Central auditory maturation and behavioral outcomes after cochlear implantation in prelingual auditory neuropathy spectrum disorder related to OTOF variants (DFNB9): Lessons from pilot study

Abstract

The cortical auditory evoked potential (CAEP)-based P1 component acts as a biomarker for cochlear implantation (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). To date, early intervention primarily before the age of two years and six months of CI usage is necessary and sufficient to achieve age-appropriate cortical maturation and good prognosis. However, varying degrees of neural dyssynchrony, resulting from the etiological heterogeneity of ANSD, may preclude uniform application of this hypothesis to ensure auditory cortical maturation. Thus, a focused evaluation of those carrying OTOF variants, which may be the salient molecular etiology of prelingual ANSD, would circumvent the issue of heterogeneity. Here, we sought to provide a much better understanding of the brain perspectives (i.e., P1 maturation) in OTOF-associated ANSD subjects and set the stage for an optimal strategy to enhance language development. We conducted a preliminary study comprising 10 subjects diagnosed with OTOF-related ANSD who underwent CI by a single surgeon and subsequently underwent measurements of the P1 component. We observed that DFNB9 subjects who received CI after 2 years of age exhibited “absent” or “anomalous” P1 components that correspond to delayed language development. However, timely implantation, as early as 12 months of age per se, might be insufficient to achieve age-appropriate cortical maturation of DFNB9 in cases with six to seven months of device use. This suggests the importance of sustained rehabilitation in DFNB9 than in other etiologies. Indeed, an additional follow-up study showed that a reduction in P1 latency was linked to an improvement in auditory performance. Collectively, our results suggest that central auditory maturation and successful outcome of CI in DFNB9 may have more demanding requirements, that is, earlier implantation and more sustained rehabilitation. We believe that the current study opens a new path toward genome-based neuroimaging in the field of hearing research.

Cochlear Implantation Outcomes in Patients with Auditory Neuropathy Spectrum Disorder of Genetic and Non-Genetic Etiologies: A Multicenter Study

“…Otoferlin, encoded by OTOF , is involved in the membrane fusion of synaptic vesicles in the inner hair cells [ 24 , 25 ]. OTOF -related ANSD belongs to “presynaptic” ANSD, and the CI outcome is expectedly good in these patients [ 26 , 27 , 28 ]. In our previous studies, we demonstrated that patients with pathogenic OTOF variants always revealed robust ECAPs during cochlear implantation.…”

“…Nine (50%) patients underwent bilateral implantation, one of whom received bilateral simultaneous implantation. The preoperative hearing threshold was 88.2 ± 14.5 (57.5-106.3) dBHL, and the CI-aided hearing threshold was 25.6 ± 4.1 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) dBHL. The median CAP and SIR scores at the latest follow-up were 7 (range, 5-7) and 5 (range, 2-5), respectively, indicating that these patients showed excellent outcomes.…”

Precision Medicine Approach to Cochlear Implantation

“…But the sensitive period for good CI outcome for DFNB9 subjects may be narrower than that for GJB2and SLC26A4-related deafness [17,[23][24][25]. 50% of Korean DFNB9 children implanted after 2 years of age showed a notably poor outcome (categories of auditory performance (CAP) scores of 3 and 4) at 24 months post-CI when compared to CAP scores of 6 and 7 achieved by children implanted early [17].…”

“…Summary of precision medicine approach to cochlear implantationRelatively poorer outcome and anomalous P1 recovery in CAEP when operated after 2 years of age than before 2 years of age(17,24) More rapid catchup in speech abilities when operated before the age of 18 months (26)…”

Full etiologic spectrum of pediatric severe to profound hearing loss of consecutive 119 cases

“…For example, SLC26A4 and GJB2 variants are the major cause of SP-SNHL with different progressive features from each other, so when they are confirmed, hearing rehabilitation can be planned accordingly 2 , 3 . And it has been reported that subjects with OTOF -related auditory neuropathy spectrum disorder could be managed effectively with timely CI after molecular etiologic confirmation, which would have been difficult without genetic confirmation 4 , 5 . In some cases etiologic diagnosis of hearing loss enables early recognition of comorbidities such as visual loss in Usher syndrome, potential thyroid issues in Pendred syndrome, and kidney disease in Alport syndrome 6 , 7 .…”