Sudden Otovestibular Dysfunction in 3 Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibitors.

Immune-related adverse events have been described in 86%-96% of high-risk melanoma patients treated with immune checkpoint inhibitors (ICI), while in 17%-59% of cases these are classified as severe or even life-threatening. The most common immune-related adverse events include diarrhea, fatigue, hypothyroidism, and hepatitis. Bilateral uveitis and unspecific vertigo have been described in 1% of cases, respectively, in the pivotal studies of ICIs, but the affection of the vestibule-cochlear system has not been reported before. In this case series, we present 3-stage IV melanoma patients with sudden onset of otovestibular dysfunction (hearing loss and vestibulopathy), partly combined with uveitis because of ICIs. We describe detailed diagnostic work-up and therapeutic interventions and discuss possible pathogenic mechanisms of this rare and disabling event.

[Cochleo-vestibular lesions and prognosis in patients with profound sudden sensorineural hearing loss: a comparative analysis].

Objective: To investigate the characteristics of cochleo-vestibular dysfunction in patients with profound sudden deafness, and the prognosis of inner ear hemorrhage. Methods: From January 2017 to December 2018, 92 inpatients with profound sudden sensorineural hearing loss were enrolled in the Department of Otorhinolaryngology, First Affiliated Hospital of Sun Yat-sen University. Our studied patients included 47 males and 45 females, aged 20-78 (39.3±6.1) years. According to the results of inner ear magnetic resonance imaging (MRI), the patients were divided into two groups: inner ear hemorrhage group and non-inner ear hemorrhage group. The clinical features, vestibular tests and audiological examination results during follow up were compared between the two groups. SPSS 22.0 software was used for statistical analysis. Results: The inner ear hemorrhage group consisted of 32 cases (34.8%, 32/92), all of whom complained of vertigo (100%, 32/32). Simultaneous vertigo attack and hearing loss occurred in 78.1% of this group (24/32). Neither semicircular canals function, nor cervical vestibular evoked myogenic potential (c-VEMP), nor ocular vestibular evoked myogenic potential (o-VEMP) in the affected side was normal (100%, 32/32). The rates of benign paroxysmal positional vertigo (BPPV) and disequilibrium were 37.5% (12/32) and 25.0% (8/32) respectively. Hearing improved in 28.1% (9/32) two weeks after treatment, and became stable at one month's follow up. In 60 cases without inner ear hemorrhage, 58.3% of them (35/60) experienced vertigo, which occurred simultaneously with hearing loss in 21 patients (60%, 21/35). The abnormal rates of semicircular canals function, c-VEMP and o-VEMP were 71.6% (43/60), 78.3% (47/60) and 66.7% (40/60), respectively. The incidence of BPPV was 16.7% (10/60) and 8.3% (5/60) in cases with disequilibrium. Hearing improved in 58.3% (35/60) two week after treatment, and became stable at three months' follow up. Significant difference was found in either vertigo rate, or simultaneous vertigo/hearing loss rate, or abnormal c-VEMP/o-VEMP rates, or accompanying BPPV, or disequilibrium rates between the two groups (P<0.05 each). Moreover, we observed better hearing recovery in non-inner ear hemorrhage group in the two weeks, one month, three months and six months' follow up, when compared with those in inner ear hemorrhage groups (P<0.05 each). Conclusions: Inner ear hemorrhage is associated with more severe cochlea-vestibular lesion and poorer prognosis, in comparison to the non-inner ear hemorrhage,in patients with profound sudden sensorineural hearing loss.

Association between speech perception in noise and electrophysiological measures: an exploratory study of possible techniques to evaluate cochlear synaptopathy in humans.

