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Timing of cochlear implantation in auditory neuropathy patients with OTOF mutations: Our experience with 10 patients

2017; Wiley; Volume: 43; Issue: 1 Linguagem: Inglês

10.1111/coa.12949

1749-4486

Chen‐Chi Wu, Chuan‐Jen Hsu, Fang‐Lih Huang, Yen‐Hung Lin, Yen‐Hung Lin, Tien‐Chen Liu, Che‐Ming Wu,

Ion Channels and Receptors

Auditory neuropathy spectrum disorder (ANSD) can be caused by a variety of pathologies ranging from inner hair cells, synapses, spiral ganglion neurons, the auditory nerve, to brainstem auditory nuclei.1 For ANSD patients who derive limited benefit from hearing aids, cochlear implantation constitutes the treatment of last resort. However, corresponding to the heterogeneity in pathology, the outcomes with cochlear implants (CIs) vary significantly among patients with ANSD.1 The decision to undertake cochlear implantation is further complicated by the fact that improvement of auditory phenotypes with age may be observed in approximately 20% of children with ANSD.2 Recent studies have shown that genetic testing is of great help in determining the site of pathology in paediatric sensorineural hearing impairment (SNHI).3, 4 Specifically, mutations in the OTOF gene, a common cause of clinical ANSD, are an indicator that the pathology is confined to the synapse5; post-synaptic neurons and nerve fibres are preserved for electrical stimulation of CI. In this study, we retrospectively analysed CI outcomes in 10 patients with OTOF mutations to explore the utility of genetic diagnosis to help determine the timing of cochlear implantation in patients with ANSD. This study was approved by the Research Ethics Committees of National Taiwan University Hospital and Chang Gung Memorial Hospital. Ten children with ANSD and biallelic OTOF mutations who underwent unilateral cochlear implantation at two tertiary referral centres from 2009 to 2015 were included in this study (Table 1). The genotypes of the 10 subjects were confirmed by Sanger sequencing of all 49 exons of the OTOF gene.6 Eight patients received the Nucleus 24RE (Cochlear, Macquarie University, NSW, Australia); two patients received the HiRes 90K Advantage (Advanced Bionics, Valencia, CA, USA). A cohort of 183 paediatric CI recipients, including 25 with biallelic GJB2 mutations and 23 with biallelic SLC26A4 mutations, were included for comparison. All participants were Han Chinese and came from families whose native language was Mandarin. Children with syndromic hearing loss, acquired hearing loss, cochlear nerve deficiency, cognitive problems or psychological problems were excluded. Immediately after insertion of the electrode array, impedance was measured in all patients. Two neural response recording systems, neural response telemetry (NRT) and neural response imaging (NRI), were used to measure the electrically evoked compound action potentials (ECAPs) in patients receiving Nucleus 24RE and HiRes 90K Advantage devices, respectively. Categories of auditory performance (CAP) and speech intelligibility rating (SIR) scores were assessed at 3 months, 6 months, 1 year, 3 years and 5 years post-implant, whereas speech perception tests were performed at 3 years post-implant.7 The duration of CI use in the 10 patients with OTOF mutations ranged from 1 to 7 year as of preparation of this article. The median CAP and SIR scores in the 10 patients with OTOF mutations were ascertained and compared to those in patients with GJB2 or SLC26A4 mutation, as well as those in the group of 183 paediatric CI recipients. The genetic and clinical features of the 10 ANSD patients with OTOF mutations are detailed in Table 1. Serial behavioural audiometric testing revealed stable hearing levels in these patients (mean, 89.0 ± 12.3 dBHL on the last visit before surgery). All patients demonstrated typical audiological features of ANSD, as evidenced by preserved cochlear microphonics or otoacoustic emissions and lack of auditory brainstem response (ABR). All 10 patients had absent ABR at 95 dBHL on serial follow-ups before surgery; this percentage did not differ from that in the comparison group of 183 patients (100% vs 86%, Fisher's exact test, P > .05). The age at cochlear implantation ranged from 1.0 to 5.6 years. Early in the present study, cochlear implantation was performed on patients DE3247 and DE4496 at the age of 5.6 years and 5.1 years, respectively, due to concerns regarding the uncertainty of CI outcomes in patients with ANSD. With the accumulation of experience, we proceeded with cochlear implantation in later ANSD patients with OTOF mutations at an earlier age. During surgery, all 10 patients with OTOF mutations revealed robust ECAPs on NRT or NRI, which were comparable to those observed in CI recipients with a definite pathology confined to the cochlea, such as patients with GJB2 mutations (Figure. 1). After cochlear implantation, all 10 patients with OTOF mutations showed good and rapid improvement. At 3 years and 5 years post-implant, there was no difference in CAP or SIR scores among patients with OTOF, GJB2 and SLC26A4 mutations (Figure. 