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Etiology of patients with residual acoustic hearing. Orange indicates genetic causes of hearing loss; yellow, other causes; grey, unknown (n ¼ 41).
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Background: Recent advances in less-invasive surgery and electrode design allow for a high degree of hearing preservation (HP) after cochlear implantation (CI), although residual hearing still deteriorates in some patients. To date, the factors predictive of preserving residual hearing remain a controversial topic.
Objective: The aim of this study...
Context in source publication
Context 1
... them, 19 patients received a genetic diagnosis, with the CDH23 gene most frequently implicated, followed by ACTG1, Mit1555A > G, MYO7A, MYO15A, SLC26A4, and TMPRSS3 (Table 2). Additionally, two patients were diagnosed with otosclerosis and congenital diaphragmatic hernia (Figure 1). ...
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Background
Registries are powerful clinical investigational tools. Although in hospitals registries may be mandated, industry-sponsored, international registries are voluntary and therefore can require clearer objectives and more planning. The registry also needs sufficient resources and appropriate measurement tools to motivate long-term participa...
Citations
... Many of the factors captured in this category are associated with the underlying pathology which, while out of scope of the projects and original hypotheses in the RHP, are important to recognise in this framework as they may contribute to ongoing hearing loss progression. Genetics for example, can heavily influence hearing loss outcomes both in terms of progression of the underling condition, and preservation following CI Yoshimura et al., 2020 ). Cochlear anatomy is subject to variation ( Avci et al., 2014 ), differences in overall Figure 1. ...
... Gender may be confounded with lifestyle factors such as occupation, potentially due to occupational noise exposure ( Le et al., 2017 ). Age is often reported to have an association with hearing outcomes after CI, with older aged subjects commonly presenting with worse hearing outcomes than younger, more often at initial activation Kopelovich et al., 2014 ;Wanna et al., 2018 ;Yoshimura et al., 2020 ). Comorbidities and unhealthy lifestyle factors have been linked with poorer medical outcomes generally and are closely as-sociated with issues related to metabolism and inflammation including dysregulated innate immunity, and chronic inflammation ( Li et al., 2021 ). ...
In 2010 Cochlear initiated a coordinated preclinical research program to identify the factors and underlying mechanisms of acoustic hearing loss following cochlear implantation and device use. At its inception the program was structured around several major hypotheses implicated in the loss of acoustic hearing. The understanding of causes evolved over the course of the program, leading to an increased appreciation of the role of the biological response in post-implant hearing loss. A systematic approach was developed which mapped the cochlear implant journey along a timeline that considers all events in an individual's hearing history. By evaluating the available data in this context, rather than by discrete hypothesis testing, causative and associated factors may be more readily detected. This approach presents opportunities for more effective research management and may aid in identifying new prospects for intervention. Many of the outcomes of the research program apply beyond preservation of acoustic hearing to factors important to overall cochlear health and considerations for future therapies.
... Lastly, affected individuals with hearing loss could benefit from the identification of their genetic causes by genomic sequencing, which may provide better preoperative evaluation and postoperative effect prediction for clinic and cochlear implant (CI). In fact, patients with CDH23 mutations were predicted to acquire an acceptable auditory and speech outcome after CI (Liu et al., 2008;Yoshimura et al., 2020;Chen et al., 2022). In our study, two affected children in family three and family four underwent bilateral CI surgery at age of 2 years and indeed showed acceptable recovery. ...
Background: Hearing loss (HL) is the most common form of sensory disorder in humans. Molecular diagnosis of HL is important for genetic counseling for the affected individuals and their families.
Methods: To identify potential genetic causes, we performed whole-exome sequencing and related biomedical informatics for 351 non-syndromic HL patients and their family members.
Results: In the present study, we report the identification of four compound heterozygous variants in the CDH23 gene from four affected families, including four novel variants (c.995C>A, p.T332K; c.2159G>A, p.R720Q; c.5534A>G, p.N1845S, and c.7055-1G>C) and two frequently reported variants (c.719C>T, p.P240L and c.4762C>T, p.R1588W).
