Cochlear implantation in a child with auditory neuropathy spectrum disorder

Objective To report outcomes of cochlear implantation (CI) in a child with auditory neuropathy spectrum disorder (ANSD) and to provide preliminary clinical evidence of the efficacy of CI in ANSD patients.Methods A 4-year-old boy with diagnosed auditory neuropathy spectrum disorder (ANSD) received implantation of a Nucleus CI24R after an unsatisfactory trial of amplification.Post-implantation performance in both hearing sensitivity and speech recognition was assessed in different sessions.Aided hearing thresholds were tested by behavioral audiometry.Mandarin Early Speech Perception Test (MESP),Meaningful Auditory Integration Scale (MAIS),category of auditory performance (CAP) and Speech Intelligibility Rating (SIR) were used to assess the benefits in auditory skills or speech recognition the boy obtained from CI.The tests were administered before surgery and at 3 months and 7 months after opening.Results The boy demonstrated improved auditory sensitivity by using CI.Concerning speech recognition and communication,both speech audiometry and questionnaires showed an obvious benefit from CI.Conclusions CI has worked efficiently in this ANSD boy.But because of limited understanding of ANSD and rehabilitation effect by cochlear implantation in this condition,the clinical decision to implant should be cautious and only after a thorough evaluation.Meanwhile,well controlled and long term studies are needed to confirm the efficacy of cochlear implantation in patients with ANSD.

HYPERBILIRUBINEMIA AND AUDITORY NEUROPATHY

Introduction Hyperbilirubinemia is common in the new born owing to their special metabolism characteristics.Physiologic bilirubin levels are protective because of their antioxidant effects[1],while pathological jaundice is harmful to the health of the neonate.Previously,most pathological studies on the jaundice of neonates have concentrat-

Retro-labyrinthine Lesion Site Detected by Galvanic Vestibular Stimulation Elicited Vestibular-evoked Myogenic Potentials in Patients with Auditory Neuropathy

Objective Auditory neuropathy(AN)is a unique pattern of hearing loss with preservation of hair cell function.The condition is characterized by the presence of otoacoustic emissions(OAE)or cochlear microphonic(CM)responses with severe abnormalities of the auditory brainstem response(ABR).The vestibular branches of the VIII cranial nerve and the structures innervated by it can also be affected.However,the precise lesion sites in the vestibular system are not well characterized in patients with AN.Methods The air-conducted sound(ACS)vestibular-evoked myogenic potentials(VEMPs)and galvanic vestibular stimuli(GVS)-VEMPs were examined in 14 patients with AN.Results On examination of VEMPs(n=14,28 ears),the absent rates of ACS-cervical VEMP(cVEMP),ACS-ocular VEMP(oVEMP),GVS-cVEMP,GVS-oVEMP and caloric test were 92.9%(26/28),85.7%(24/28),67.9%(19/28),53.6%(15/28),and 61.5%(8/13),respectively.Impaired functions of the saccule,inferior vestibular nerve,utricle,superior vestibular nerve,and horizontal semicircular canal were found in 25.0%(7/28),67.9%(19/28),32.1%(9/28),53.6%(15/28)and 61.5%(8/13)patients,respectively.On comparing the elicited VEMPs parameters of AN patients with those of normal controls,both ACS-VEMPs and GVS-VEMPs showed abnormal results in AN patients(such as,lower presence rates,elevated thresholds,prolonged latencies,and decreased amplitudes).Conclusion The study suggested that patients with AN often have concomitant vestibular disorders.Retro-labyrinthine lesions were more frequently observed in this study.GVS-VEMPs combined with ACS-VEMPs may help identify the lesion sites and facilitate detection of areas of vestibular dysfunction in these patients.

