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The Egyptian Journal of Otolaryngology
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  • Review Article
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Systematic review of outcomes of cochlear implantation of different genotypes in patients with auditory neuropathy spectrum disorder

The Egyptian Journal of Otolaryngology volume 40, Article number: 102 (2024) Cite this article

Abstract

Background

The diagnosis of auditory neuropathy spectrum disorder (ANSD) is based on the existence of cochlear microphonics or otoacoustic emissions, as well as aberrant or nonexistent-evoked auditory brainstem responses. The outcomes of cochlear implantation (CI) are thought to be significantly influenced by genetic reasons in ANSD.

Objective

The purpose of this systematic review was to gather more information regarding the relationship between various genetic variants and the outcomes of cochlear implantation in adult and pediatric patients with ANSD (both syndromic and non-syndromic).

Methods

Electronic databases “Medline/PubMed, Google Scholar, ScienceDirect, Europe PMC, and Cochrane Library” were searched for this systematic review. For cohort studies, the Newcastle–Ottawa scale (NOS score) was used to assess the quality of the retrieved research. The standardized mean difference produced by the Cohen’s d or Hedges’ g tests was used to assess the effect size measure.

Results

This comprehensive study showed that OTOF, GJB2, ATPA3, and OPA1 were among the genetic variants with improved CI outcomes. On the other hand, other genetic mutations displayed variable results (TMPRSS3) or worse CI outcomes (PJVK). For OTOF mutations, CI had a moderate effect (Hedges’ g = 0.7), which led to good cochlear implant outcomes. The results of the GJB2 cochlear implant showed a significant effect size when pre- and post-implant assessments were compared. The results of CI for TMPRSS3 mutations were inconsistent, with one study demonstrating a negligible effect (Hedges’ g = 0.2), and another study found a negative impact (Hedges’ g =  − 2.17).

Poor CI results were indicated by PJVK mutations impacting CI outcomes. A significant impact was observed when comparing pre- and postimplantation outcomes (Cohen’s d > 1) in cases of ATP1A3 mutations (CAPOS syndrome) and OPA1 mutations. In addition, early implantation produced better results than late implantation in certain genetic variations.

Conclusion

Some genetic variants, such as OTOF, GJB2, ATPA3, and OPA1, had improved CI outcomes, according to data extraction and synthesis of the systematic review’s findings. Conversely, PJVK displayed worse CI results and inconsistent results for TMPRSS3 genetic mutations.

Background

“Auditory neuropathy spectrum disorder” can be attributed to both genetic and nongenetic factors. Nongenetic cases are frequently associated with prematurity, infections, congenital cytomegalovirus (CMV), hyperbilirubinemia, hypoxia, and tumors. Genetic studies indicate that mutations account for approximately 60–80% of congenital hearing loss, with around 70% being non-syndromic and 30% syndromic [1]. Congenital ANSD may manifest as an isolated condition or as part of syndromes such as Charcot–Marie–Tooth (CMT) disease and Leber’s hereditary optic neuropathy (LHON) [2]. Additionally, it is linked to “autosomal dominant optic atrophy (ADOA)” [3]. Mutations in the otoferlin gene (OTOF) lead to non-syndromic autosomal-recessive ANSD, primarily affecting the inner and outer hair cells [4]. Other gene mutations, including OTOF, CACNA1D, CABP2, SLC17A8, pejvakin, and GJB2, result in presynaptic lesions [5].

Main text

The auditory nerve pathway malfunction can be either presynaptic or postsynaptic, with auditory ganglion cells or myelinated axons involved in cases of postsynaptic auditory neuropathy [6]. Cochlear implantation for the management of auditory neuropathy spectrum disorder (ANSD) can enhance the synchronization of auditory signals, particularly when the stimulation pulse rate is reduced. Due to the highly heterogeneous nature of ANSD, predicting the outcomes of cochlear implantation poses significant challenges [7, 8].

Therefore, this systematic review was designed to effectively consolidate information, providing data in an evidence-based manner to explore the potential impact of various genetic mutations on cochlear implantation outcomes in patients with ANSD, as well as to address the PICO research questions:

  1. 1.

    Can genetic variants predict cochlear implantation outcomes in patients with auditory neuropathy?

  2. 2.

    How does the timing of cochlear implantation influence outcomes in children diagnosed with ANSD?

  3. 3.

    What is the optimal time frame for achieving better post-implant performance, particularly in children with prelingual hearing loss?

  4. 4.

    Does a short duration of hearing loss and/or consistent use of hearing aids impact the outcomes of cochlear implantation?

  5. 5.

    What differences exist in cochlear implant outcomes between syndromic and non-syndromic ANSD patients?