Conclusion: Our findings significantly expanded the mutation spectrum of CDH23-associated autosomal recessive hearing loss.
... Calculating the effect of age resulted in a significant difference in favor of patients under 45 years of age. This confirmed earlier reports showing better HP in children and younger adults (7,27,(41)(42). ...
... Concerning long-term results for EAS patients using mediumlength electrodes, postoperative residual hearing declines over time, and the deterioration of residual hearing of the implanted ear is related to the rate of progression in the contralateral ear (45,46). A causative gene was detected that caused progressive hearing loss in half of the patients receiving EAS (42), suggesting that various genes are responsible in EAS patients. ...
Background
The last two decades have demonstrated that preoperative functional acoustic hearing (residual hearing) can be preserved during cochlear implant (CI) surgery. However, the relationship between the electrode array length and postoperative hearing preservation (HP) with lateral wall flexible electrode variants is still under debate.Aims/Objectives
This is a systematic literature review that aims to analyze the HP rates of patients with residual hearing for medium-length and longer-length lateral wall electrodes.MethodA systematic literature review methodology was applied following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations to evaluate the HP rates of medium-length and longer-length lateral wall electrodes from one CI manufacturer (medium length FLEX 24, longer length FLEX 28 and FLEX SOFT, MED-EL, Innsbruck, Austria). A search using search engine PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) was performed using the search terms “hearing preservation” or “residual hearing” and “cochlear implant” in “All fields.” Articles published only in English between January 01, 2009 and December 31, 2020 were included in the search.ResultsThe HP rate was similar between medium-length (93.4%–93.5%) and longer (92.1%–86.8%) electrodes at 4 months (p = 0.689) and 12 months (p = 0.219). In the medium-length electrode group, patients under the age of 45 years had better HP than patients above the age of 45 years.Conclusions
Both medium-length and longer electrode arrays showed high hearing preservation rates. Considering the hearing deterioration over time, implanting a longer electrode at primary surgery should be considered, thus preventing the need for future reimplantation.
... Additionally, identifying genetic etiologies has implications for hearing preservation with CI. Yoshimura et al. identified three causative gene mutations only expressed in hair cell stereocilia that permitted improved hearing preservation outcomes, compared with other genetic disruptors of cochlear function [155]. A recent large-cohort study of 459 CI recipients identified causative genetic mutations in 48% of children and 22% of adults, establishing a foundation for future studies correlating genetic cause with CI performance [156]. ...
As biomolecular approaches for hearing restoration in profound sensorineural hearing loss evolve, they will be applied in conjunction with or instead of cochlear implants. An understanding of the current state-of-the-art of this technology, including its advantages, disadvantages, and its potential for delivering and interacting with biomolecular hearing restoration approaches, is helpful for designing modern hearing-restoration strategies. Cochlear implants (CI) have evolved over the last four decades to restore hearing more effectively, in more people, with diverse indications. This evolution has been driven by advances in technology, surgery, and healthcare delivery. Here, we offer a practical treatise on the state of cochlear implantation directed towards developing the next generation of inner ear therapeutics. We aim to capture and distill conversations ongoing in CI research, development, and clinical management. In this review, we discuss successes and physiological constraints of hearing with an implant, common surgical approaches and electrode arrays, new indications and outcome measures for implantation, and barriers to CI utilization. Additionally, we compare cochlear implantation with biomolecular and pharmacological approaches, consider strategies to combine these approaches, and identify unmet medical needs with cochlear implants. The strengths and weaknesses of modern implantation highlighted here can mark opportunities for continued progress or improvement in the design and delivery of the next generation of inner ear therapeutics.
... Figure 5 clearly shows the benefits of HAs and/or CI/ EAS. In terms of CI/EAS, our series of papers demonstrated that CI is a good therapeutic option for patients with hearing loss over all frequencies, and EAS is a good option for patients with residual hearing (Usami et al. 2012b(Usami et al. , 2020Miyagawa et al. 2013;Moteki et al. 2017Moteki et al. , 2018Yoshimura et al. 2020). As a significant portion of patients with CDH23 variants have residual hearing, it is extremely important to perform atraumatic CI surgery to preserve residual hearing for this particular category of patients. ...