Objective: The primary aim of this study was to investigate whether scores for a speech-in-noise test were associated with the results of two electrophysiological techniques mainly targeting low spontaneous rate, high-threshold auditory fibres.Design: Cross-sectional study. Participants were evaluated with the hearing-in-noise test (HINT), along with the Auditory Brainstem Response (ABR) with and without ipsilateral noise. The wave V/I amplitude ratio for the ABR without ipsilateral noise and ABR wave V latency shift in the presence of ipsilateral noise were obtained.Study sample: Twenty adults aged between 20 and 34 years (10 females) who did not report occupational exposure to noise were selected. All participants presented with normal hearing thresholds (0.250-8 kHz) and the presence of distortion product otoacoustic emissions, bilaterally.Results: A significant association between the wave V/I amplitude ratio for the left ear and the HINT scores for the left ear was found.Conclusions: Based on the results of this study, in normal-hearing listeners, the wave V/I ratio is associated with speech-in-noise performance, specifically in the left ear. This non-invasive procedure has the potential to be used in clinical populations who present with speech-in-noise difficulties despite having normal audiograms.

Identification of MYO6 copy number variation associated with cochlear aplasia by targeted sequencing.

Copy number variation is an extensively studied cause of hereditary diseases. However, its role in hereditary sensorineural deafness has been rarely reported. Using targeted sequencing, SNP array and qPCR, we found a novel 622.2 kb duplication of 6q14.1 in a patient with congenital sensorineural hearing loss and cochlear aplasia. The duplication included MYO6 and IMPG1 genes. FISH study confirmed that this duplication was inherited from the patient's mosaic mother.

Hidden hearing deficits in military service members with persistent post concussive symptoms.

INTRODUCTION: Individuals with persistent symptoms after mild traumatic brain injury (mTBI) often have auditory complaints. In this study, we used the auditory brainstem response (ABR) to determine whether cochlear synaptopathy could explain auditory symptoms. METHODS: 69 adult military service members with mTBI and 25 adults without brain injury (NCT01611194 and NCT01925963) completed pure-tone audiometry, ABR, and central auditory processing tests. All participants were male, ages 21-50. RESULTS: 37/69 mTBI participants had measurable hearing loss, while another 20%-30% had hearing complaints or tinnitus. While mTBI participants with measurable hearing loss had reduced wave I and III amplitude and decreased III-V interpeak latency, those with no measurable hearing loss did not significantly differ from controls on any ABR parameter. Those with measurable hearing loss were also more likely to have abnormal central auditory processing. mTBI participants with no measurable hearing loss but who reported hearing concerns had some ABR findings (III-V interpeak latency, I and V amplitudes, V/I amplitude ratio) more like the measurable hearing loss mTBI group than normative controls. CONCLUSION: Cochlear synaptopathy may have contributed to some of the auditory impairment in service members with mTBI with measurable hearing loss. However, these results are likely confounded by cochlear hair cell damage.

Subclinical cochlear dysfunction in newly diagnosed relapsing-remitting multiple sclerosis.

BACKGROUND: Hearing impairment in multiple sclerosis has long been considered a process mainly related to the central auditory system. However, increasing evidence also suggests a peripheral involvement of the inner ear. The objective of this study was to investigate subclinical cochlear dysfunction and possible correlation with disease severity in untreated newly diagnosed multiple sclerosis patients using transient-evoked and distortion-product otoacoustic emissions. METHODS: Forty patients with newly diagnosed relapsing-remitting multiple sclerosis, clinically normal hearing and no brainstem lesions (study group) and forty matched controls (control group) were included in the study. All subjects had a routine audiological evaluation including history and clinical examination, pure tone audiometry, acoustic immittance test, auditory brainstem response and otoacoustic emissions recording. Self-administered questionnaires were used to evaluate self-perception of hearing disability. RESULTS: Auditory brainstem response and pure tone audiometry thresholds resulted within normal range in all patients. The amplitudes of transient-evoked and distortion-product otoacoustic emissions responses were significantly reduced at 1000, 1500, 2000 and 3000 Hz in the study group compared to the control group. CONCLUSIONS: This study shows decreased otoacoustic emission amplitudes in untreated multiple sclerosis patients with clinically normal hearing and no brainstem demyelinating plaques, suggesting a subclinical cochlear impairment. This alteration may represent an early sign of peripheral hearing damage, suggesting a role for otoacoustic emissions in the early diagnosis of cochlear dysfunction in multiple sclerosis patients. However, given that otoacoustic emissions primarily reflects cochlear function, and that the wave I of the auditory brainstem responses was spared, the evidence supporting a peripheral involvement of acoustic pathways due to multiple sclerosis can only be hypothetically attributed to an early subclinical involvement of outer hair cells.