Profiles and predictors of onset based differences in vocal characteristics of adults with auditory neuropathy spectrum disorder(ANSD)

Purpose:Onset-based differences are understudied in Auditory Neuropathy Spectrum Disorder(ANSD)in dimensions such as voice,which is addressed in the study.The study aimed to profile and predict the best metrics of onset-related differences in acoustic vocal characteristics of early and late-onset ANSD patients.Methods:31 participants(15 early and 16 late-onset)aged 15e30 years diagnosed with ANSD were included in the study.The sustained phonation of vowel/i/recorded by the participants using android based smartphones of selected configuration was sent over email to the experimenter.Acoustic parameters(fundamental frequency,harmonic frequencies,jitter,shimmer,harmonic-to-noise ratio,cepstral peak prominence-CPP,and pitch sigma)were analysed using Praat software.Results:Results revealed significantly increased(p<0.05)fundamental frequency along with decreased F2 and F3 of/i/in the early-onset ANSD compared to the late-onset group,which can be explained based on differences in the pathophysiology of the disorder.Although not statistically significant,mean perturbations(jitter and shimmer),harmonic-to-noise ratio,cepstral peak prominence,and pitch sigma were more affected in the early-onset group,reflective of lowered auditory feedback and periodicity in their voice samples.Results of discriminant analysis marked the emergence of F2,F3,and CPP as the most sensitive metrics for onset-based group differences in voice characteristics.Conclusions:The findings from the study highlight the role of acoustical voice evaluation(especially CPP,F2&F3)in verifying the onset of ANSD disorder.The insights from the onset-based differences seen in vocal characteristics can indirectly help audiologists in deciding the management options for ANSD.

Auditory neuropathy in a patient with hemochromatosis

Objective:To evaluate the auditory function of an individual with genetically confirmed hemochromatosis. Methods: A 57 year old male with mildly impaired sound detection thresholds underwent a range of behavioural, electroacoustic and elec-trophysiologic assessments. These included the recording of otoacoustic emissions and auditory brainstem responses, measurement of monaural temporal resolution and evaluation of binaural speech processing. Findings for this patient were subsequently compared with those of 80 healthy controls with similar audiometric thresholds. Results: The patient showed the three cardinal features of auditory neuropathy, presenting with evidence of normal cochlear outer hair cell function, disrupted neural activity in the auditory nerve/brainstem and impaired temporal processing. His functional hearing ability (speech perception) was significantly affected and suggested a reduced capacity to use localization cues to segregate signals in the presence of back-ground noise. Conclusion:We present the first case of an individual with hemochromatosis and auditory neuropathy. The findings for this patient highlight the need for careful evaluation of auditory function in individuals with the disorder.

Autosomal recessive hereditary auditory neuropathy

Objectives: Auditory neuropathy (AN) is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses (ABRs) and normal cochlear outer hair cell function as measured by otoacoustic emissions (OAEs). Many risk factors are thought to be involved in its etiology and pathophysiology. Three Chinese pedigrees with familial AN are presented herein to demonstrate involvement of genetic factors in AN etiology. Methods: Probands of the above - mentioned pedigrees, who had been diagnosed with AN, were evaluated and followed up in the Department of Otolaryngology Head and Neck Surgery, China PLA General Hospital. Their family members were studied and the pedigree diagrams were established. History of illness, physical examination,pure tone audiometry, acoustic reflex, ABRs and transient evoked and distortion- product otoacoustic emissions (TEOAEs and DPOAEs) were obtained from members of these families. DPOAE changes under the influence of contralateral sound stimuli were observed by presenting a set of continuous white noise to the non - recording ear to exam the function of auditory efferent system. Some subjects received vestibular caloric test, computed tomography (CT)scan of the temporal bone and electrocardiography (ECG) to exclude other possible neuropathy disorders. Results: In most affected subjects, hearing loss of various degrees and speech discrimination difficulties started at 10 to16 years of age. Their audiological evaluation showed absence of acoustic reflex and ABRs. As expected in AN, these subjects exhibited near normal cochlear outer hair cell function as shown in TEOAE & DPOAE recordings. Pure- tone audiometry revealed hearing loss ranging from mild to severe in these patients. Autosomal recessive inheritance patterns were observed in the three families. In Pedigree Ⅰ and Ⅱ, two affected brothers were found respectively, while in pedigree Ⅲ, 2 sisters were affected. All the patients were otherwise normal without evidence of peripheral neuropathy at the time of this writing. Conclusions: In this study, patients with feature of non- syndromic hereditary auditory neuropathy were identified in three Chinese families.Pedigree analysis indicates autosomal recessive inheritances in the pedigrees. The observed inheritance and clinical audiologic findings are different from those previously described for non-syndromic low-frequency sensorineural hearing loss. This information should facilitate future molecular candidate genes screening for understanding the mechanism of AN.