... As a significant portion of patients with CDH23 variants have residual hearing, it is extremely important to perform atraumatic CI surgery to preserve residual hearing for this particular category of patients. With regard to postoperative residual hearing after EAS, we have demonstrated that the hearing preservation rate among patients with mutations in stereocilia-related genes, such as CDH23, MYO7A, or MYO15A, was statistically better compared to the patients with other etiologies (Yoshimura et al. 2020). With regard to the progression of hearing loss in patients with CDH23 mutations, it is better to use long electrodes for CI/EAS that can cover low-frequency region (Usami et al. 2020). ...
Variants in the CDH23 gene are known to be responsible for both syndromic hearing loss (Usher syndrome type ID: USH1D) and non-syndromic hearing loss (DFNB12). Our series of studies demonstrated that CDH23 variants cause a broad range of phenotypes of non-syndromic hearing loss (DFNB12); from congenital profound hearing loss to late-onset high-frequency-involved progressive hearing loss. In this study, based on the genetic and clinical data from more than 10,000 patients, the mutational spectrum, clinical characteristics and genotype/phenotype correlations were evaluated. The present results reconfirmed that the variants in CDH23 are an important cause of non-syndromic sensorineural hearing loss. In addition, we showed that the mutational spectrum in the Japanese population, which is probably representative of the East Asian population in general, as well as frequent CDH23 variants that might be due to some founder effects. The present study demonstrated CDH23 variants cause a broad range of phenotypes, from non-syndromic to syndromic hearing loss as well as from congenital to age-related hearing loss. Genotype (variant combinations) and phenotype (association with retinal pigmentosa, onset age) are shown to be well correlated and are thought to be related to the residual function defined by the CDH23 variants.
... We first recruited Korean patients who visited Seoul National University Bundang Hospital and met the criteria for ski-slope hearing loss patients presented below from 2015 to 2021. Although no solid audiological definition of ski-slope hearing loss exists, numerous researchers have defined ski-slope hearing loss in their own ways, such as hearing loss that is "much worse" in the high frequencies than in the lower frequencies [4]; pure tone thresholds less than or equal to 25 dB HL at and 250 Hz and 500 Hz and 15 dB/octave in the higher frequencies [5]; and a mean lowfrequency threshold less than 80 dB HL at 125, 250 and 500 Hz [6]. In this study, ski-slope hearing loss was defined as a mean low-frequency threshold at 250 Hz and 500 Hz less than or equal to 50 dB HL and worse hearing at frequencies higher than 1000 Hz. ...
... Each genetic aetiology of hearing loss is related to a certain structural and functional defect of the inner ear. For example, the genetic aetiology restricted to hair cell dysfunction might lead to better hearing preservation than other aetiologies mainly affecting stria vascularis, spiral ligament or spiral ganglion neurons as previously hypothesised [6]. According to what Yoshimura et al. [6] proposed, the pathogenic variants of genes only expressed in the stereocilia of the hair cells (CDH23, MYO7A, or MYO15A) were especially resistant to low-frequency hearing deterioration because CI insertion and its electrical stimulation would not interfere with the functions of the hair cells [6,36]. ...
... For example, the genetic aetiology restricted to hair cell dysfunction might lead to better hearing preservation than other aetiologies mainly affecting stria vascularis, spiral ligament or spiral ganglion neurons as previously hypothesised [6]. According to what Yoshimura et al. [6] proposed, the pathogenic variants of genes only expressed in the stereocilia of the hair cells (CDH23, MYO7A, or MYO15A) were especially resistant to low-frequency hearing deterioration because CI insertion and its electrical stimulation would not interfere with the functions of the hair cells [6,36]. Although no statistical significance was noted, a trend towards better preservation was seen in our cohort from the genetically diagnosed group, especially in the early postoperative period (Figs. ...
Purpose
A challenge for patients with ski-slope hearing loss is that hearing aids do not adequately amplify the mid-to-high frequencies necessary for speech perception and conversely, cochlear implant (CI) may damage low-frequency hearing. We aimed to describe the clinical profile of patients with ski-slope hearing loss, with a special focus on aetiology of such hearing loss and audiological course of low-frequency hearing after CI.