Rising-frequency chirp stimulus to effectively enhance wave-I amplitude of auditory brainstem response.

This study aims to find an effective chirp signal that enhances the amplitude of wave-I of auditory brainstem response (ABR) to diagnose "cochlear synaptopathy." Although several chirp signals have been proposed to enhance the amplitude of wave-V, the effect on wave-I has not been clarified yet. Ten chirp signals, which have shorter group delays than the commonly used "CE-chirp," were produced to measure the amplitudes of wave-I and wave-V of the ABRs. The results show that one of the chirp signals significantly enhanced the amplitude of wave-I, where the group delay is approximately half of the CE-chirp.

Use of non-invasive measures to predict cochlear synapse counts.

Cochlear synaptopathy, the loss of synaptic connections between inner hair cells (IHCs) and auditory nerve fibers, has been documented in animal models of aging, noise, and ototoxic drug exposure, three common causes of acquired sensorineural hearing loss in humans. In each of these models, synaptopathy begins prior to changes in threshold sensitivity or loss of hair cells; thus, this underlying injury can be hidden behind a normal threshold audiogram. Since cochlear synaptic loss cannot be directly confirmed in living humans, non-invasive assays will be required for diagnosis. In animals with normal auditory thresholds, the amplitude of wave 1 of the auditory brainstem response (ABR) is highly correlated with synapse counts. However, synaptopathy can also co-occur with threshold elevation, complicating the use of the ABR alone as a diagnostic measure. Using an age-graded series of mice and a partial least squares regression approach to model structure-function relationships, this study shows that the combination of a small number of ABR and distortion product otoacoustic emission (DPOAE) measurements can predict synaptic ribbon counts at various cochlear frequencies to within 1-2 synapses per IHC of their true value. In contrast, the model, trained using the age-graded series of mice, overpredicted synapse counts in a small sample of young noise-exposed mice, perhaps due to differences in the underlying pattern of damage between aging and noise-exposed mice. These results provide partial validation of a noninvasive approach to identify synaptic/neuronal loss in humans using ABRs and DPOAEs.

Utilizing prestin as a predictive marker for the early detection of outer hair cell damage.

PURPOSE: To evaluate prestin as a biomarker for the identification of early ototoxicity. MATERIALS AND METHODS: Rats (n = 47) were randomly assigned to five groups: low-dose (LAG) or high-dose (HAG) amikacin (200 and 600 mg/kg/day, respectively, for 10 days), low-dose (LCIS)or high-dose (HCIS) cisplatin (single doses of 5 and 15 mg/kg, respectively, for 3 days), and control (n = 8). At the end of the experiment, measurement of distortion product-evoked otoacoustic emissions (DPOAE) were performed to evaluate hearing, then blood samples and both ear tissues were collected under anesthesia. Prestin levels were determined by ELISA. Cochlear damage was evaluated histologically using a 4-point scoring system. RESULTS: The mean serum prestin levels were 377.0 ±â€¯135.3, 411.3 ±â€¯73.1, 512.6 ±â€¯106.0, 455.0 ±â€¯74.2 and 555.3 ±â€¯47.9 pg/ml for control, LCIS, HCIS, LAG and HAG groups, respectively. There was significant difference between prestin levels of Control-LCIS-HCIS groups (p = 0.031) and prestin levels of Control-LAG-HAG groups (p = 0.003). There were also significant differences in prestin levels between the low- and high-dose cisplatin and amikacin groups (p = 0.028 and p = 0.011, respectively). Each group had significantly lower DPOAE results at 4, 6 and 8 kHz than control groups (p < 0.001). The LAG, HAG, LCIS and HCIS groups had significantly higher cochlear damage scores than the control group (p < 0.05). CONCLUSIONS: Higher doses of cisplatin and amikacin were associated with the greatest increases in serum prestin level and cochlear damage score. The results of this study suggest that prestin is a promising early indicator of cochlear damage.

