabling Tremor: A Case Series

The AIFM1 gene encodes a mitochondrial protein that acts as a flavin adenine dinucleotide-dependent nicotinamide adenine dinucleotide oxidase and apoptosis regulator. Monoallelic pathogenic AIFM1 variants result in a spectrum of X-linked neurological disorders, including Cowchock syndrome. Common features in Cowchock syndrome include a slowly progressive movement disorder, cerebellar ataxia, progressive sensorineural hearing loss, and sensory neuropathy. We identified a novel maternally inherited hemizygous missense AIFM1 variant, c.1369C>T p.(His457Tyr), in two brothers with clinical features consistent with Cowchock syndrome using next-generation sequencing. Both individuals had a progressive complex movement disorder phenotype, including disabling tremor poorly responsive to medications. Deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus ameliorated contralateral tremor and improved their quality of life; this suggests the beneficial role for DBS in treatment-resistant tremor within AIFM1-related disorders.

Retrospective Study of 157 Patients with Otosclerosis to Evaluate Association Between Carhart Notch on the Preoperative Bone-Conduction Audiogram and Postoperative Hearing and Balance Evaluated by the Vestibular Disorders Activities of Daily Living Scale.

BACKGROUND A Carhart notch in the pure tone audiogram can be an indicator of stapes fixation in otosclerosis. This retrospective study of 157 patients with otosclerosis aimed to evaluate the association between the presence of a Carhart notch on the preoperative bone-conduction audiogram and postoperative hearing and balance evaluated by the Vestibular Disorders Activities of Daily Living scale. MATERIAL AND METHODS Patients with suspected otosclerosis based on medical history and audiometric tests were considered. The analysis included 157 consecutive patients who underwent surgery in the years 2016 to 2019, in whom the diagnosis of otosclerosis was confirmed during surgery. Carhart notch was defined as an impairment in the bone conduction threshold of ≥7.5 dB for 2000 Hz frequencies above the mean thresholds at higher and lower adjacent frequencies. The Vestibular Disorders Activities of Daily Living subjective scale was used in the preoperative period and 4 and 12 months after surgery. RESULTS The preoperative presence of Carhart notch and progressive sensorineural hearing loss were statistically significantly correlated with more common onset of tinnitus and then dizziness (P=0.006). Preoperative vertigo was observed in patients who had Carhart notch observed in the preoperative audiometric test. This vertigo more commonly coexisted with profound sensorineural hearing loss and minor or no improvement in average values of bone conduction after surgery (P=0.002). CONCLUSIONS Preoperative Carhart notch on audiogram and the severity of sensorineural hearing loss were associated with tinnitus and vertigo. However, preoperative Carhart notch was not associated with persistent postoperative tinnitus in patients with cochlear otosclerosis.

両側人工内耳手術を施行した小児蝸牛型耳硬化症例

A cavernous change due to otosclerosis that extends to the cochlear axis is called cochlear otosclerosis, which causes progressive sensorineural hearing loss (SNHL); cochlear implantation (CI) is considered in cases with severe to profound deafness. There are many reports of CI for adult cochlear otosclerosis, whereas this is only the second report of CI for a pediatric case of cochlear otosclerosis.

A Case of Bilateral Cochlear Implantation for Congenital Visual-Auditory Dual Disability Associated with Wolfram Syndrome and Osteogenesis Imperfecta

We report a case of bilateral cochlear implant surgery performed for profound sensorineural hearing loss in a 2-year-old girl with Wolfram syndrome and osteogenesis imperfecta type I. Wolfram syndrome is a rare autosomal-recessive genetic disorder characterized by juvenile diabetes mellitus and visual impairment. The hearing loss in Wolfram syndrome is typically a slowly progressive sensorineural hearing loss, primarily in the high-frequency range. Genetic testing of our patient showed mutations in WFS1 and COL1A1. Bilateral cochlear implant surgery was performed, because adequate wearing thresholds could not be achieved with hearing aids. This report is the first case of a patient with Wolfram syndrome with profound congenital hearing loss who benefited from cochlear implant surgery. The patient had a visual-auditory dual disability and lacked external stimuli. The cochlear implant provided valuable auditory compensation to ensure auditory stimulation. In the future, it is necessary to continue comprehensive rehabilitation for the patient with collaboration among the parents, speech-language pathologists, and rehabilitation facilities.