Methods
We recruited hearing-impaired patients who visited a tertiary referral centre and met the criteria for ski-slope hearing loss patients from 2015 to 2021. Genetic testing was performed in all ski-slope hearing loss patients unless refused. Baseline audiograms of patients who continued to use hearing aids or who finally underwent CIs were reviewed. As for CI patients, outcome and hearing preservation rate were rigorously analysed.
Results
Of 46 recruited patients with ski-slope hearing loss, 45 agreed to undergo genetic testing and causative variants were identified in 17 (37.8%) patients. The TMC1, MYO7A, and TMPRSS3 variants were the most common, while LRTOMT was newly identified as a causative gene. Twenty-five patients eventually received CI, while 13 continued to wear the hearing aid and 8 patients did not ever try hearing aids. CI in ski-slope hearing loss led to immediate and sufficient improvement of sentence recognition by as early as 3 months, however, the duration of hearing loss was inversely correlated with the sentence recognition score. The average hearing preservation rate (using the HEARRING classification) after CI was 53.0% (SD 30.0) and 45.6% (SD 31.1) at 1 year. Seventy-nine percent of implantees maintained functional low-frequency hearing (better than 85 dB at 250 and 500 Hz) eligible for electric-acoustic stimulation (EAS). A trend was found that patients with hair cell stereocilia-associated genetic variants may have a slightly better preservation, albeit with no statistical significance.
Conclusion
Detection rate of a molecular genetic aetiology of ski-slope hearing loss appears to be lower than other type of hearing loss reported in the literature. Especially with short hearing loss duration, CI in ski-slope hearing loss leads to immediate and sufficient speech improvement, while preserving functional low-frequency hearing eligible for EAS as many as in 79%. A certain genetic aetiology might be associated with a trend towards better low-frequency hearing preservation.
... The phenotype range of CDH23-associated HL varies from congenital profound HL to adult-onset high-frequency-involved HL [16]. CI has been applied for patients with insufficient amplification by hearing aids, and EAS devices are a good therapeutic option for patients with residual hearing [15,17,18]. In this study, two of three DFNB12 cases who did not have sufficient amplification by hearing aids received CI and showed good performance. ...
Genetic testing for congenital or early-onset hearing loss patients has become a common diagnostic option in many countries. On the other hand, there are few late-onset hearing loss patients receiving genetic testing, as late-onset hearing loss is believed to be a complex disorder and the diagnostic rate for genetic testing in late-onset patients is lower than that for the congenital cases. To date, the etiology of late-onset hearing loss is largely unknown. In the present study, we recruited 48 unrelated Japanese patients with late-onset bilateral sensorineural hearing loss, and performed genetic analysis of 63 known deafness gene using massively parallel DNA sequencing. As a result, we identified 25 possibly causative variants in 29 patients (60.4%). The present results clearly indicated that various genes are involved in late-onset hearing loss and a significant portion of cases of late-onset hearing loss is due to genetic causes. In addition, we identified two interesting cases for whom we could expand the phenotypic description. One case with a novel MYO7A variant showed a milder phenotype with progressive hearing loss and late-onset retinitis pigmentosa. The other case presented with Stickler syndrome with a mild phenotype caused by a homozygous frameshift COL9A3 variant. In conclusion, comprehensive genetic testing for late-onset hearing loss patients is necessary to obtain accurate diagnosis and to provide more appropriate treatment for these patients.
... Several studies have published epidemiological data for CI patients, but these have been limited in scope or population size. 5,6,9,11 To our knowledge, our data set of 459 CI recipients is the largest to include comprehensive genetic testing. The difference in diagnostic rate between adults and children is expected and reflects our greater understanding of genetic contributors to congenital and childhood hearing loss. ...