Effects of lifetime noise exposure on the middle-age human auditory brainstem response, tinnitus and speech-in-noise intelligibility.

Recent animal studies have shown that the synapses between inner hair cells and the dendrites of the spiral ganglion cells they innervate are the elements in the cochlea most vulnerable to excessive noise exposure. Particularly in rodents, several studies have concluded that exposure to high level octave-band noise for 2 h leads to an irreversible loss of around 50% of synaptic ribbons, leaving audiometric hearing thresholds unaltered. Cochlear synaptopathy following noise exposure is hypothesized to degrade the neural encoding of sounds at the subcortical level, which would help explain certain listening-in-noise difficulties reported by some subjects with otherwise 'normal' hearing. In response to this peripheral damage, increased gain of central stages of the auditory system has been observed across several species of mammals, particularly in association with tinnitus. The auditory brainstem response (ABR) wave I amplitude and waves I-V amplitude ratio have been suggested as non-invasive indicators of cochlear synaptopathy and central gain activation respectively, but the evidence for these hearing disorders in humans is inconclusive. In this study, we evaluated the influence of lifetime noise exposure (LNE) on the human ABR and on speech-in-noise intelligibility performance in a large cohort of adults aged 29 to 55. Despite large inter-subject variability, results showed a moderate, but statistically significant, negative correlation between the ABR wave I amplitude and LNE, consistent with cochlear synaptopathy. The results also showed (a) that central gain mechanisms observed in animal studies might also occur in humans, in which higher stages of the auditory pathway appear to compensate for reduced input from the cochlea; (b) that tinnitus was associated with activation of central gain mechanisms; (c) that relevant cognitive and subcortical factors influence speech-in-noise intelligibility, in particular, longer ABR waves I-V interpeak latencies were associated with poorer performance in understanding speech in noise when central gain mechanisms were active; and (d) absence of a significant relationship between LNE and tinnitus, central gain activation or speech-in-noise performance. Although this study supports the possible existence of cochlear synaptopathy in humans, the great degree of variability, the lack of uniformity in central gain activation and the significant involvement of attention in speech-in-noise performance suggests that noise-induced cochlear synaptopathy is, at most, one of several factors that play a role in humans' speech-in-noise performance.

Cochleotoxicity monitoring protocol.

INTRODUCTION: Cochlear damage is frequent in long-term aminoglycosides therapy or chemotherapeutic treatments with platinum-based agents. Despite its prevalence, it is currently underestimated and underdiagnosed. A monitoring protocol is vital to the early detection of cochleotoxicity and its implementation is widely encouraged in every hospital unit. Our aim was to elaborate a cochleotoxicity monitoring protocol for patients treated with platinum compounds or aminoglycosides antibiotics. METHODS: PubMed® database was searched using terms relevant to drug cochleotoxicity in order to identify the most adequate protocol. Several articles and guidelines influenced our decision. RESULTS: There is no consensus on a universal monitoring protocol. Its formulation and application rely heavily on available resources and personnel. High-frequency audiometry and otoacoustic emissions play an important role on early detection of cochleotoxicity caused by aminoglycoside antibiotics and platinum compounds. CONCLUSION: A cochleotoxicity monitoring protocol consisting on an initial evaluation, treatment follow-up and post-treatment evaluation is proposed.

[The results of bilateral cochlear implantation in the children who survived meningitis]. / Rezul'taty bilateral'noi kokhlearnoi implantatsii u detei, perenesshikh meningit.