Accelerated Cognitive Decline Associated With Hearing Loss and Bilateral Vestibulopathy: Insights From a Prospective Cross-Sectional Study Using the Repeatable Battery for the Assessment of Neuropsychological Status Adjusted for the Hearing Impaired in the DFNA9 Population.

DeaFNess Autosomal dominant 9 (DFNA9) is a hereditary disorder known to affect both hearing and vestibular function in its carriers. Its phenotype is characterized by progressive sensorineural hearing loss (SNHL) and vestibular dysfunction evolving towards bilateral vestibulopathy (BV) by the 3rd to 5th life decade. Recent studies have identified the impact of hearing loss and vestibular dysfunction on cognitive functioning. The main objective of this study was to investigate how the cognitive functioning of carriers of the p.Pro51Ser variant in the COCH gene is affected by the disease and compare these results with a matched healthy control group. Forty-six carriers of the pathogenic p.Pro51Ser variant in the COCH gene were included in this study, of which 38 met the Bárány Society criteria and were thus diagnosed with BV. All subjects were between the age of 22 and 72 years old. Each control was individually matched based on age, gender, and education level. A cognitive, vestibular, and hearing assessment was performed in all subjects. All participants completed the Repeatable Battery for the Assessment of Neuropsychological Status, adjusted for the Hearing Impaired (RBANS-H), a cognitive test battery that includes subtests probing Immediate and Delayed Memory, Visuospatial/Constructional, Language, and Attention. Overall, the DFNA9 patients demonstrated significantly lower scores on the Immediate Memory subscale and lower Total Scale scores than their healthy matched controls. The total sample was divided into two groups: age <55 years old and age ≥55 years old. The DFNA9 group aged ≥55 years old obtained significantly lower scores on the Attention subscale and lower Total Scale scores than their matched controls. Cognition of DFNA9 patients aged <55 years old no longer differed significantly from their matched controls. This cross-sectional study found that DFNA9 patients demonstrated cognitive deficits in comparison with their healthy matched controls. The DFNA9 group aged ≥ 55 years old obtained significantly lower scores on the Total Scale and Attention subscale. This finding; however, was not observed for the age group younger than 55 years old. Further research is needed on the individual trajectory of SNHL and vestibular function, and how hearing rehabilitation affects cognitive functioning.

Pathogenic REST variant causing Jones syndrome and a review of the literature

Jones syndrome is a rare dominantly inherited syndrome characterized by gingival fibromatosis and progressive sensorineural hearing loss becoming symptomatic in the second decade of life. Here, we report a father and his two daughters presenting with a typical Jones syndrome (OMIM %135550) phenotype. Exome sequencing identified a repressor element 1-silencing transcription factor (REST, OMIM *600571) (NM_005612.5) c.2670_2673del p.(Glu891Profs*6) heterozygous variant segregating with Jones syndrome in the family. We review the clinical data from all previously published patients with Jones syndrome and previously published patients with pathogenic REST variants associated with gingival fibromatosis or sensorineural hearing loss. This study suggests that pathogenic REST variants cause Jones syndrome.