Understanding genetic causes of hearing loss can determine the pattern and course of a patient’s hearing loss and may also predict outcomes after cochlear implantation. Our goal in this study was to evaluate genetic causes of hearing loss in a large cohort of adults and children with cochlear implants. We performed comprehensive genetic testing on all patients undergoing cochlear implantation. Of the 459 patients included in the study, 128 (28%) had positive genetic testing. In total, 44 genes were identified as causative. The top 5 genes implicated were GJB2 (20, 16%), TMPRSS3 (13, 10%), SLC26A4 (10, 8%), MYO7A (9, 7%), and MT-RNR1 (7, 5%). Pediatric patients had a higher diagnostic rate. This study lays the groundwork for future studies evaluating the relationship between genetic variation and cochlear implant performance.
... tients in need of targeted rehabilitation due to a predicted risk of poor performance. There is a growing body of evidence on the use of genetic diagnosis for prediction of cochlear implantation outcomes,14,15 and in SNHL associated with enlarged vestibular aqueducts, the presence or absence of key genomic variants may also be of prognostic value for hearing loss severity and/or progression.16 Early genetic diagnosis can inform clinical care teams of an increased risk of hearing loss progression, warranting closer surveillance that prompts early consideration of cochlear implantation.Finally, genomic findings are clinically relevant to family members, permitting confirmatory testing and accurate counselling about reproductive risks and choices. ...
• Genetic aetiologies are an important cause of congenital ear anomalies and hearing impairment.
• Next-generation sequencing (NGS) strategies, such as targeted gene panels or clinical exome sequencing (CES) are effective tools in the diagnosis of patients with inherited hearing impairment, with clear advantages over previous genetic testing approaches.
• CES in our cohort shows the genetic heterogeneity of syndromic and non-syndromic congenital ear and hearing disorders, highlighting the clinical utility of undergoing genomic investigations.
• Multidisciplinary decision-making for diagnostic workup and management, including close collaboration between Genetics, Otolaryngology, Audiology and other allied specialties, is key in the investigation of congenital ear and hearing disorders.
• Timely molecular genetic diagnosis can streamline patient care and potentially improve clinical outcomes.
... from the Matsumoto University in Japan in an adult patient of age 31 who chose MED-EL EAS TM hearing system. FLEX 28 electrode was chosen in this patient [19]. ...
... In 2020, Dr Yoshimura, Prof. Usami and their colleagues carried out genetic testing that has the potential to impact HP, following CI [19]. Forty-four patients (forty-one families) with age at implantation above six and with measurable residual hearing in the LF with a threshold less than 80 dB HL were implanted with FLEX24 TM , FLEX28 TM or FLEXSOFT TM . ...
... (A) (n ¼ 41): orange indicates genetic causes of HL; yellow indicates other causes; grey indicates unknown. (B): comparison of HP scores in each group[19]. Reproduced by permission of Taylor and Francis Group. ...
Electric-acoustic stimulation (EAS) is a special treatment modality for those patients who are profoundly deaf in the high-frequency (HF) region and retain usable hearing in the low-frequency (LF) region. Combining the electric stimulation with cochlear implant (CI) in the HF and acoustic amplification of residual hearing using a conventional hearing aid (HA) in the LF region defines EAS. The EAS concept was first proposed by C. von Ilberg from Frankfurt, Germany in the year 1997. In association with MED-EL, all the necessary safety studies were performed in non-human subjects before the first patient received it in 1997. In association with MED-EL, all the necessary safety studies were performed in non-human subjects before the first patient received it in 1999. For the patient to successfully use the EAS concept, the residual hearing needs to be preserved to a high extent and for several years. This requires a highly flexible electrode array in safeguarding the intra-cochlear structures during and after the CI electrode array insertion. Combining the HA unit with the audio processor unit of the CI was necessary for the convenient wearing of the unified audio processor. Fitting of the unified audio processor is another important factor that contributes to the overall success of the EAS treatment. The key translational research efforts at MED-EL were on the development of flexible electrodes, a unified audio processor, innovations in the fitting process, intra-operative monitoring of cochlear health during electrode insertion, pre-operative soft-ware tool to evaluate the cochlear size and electrode selection and some new innovations tried within EAS topic. This article covers the milestones of translational research from the first concept to the widespread clinical use of EAS.