The objective of the present study was the prospective analysis of the results of bilateral cochlear implantation (CI) in the children presenting with bilateral ossification of the cochlea after they had survived meningitis. A total of 15 patients underwent the surgical intervention. In those exhibiting bilateral ossification of the basal cochlear helix over the 5 mm segment (up to first bend of the cochlear turn) and partial ossification of the second helix (in 6 children), the affected portions were removed with the placement of two choleostomies, the lower one (from the ossified membrane of the cochlear window) and the upper one (toward the second helix). Activation of the speech processors of the CI systems was carried out within 4-6 weeks after surgery. The hearing abilities of the children were evaluated in accordance with the 'Estimation of the auditory perception categories', 'Estimation of the child's apprehension capacity', and 'Analysis of speech intelligibility rating' guidelines. In all the children with ossification over less than 5 mm of the basal cochlear helix, it proved possible to introduce the whole intracochlear electrode grid whereas only half of the electrode array was implanted in the cases of overall ossification of the basal helix. The first results obtained by telemetry and surdopedagogical testing gave evidence of the possibility of identifying various sources of non-verbal and speech stimuli in all the treated children at a small (up to 3 meters) distance.

[The fistula of the round window of the cochlea]. / Fistula okna ulitki.

This article presents the data on the frequency, diagnostics, and variants of the surgical treatment of the fistula of the round window of the cochlea. A case of this pathology is reported with the special emphasis placed on the approaches to the diagnostics and surgical management of this condition.

A systematic review of stimulus parameters for eliciting distortion product otoacoustic emissions from adult humans.

OBJECTIVE: The objective of this study is to review the scientific literature to determine if a set of stimulus parameters can be described to elicit distortion product otoacoustic emissions (DPOAEs) of higher absolute level and/or greater reliability in healthy adult humans and higher sensitivity and specificity in adults with cochlear lesions. DESIGN: Systematic review. STUDY SAMPLE: Searches of four electronic databases yielded 47 studies that had used different parameters to elicit DPOAEs from within or between-groups of adult humans. RESULTS: The wide range of stimulus parameters used in the reviewed studies saw a wide range of reported values for DPOAE level, reliability, and sensitivity and specificity to cochlear lesions. CONCLUSION: The most commonly used stimulus parameters for eliciting DPOAEs from adult humans have included frequency ratios for the two primary tones (f2/f1) of between 1.04 and 1.4 and levels (L1/L2) of 65/55 dB SPL. The most commonly used parameters for eliciting DPOAEs of higher level in healthy adults appear to be linked to f2/f1 values between 1.20 and 1.22 and L1/L2 levels of 75/75 dB SPL. The stimulus parameters for eliciting DPOAEs of greater reliability in healthy adults and higher sensitivity and specificity in adults with cochlear lesions have yet to be clearly determined.

Electrococleografía extratimpánica en una población normal. Estudio descriptivo / Extra-tympanic electrocochleography in a normal population. A descriptive study

Introducción y objetivos: La electrococleografía extratimpánica es un registro elecrofisiológico que refleja la actividad eléctrica acontecida en la cóclea tras un estímulo sonoro. Se obtiene mediante la aplicación del estímulo en el conducto auditivo externo y el registro de la actividad eléctrica mediante electrodos de superficie. Dada la escasa literatura existente acerca de la exploración electrococleográfica normal en nuestro medio, este estudio busca regularizar los valores obtenidos mediante esta exploración en sujetos sin enfermedad otoneurológica y explicar detalladamente el proceso mediante el cual se obtiene el registro. Métodos: Exploración mediante electrococleografía extratimpánica de 60 oídos sin enfermedad otoneurológica y análisis estadístico de los resultados obtenidos. De ellos, 30 oídos fueron explorados a 90dB mientras que otros 30 oídos fueron estimulados a 80dB. Resultados: Se muestran los valores medios de amplitud y latencia del potencial de sumación y del potencial de acción, así como las latencias medias de la onda I y la onda II. Asimismo, se presenta el cálculo del cociente potencial de sumación/potencial de acción. Obtenidos estos resultados se comparan en función de la intensidad del estímulo, del sexo del paciente, del oído estudiado y del grupo etario. Conclusiones: Este estudio recopila datos sobre la electrococleografía en una población normal. Los valores obtenidos están en el rango de los valores normales de otros países, expuestos en la literatura internacional. Estos datos pueden ser muy útiles como referencia a la hora de valorar exploraciones en pacientes con dolencias que afectan la estructura o la función coclear (AU)