A Woman With Kelch-like Protein-11 Encephalitis and Unmasked Metastatic Carcinoma

Objective To illustrate a case of a woman with rhombencephalitis with antibodies to Kelch-like protein-11 (KLHL11) and a metastatic carcinoma. Background KLHL11 encephalitis is an autoimmune paraneoplastic syndrome first described in 2019. The clinical presentation consists of a brainstem cerebellar syndrome with symptoms of hearing loss, diplopia, vertigo and ataxia. This entity has been mostly described in male patients with associated testicular seminomas. Few cases have been described in women. This is a case of a woman with a history of hysterectomy and oophorectomy with KLHL11 encephalitis and an associated aortocaval tumor. Design/Methods NA. Results The patient was a 62-year-old woman that presented to clinic with a 9-month history of vertigo, progressive bilateral sensorineural hearing loss, diplopia, oscillopsia, ataxia and bilateral tremor. Her MRI brain obtained 8 months after symptom onset showed T2 hyperintense lesions in the inferior cerebellar hemispheres and right medial hippocampus with mild contrast enhancement in these areas. Cerebral spinal fluid analysis showed a lymphocytic pleocytosis, elevated protein, and negative infectious work-up. She completed 5 days of intravenous methylprednisolone and continued a steroid taper. She noted mild to moderate improvement in tremors, gait, and diplopia after steroids. Her symptoms, however worsened as she tapered her steroid dose. Serum KLHL11 antibody levels were positive at a titer of 1:7680. Computed tomography of the chest, abdomen and pelvis did not reveal any evidence of malignancy. However, whole body proton emission tomography/computed tomography (PET CT) revealed a large hypermetabolic aortocaval mass soft tissue mass. A biopsy of the mass showed pathology consistent with a metastatic carcinoma of gynecologic origin for which the patient is undergoing chemotherapy with plans for possible tumor debulking. Conclusions This case highlights the importance of considering KLHL-11 encephalitis in female patients presenting with rhombencephalitis, and the need for adequate malignancy evaluation in this disorder.

An uncommon “third window” in retrofenestral otosclerosis

Otosclerosis is an otologic disease characterized by disordered resorption and deposition of the otic capsule bone. It can lead to progressive conductive, mixed or sensorineural Hearing Loss (HL). In rare cases, it manifests itself with a tendency for massive bone resorption with subsequent formation of cavities (“cavitating otosclerosis”). Cavities can sometimes realize communication between the Cerebrospinal Fluid (CSF) at the Internal Auditory Canal (IAC) and the cochlear duct. In these uncommon cases, a “third-window” phenomenon may be established as a concomitant cause of conductive HL. Therefore, the feasibility of stapes surgery should be evaluated, without underestimating the risk of gusher complications. In this report, we discuss the case of a female patient affected by cavitating otosclerosis realizing a connection between IAC and cochlear duct, with mixed hearing loss.

The Absence of Permanent Sensorineural Hearing Loss in a Cohort of Children with SARS-CoV-2 Infection and the Importance of Performing the Audiological "Work-Up".

Currently, the novel coronavirus (SARS-CoV-2) causes an acute respiratory illness named COVID-19 and is a controversial risk factor for hearing loss (HL). Herein, we aim to describe the associated symptoms and to evaluate hearing function in the COVID-19 pediatric population. A retrospective cross-sectional observational study was carried out on 37 children who contracted COVID-19 infection with no previous audio-vestibular disorders. Clinical data on the infections were collected, and an audiological assessment of all affected children was performed by using different diagnostic protocols according to their age. Fever, upper respiratory and gastrointestinal manifestations were common presentations of infection. Audiological function was normal in 30 (81.08%) children, while 7 children showed an increased hearing threshold: 6 (16.21%) had transient conductive hearing loss (CHL) due to middle ear effusion and normalized at the follow-up and 1 had sensorineural hearing loss (SNHL). A single child was affected by bilateral SNHL (2.7%); however, he underwent a complete audiological work-up leading to a diagnosis of genetic HL due to a MYO6 gene mutation which is causative of progressive or late onset SNHL. HL needs to be considered among the manifestations of COVID-19 in children, nevertheless, we found cases of transient CHL. The onset of HL during or following COVID-19 infection does not eliminate the indication for maintaining audiological surveillance and audiological work-ups, including genetic diagnosis, to avoid the risk of mistaking other causes of HL.