COCHLEAR IMPLANT AS AN INTERVENTION IN PATIENTS WITH AUDITORY NEUROPATHY

Auditory neuropathy(AN)is a hearing disorder char acterized by absence of auditory brainstem responses de spite preservation of outer hair cell function,and has at tracted attentions from researchers and audiologists since reported by Starr et al[1].Clinical manifestations in AN patients include abnormal auditory brainstem responses normal otoacoustic emissions,lack of acoustic reflexes large cochlear microphonics,speech perception deteriora

INFLUENCE ON VESTIBULAR FUNCTION BY AUDITORY NEUROPATHY

Objective The main purpose of the present study was to describe the vestibular function in patients with auditory neuropathy (AN), and to assess their ability to maintain balance. Methods Vestibular function tests were performed on 32 patients with AN and 36 normal subjects including electronystagmopraphy(ENG) and static postrography(SPG). The results from the two groups were compared. Results Equilibrium function in patients with AN, was abnormal, compared to normal subjects. Conclusion Vestibular function tests, espe-cially static postrography, should be performed on patients with AN.

Neurophysiological characteristics in infants and young children with auditory neuropathy

Objective:To analyze neurophysiological characteristics in infants and young children with auditory neuropathy(AN) and explore their clinical significance.Methods: Audiological measurements(acoustic immittance, EOAEs, ABR, CM, MLR and ERPs) and peripheral neurological tests were conducted and evaluated in 13 infants and young children with AN. Six of them received high-resolution temporal bone CT scans and/or cerebral MRI examinations.Results: All of the children showed type “A” tympanograms with abseatation of stapedial reflexes. EOAEs were normal in 12 of 13 subjects. In one child who had a history of anoxia during the birth,the EOAEs were not elicited. Click-evoked ABRs were absent in 12 of 13 subjects when maximum output of the instrument was reached. The CM potentials were presented bilaterally in all individuals,which were independent of the EOAEs and ABR. Of eight cases tested,all had clear MLR and six showed normal ERPs(P300 and MMN). Peripheral neurological tests and radiological findings were within the normal ranges. Conclusion: The diagnosis of AN in infants and young children should focus on analyzing their neurophysiological characteristics,especially on CM,MLR and ERPs. Combined use of EOAEs, ABR and CM was recommended for hearing screening on newborns with high risk factors.

Diagnosis and Treatment of Auditory Neuropathy and Related Research

Introduction Deafness is one of the most common otologic diseases and a major disease that greatly impacts the Chinese population. From the Second National Sample Survey of Disabled Persons, it is estimated that there are 27,800,000 hearing disabled persons in China, about 2.14% of

Effects of glutamate on distortion-product otoacoustic emissions and auditory brainstem responses in guinea pigs

Objectives To investigate changes in evoked potentials and structure of the guinea pig cochleae during whole cochlear perfusion with glutamate. Methods CM, CAP, DPOAE, and ABR were recorded as indicators of cochlear functions during whole cochlear perfusion. The morphology of the cochlea was studied via transmission electron microscopy. Results There were no significant changes in DPOAE amplitude before and after glutamate perfusion. CM I/O function remained nonlinear during perfusion. ABR latencies were delayed following glutamate perfusion. The average CAP threshold was elevated 35 dB SPL following glutamate perfusion.. The OHCs appeared normal, but the IHCs and afferent dendrites showed cytoplasmic blebs after glutamate perfusion. Conclusions While being a primary amino acid neurotransmitter at the synapses between hair cells and spiral ganglion neurons, excessive glutamate is neurotoxic and can destroy IHCs and spiral ganglion neurons. The technique used in this study can also be used to build an animal model of auditory neuropathy.