Introduction and objectives: Extra-tympanic electrocochleography is an electrophysiological register obtained after stimulating the cochlea with an audible stimulus. This stimulus is applied using an earphone over the external auditory canal, while the electrical activity is registered by surface electrodes. There are few studies that analyse normal electrocochleography in our environment. Thus, the main objective of our study was to regularize the values obtained with electrocochleography in ears without any otoneurological diseases. We explain in detail the process of obtaining the register. Methods: Sixty healthy ears were studied by extratympanic electrocochleography. Statistical results were analysed. While 30 ears were studied with a stimulus at 90dB, another 30 ears were studied with a stimulus at 80dB. Results: Summating potential and action potential latencies and amplitudes were measured. Summating potential/action potential ratios were calculated. Wave I and wave II latencies were also determined. These results were analysed in function of stimulus intensity, patient gender, patient age group and ear side studied. Conclusions: This study collected extra-tympanic electrocochleography data in a normal population and the results were in the range of other international studies obtained in other countries. These data can be used as a reference to evaluate illnesses that affect cochlear structure or functions (AU)

[The non-damaging method for the insertion of a standard electrode for cochlear ossification].

The objective of the present study was to develop the non-damaging method for the insertion of a standard electrode for cochlear ossification with a view to improving the results of hearing and speech rehabilitation of the patients presenting with grade IV sensorineural impairment of hearing. Twenty preparations of the cadaveric temporal bone were used to investigate topographic and anatomical relationships in the main structures of the middle and internal ears, viz. the second cochlear coil, vestibulum and its windows, processus cochleaformis, spiral lamina, and modiolus. The optimal method for the insertion of a standard electrode into the spiral canal of the cochlea after the removal of the ossified structures is proposed. The optimal site for constructing the second colostomy is determined that allows the spiral plate and modiolus to be maximally preserved. The proposed method was employed to treat 11 patients with grade IV sensorineural impairment of hearing and more than 5 mm ossification of the basal cochlear coil. With this method, it proved possible to insert the maximum number of electrodes into the cochlear spiral canal and thereby to obtain excellent results of hearing and speech rehabilitation in the patients with the ossified cochlea.

Perilymphatic fistula after underwater diving: a series of 11 cases.

INTRODUCTION: Onset of cochleovestibular symptoms (hearing loss, dizziness or instability, tinnitus) after a dive (scuba or breath-hold diving) warrants emergency transfer to an otology department. One priority is to investigate the possibility of the development of decompression sickness with a view to hyperbaric oxygen treatment of bubble-induced inner-ear damage. If this injury is ruled out, inner-ear barotrauma should be considered together with its underlying specific injury pattern, perilymphatic fistula. METHODS: We report on a series of 11 cases of perilymphatic fistula following ear barotrauma between 2003 and 2015, eight after scuba diving and three after free diving. All patients underwent a series of laboratory investigations and first-line medical treatment. RESULTS: Seven patients had a perilymphatic fistula in the left ear and four in the right. Eight cases underwent endaural surgical exploration. A fistula of the cochlear fenestra was visualised in seven cases with active perilymph leakage seen in six cases. After temporal fascia grafting, prompt resolution of dizziness occurred, with early, stable, subtotal recovery of hearing in seven. Of six patients in whom tinnitus occurred, this disappeared in two and improved in a further two. Two patients were not operated on because medical treatment had been successful, and one patient refused surgery despite the failure of medical treatment. Median follow-up time was 7.4 years (range 0.3 to 12). CONCLUSION: The diagnosis of perilymphatic fistula is based on clinical assessments and various laboratory findings. When there was strong evidence of this condition, surgery yielded excellent functional outcomes in all patients treated early.