2; Kruskal-Wallis test, P > .05). At 3 years post-implant, the mean speech discrimination score in patients with OTOF mutations was 77.5 ± 37.1, which was not different from that in patients with GJB2 (79.4 ± 22.3) or SLC26A4 (86.6 ± 26.5) mutations (ANOVA, P > .05). Our results demonstrated that ANSD patients with OTOF mutations exhibited excellent electrophysiological responses and auditory and speech performances using CIs. All 10 patients revealed robust ECAPs on NRT or NRI during surgery; postoperatively, these patients showed good and rapid improvement in CAP and SIR scores, comparable to those with cochlear SNHI of other genetic causes. Before the operation, these patients did not experience spontaneous recovery in hearing thresholds or ABR with age. Given the stable auditory phenotypes observed preoperatively and the satisfactory CI outcomes, cochlear implantation should be performed in patients with OTOF mutations whenever indicated, without unnecessary delay. Favourable CI outcomes have been documented in a few patients with OTOF mutations (Table 2). Rouillon et al8 were among the first to describe CI outcomes in detail by reporting good auditory and speech performance in two patients with OTOF mutations. Runge et al9 identified a novel OTOF mutation in a multiplex ANSD family with two affected siblings. Both siblings underwent unilateral cochlear implantation. One showed favourable speech perception performance 3 years after implantation; the other's speech perception performance was mediocre. Santarelli et al5 performed disyllabic recognition testing in six ANSD patients with biallelic OTOF mutations and reported that all six patients attained speech perception scores of 90%-100% at 1-1.5 year after surgery. Of note, in contrast to previous studies, which reported CI outcomes in OTOF-related ANSD patients of severe-to-profound hearing impairment, Zhang et al10 presented a case of temperature-sensitive ANSD resulting from specific OTOF mutations. Despite moderate hearing levels when afebrile, this patient was implanted unilaterally at age 4 due to comprehension and pronunciation difficulties. Two years after surgery, the patient exhibited excellent speech perception performance with a recognition score of 93% on open-set words and 98% on open-set sentence identification. Cochlear implantation in patients with ANSD requires special consideration because the outcome is more unpredictable than in patients with cochlear SNHI. By demonstrating satisfactory CI outcomes in ANSD patients with OTOF mutations, this study confirms the utility of genetic diagnosis to identify a specific subset of suitable CI candidates among patients with ANSD. These findings have important clinical implications: genetic examination should be included in the pre-CI evaluation battery in ANSD to improve outcome prediction capabilities. To our knowledge, this study represents the largest series in the literature documenting electrophysiological data and auditory and speech performances of cochlear implantation in ANSD patients with OTOF mutations. By cross-referring these results to those observed in patients with GJB2 or SLC26A4 mutations, we provide direct evidence that CI outcomes in ANSD patients with OTOF mutations are as favourable as those in CI recipients with a definite cochlear pathology. However, because the number of patients is limited, more cases need to be accumulated to validate our conclusion. Some limitations of this study deserve discussion. First, ANSD is very aetiologically heterogeneous, and screening for OTOF mutations could only identify the CI candidates predicted to have good outcomes, not those with unfavourable outcomes. However, this limitation could be overcome with the availability of high-throughput DNA sequencing to address paediatric SNHI. By simultaneously screening 129 deafness genes using the massively parallel sequencing technique, our recent study demonstrated that mutations in DFNB59 and PCDH15, two genes expressed in the spiral ganglion neurons and/or brainstem auditory nuclei, were associated with unfavourable CI outcomes.4 Second, as in most previous reports, all 10 patients with OTOF mutations in this study had stationary severe-to-profound hearing levels before surgery, and the decision to perform cochlear implantation in these patients at an earlier age is less controversial. This “early-intervention” strategy may not be applicable for patients with certain uncommon OTOF mutations related to less severe or fluctuating hearing levels. Although favourable CI outcomes have been reported in a temperature-sensitive ANSD case resulting from specific OTOF mutations, a longer period of observation of these patients may be necessary to ensure that indications for cochlear implantation are fulfilled. ANSD patients with OTOF mutations do not experience spontaneous recovery of auditory phenotypes with age, but demonstrate favourable CI outcomes comparable to patients with cochlear SNHI of other genetic causes. Accordingly, early implantation is indicated in ANSD patients with OTOF mutations to achieve optimal CI performance. This study was supported by research grants from the National Health Research Institute (NHRI-EX105-10414PC), National Taiwan University Hospital (NTUH-105-S3165) and Chang Gung Memorial Hospital (CMRPG3E0413 and CMRPG3E1662). We also wish to thank all subjects for participating in the present study. None to declare.