A METHOD FOR ESTABLISHING AN ANIMAL MODEL OF LIKE-AUDITARY NEUROPATHY

Objective: To establish an animal model of like-auditory neuropathy in neonatal rat. Methods The ani-mals were injected with phenylhydrazine hydrochloride or saline at 7-day of age. ABR and DPOAE were performed to assess the auditory function. The cochlea basilar membrane stretched preparation and cochlear frozen sections were prepared for immunohistochemical staining to examine the morphological change of hair cells and spiral ganglion cells (SGNs). Results At 7-day age the ABR waveI, III, V, latencies andI-III,I-V IWIs in the experimental group were significantly prolonged compared with those in the control group. The ABR thresholds were also elevated in the experimental group. We found there is no significant differ-ence in DPOAE in phenylhydrazine hydrochloride exposure group compare to control group. The cochlear hair cells showed no signs of loss in both group, but the total number of neurofilaments positive cells in SGNs were significantly reduced in the phenylhydrazine treated animals. Conclusion Our study suggests that phenylhydrazine hydrochloride can change the auditory function and induce peripheral nerve pathology by targeted mainly the SGNs in neonatal rat.

AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization

Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair cell function.ANSD represents up to 15%of individuals with hearing impairments.Through mutation screening,bioinformatic analysis and expression studies,we have previously identified several apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants in ANSD families and in some other sporadic cases.Here,to elucidate the pathogenic mechanisms underlying each AIFM1 variant,we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system and constructed AIF-wild type(WT)and AIF-mutant(mut)(p.T260A,p.R422W,and p.R451Q)stable transfection cell lines.We then analyzed AIF structure,coenzyme-binding affinity,apoptosis,and other aspects.Results revealed that these variants resulted in impaired dimerization,compromising AIF function.The reduction reaction of AIF variants had proceeded slower than that of AIF-WT.The average levels of AIF dimerization in AIF variant cells were only 34.5%-49.7%of that of AIF-WT cells,resulting in caspase-independent apoptosis.The average percentage of apoptotic cells in the variants was 12.3%-17.9%,which was significantly higher than that(6.9%-7.4%)in controls.However,nicotinamide adenine dinucleotide(NADH)treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells.Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD,and introduce NADH as a potential drug for ANSD treatment.Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.

Understanding auditory neuropathy spectrum disorder： a system- atic review in transgenic mouse models

Auditory neuropathy spectrum disorder is a unique group of hearing dysfunctions characterized by preserved outer hair cell function and abnormal neural conduction of the auditory pathway. However, the pathogenic mechanism underlying this disorder is not clear. We therefore performed a systematic review of genetic mouse models with different gene mutations to provide a valuable tool for better understanding of the process and the possible molecular mechanisms. Of the 18 articles retrieved, nine met the required criteria. All biochemical, histological, and electrophysiological results were recorded for each of the mouse models, as was the transgenic technology. This review provides a summary of different mouse models that may play an important role in the diagnosis and management of auditory neuropathy spectrum disorder in the future.

The genetic load for hereditary hearing impairment in Chinese population and its clinical implication

Objective To understand the genetic load in the Chinese population for improvement in diagnosis, prevention and rehabilitation of deafness. Methods DNA samples, immortalized cell lines as well as detailed clinical and audiometric data were collected through a national genetic resources collecting network. Two conventional genetic approaches were used in the studies. Linkage analysis in X chromosome and autosomes with microsatellite markers were performed in large families for gene mapping and positional cloning of novel genes. Candidate gene approach was used for screening the mtDNA 12SrRNA, GJB2 and SLC26A4 mutations in population -based samples. Results A total of 2,572 Chinese hearing loss families or sporadic cases were characterized in the reported studies, including seven X-linked, one Y-linked, 28 large and multiplex autosomal dominant hearing loss families, 607 simplex autosomal recessive hereditary hearing loss families, 100 mitochondrial inheritance families, 147 GJB2 induced hearing loss cases, 230 cases with enlarged vestibular aqueduct (EVA) syndrome, 169 sporadic cases with auditory neuropathy, and 1,283 sporadic sensorineural hearing loss cases. Through linkage analysis or sequence analysis, two X-linked families were found transmitting two novel mutations in the POU3F4 gene, while another X -linked family was mapped onto a novel locus, nominated as AUNX1 (auditory neuropathy, X-linked locus 1). The only Y-linked family was mapped onto the DFNY1 locus(Y-linked locus 1, DFNY1). Eight of the 28 autosomal dominant families were linked to various autosomal loci. In population genetics studies, 2,567 familial cases and sporadic patients were subjected to mutation screening for three common hearing loss genes: mtDNA 12S rRNA 1555G, GJB2 and SLC26A4. The auditory neuropathy cases in our samples were screened for OTOF gene mutations. Conclusions These data show that the Chinese population has a genetic load on hereditary hearing loss. Establishing personalized surveillance and prevention models for hearing loss based on genetic research will provide the opportunity to decrease the prevalence of deafness in the Chinese population.

Application of intraoperative round window electrocochleography for screening the patients with auditory neuropathy

Background Most patients with auditory neuropathy （AN） could receive good even the best effects after cochlear implantation. How to diagnose AN objectively and accurately is very important. In this study, we screened the patients with AN according to the presence or absence of compound action potential （CAP） of intraoperative round window electrocochleography （RW ECochG）. Methods Intraoperative RW ECochG was performed on 32 patients with profound sensorineural deafness, who had normal cochlea during cochlear implantation surgery under general anesthesia in the standard operating room. The cochlear microphonic （CM） and CAP of RW ECochG was observed and recorded. Results The presence of CM but the absence of CAP of RW ECochG occurred in 12 among the 32 patients. They were suspected to suffer from AN. The rest patients who had CM and CAP of RW ECochG were thought not to suffer from AN. Conclusion Application of intraoperative RW ECochG during the cochlear implantation surgery may objectively and accurately screen the patients with AN, and can give a meaningful clue for implanted device working.

Cochlear implants in genetic deafness

Genetic defects are one of the most important etiologies of severe to profound sensorineural hearing loss and play an important role in determining cochlear implantation outcomes.While the pathogenic mutation types of a number of deafness genes have been cloned,the pathogenesis mechanisms and their relationship to the outcomes of cochlear implantation remain a hot research area.The auditory performance is considered to be affected by the etiology of hearing loss and the number of surviving spiral ganglion cells,as well as others.Current research advances in cochlear implantation for hereditary deafness,especially the relationship among clinic-types,genotypes and outcomes of cochlear implantation,will be discussed in this review.

Audiological evaluation in Chinese patients with mitochondrial encephalomyopathies

Background Hearing impairment has been reported to be common in patients with mitochondrial disorders,a group of diseases characterized by pleiomorphic clinical manifestations due to defects in oxidative phosphorylation of mitochondria.This study aimed to investigate the audiological characteristics in a large cohort of patients with mitochondrial disease.Methods Comprehensive audiological evaluations,including pure tone audiometry,tympanometry,speech audiometry,otoacoustic emissions,electrocochleography and auditory brainstem evoked potentials,were performed in 73 Chinese patients with mitochondrial encephalomyopathy and with confirmed mitochondrial DNA （mtDNA） defects.Results Among the patients,71％ had hearing impairment.However,the incidence rate and severity of hearing impairment were much less in the chronic progressive external ophthalmoplegia （CPEO） subtype than in the mitochondrial encephalomyopathy,lactic acidosis,and stroke-like episodes （MELAS）,myoclonic epilepsy with ragged red fibers （MERRF） and Kearns-Sayre syndrome （KSS） subtypes.While most of our patients had a predominantly cochlea origin for the hearing deficit,five patients had an auditory neuropathy spectrum disorder and three patients had impairment of both cochlea and auditory codex.Conclusions Various portions of the auditory system could be involved in patients with mitochondrial diseases,including cochlea,auditory nerve,auditory pathway and cortex.Hearing loss was more associated with multisystem involvement.Genotype,mutant load of mtDNA and other unknown factors could contribute to heterogeneity of hearing impairment in mitochondrial disease.