Methods

Study design

The current systematic review protocol was developed following PRISMA guidelines “The Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-2020)” [9]

Protocol registration

The protocol has been registered with “PROSPERO (International Prospective Register of Systematic Reviews – NIHR)” and “PROSPERO (International Prospective Register of Systematic Reviews –NIHR crd.york.ac.uk),”

ID number PROSPERO 2022 CRD42022362677 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022362677.

Literature selection — search strategy

The search was conducted across several electronic databases, including MEDLINE/PubMed, Google Scholar, ScienceDirect, Europe PMC, and the Cochrane Library. This search incorporated free-text terms published between 2005 and 2022, with a restriction to English-language publications and no limitations concerning the country, patient age, race, or gender. References from the selected papers were also reviewed to identify any relevant studies that may have been overlooked in the electronic searches.

For the PubMed/MEDLINE database, the following inclusive search sequence was used. MeSH (Medical Subject Headings) terms and keyword terms were used to accomplish searches. The search parameters for the PubMed/MEDLINE database included MeSH terms: "Auditory neuropathy spectrum disorder or non syndromic auditory neuropathy or syndromic auditory neuropathy ANDCochlear implantation" AND"OTOF gene mutation " OR DFNB9 OR connexin 26 OR GJB2 OR DFNB1 OR " TMPRSS3 gene mutation" or DFNB10 OR Optic Atrophy OR OPA1 OR " ATP1A3 gene mutation" or CAPOS syndrome OR PJVK.

In order to get the best results, this search term was modified according on each database. For example, for the databases Europe PMC, ScienceDirect, Google Scholar, and Cochrane Library, the search string for each gene was utilized separately as follows: "cochlear implant" OR "cochlear implantation" AND "auditory neuropathy" OR "ANSD" AND "OTOF gene mutations."

Manual searches of the identified articles yielded more articles. Each of the above procedures was carried out by two impartial reviewers, and all included articles had an additional evaluation regarding the inclusion criteria.

Screening and study selection

Following the inclusion and exclusion criteria for screening titles and abstracts, the retrieved citations underwent a systematic screening and selection process. Getting and choosing pertinent (full-text) articles were done in the second step.

Eligibility criteria

For primary research to be incorporated into this systematic review, it must meet the eligibility requirements.

Inclusion criteria

  • Cohort studies and systematic reviews

  • Adults and children cochlear implant candidates with auditory neuropathy and identification of pathogenic genetic variant

  • English is the language

  • Study outcomes: Postimplantation outcomes data either good or poor was included.

Exclusion criteria

  • Reviews, letters, editorials, unpublished manuscripts, books, and lectures

  • Case reports and series and experimental studies

  • Studies including ANSD patients without genetic assessment

  • Studies without postoperative implantation outcomes

  • Studies including patients with congenital gross anomalies as like as cochlear nerve hypoplasia or aplasia

To get rid of duplicates, the gathered data was imported into a single EndNote library.

The number of articles included or excluded from the selection process was displayed in a PRISMA flow chart (Fig. 1).

Fig. 1
figure 1

PRISMA flow chart of included studies

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Appraisal of studies quality

The Newcastle–Ottawa Scale (NOS) scale [10] was employed for assessment of risk of bias (ROB). The NOS is determined by adding together the scores for the three categories of outcome, comparability, and selection. Nine criteria were used in the assessment of the studies. We have 9 points total because each criterion is represented by 1 point.

The nine criteria included patient’s representativeness, confounders, randomization, comparability, hearing aid assessment, post-CI speech perception scores, measure tests, blind assessment, and loss of follow-up.

Therefore, studies scoring 6 to 9 were deemed to have a low risk of bias (ROB), studies scoring 4 to 5 were deemed to have a medium ROB, and studies scoring 4 to 5 were deemed to have a high ROB.

Quality of evidence

The quality and strength of the evidence (DOE) was evaluated using “the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool” [11]. In this review, five categories were assessed: risk of bias, comparison details, standardization of CI, standardization of outcome, and follow-up (Table 2).

Effect size estimation (measures of effect)

Each study’s impact size was calculated using the “standardized mean difference” method. This metric compares the means of the genetic and control groups by calculating the mean difference—that is, the difference between their sample means.

Cohen’s d was the most accurate when a study had identical sample sizes and standard deviations for the genetic and control groups. Cohen’s d was determined by calculating the mean difference between the two groups and then dividing the result by the pooled standard deviation (SD pooled).

  • Cohen’s d = (M2 − M1)⁄SD pooled

  • SD pooled = √((SD12 + SD22)⁄2)

While the studies had different sample sizes, Hedges’ g was the suitable effect size measure.

Interpretation of various standardized mean difference values

  • There was an adverse effect if the “standardized mean difference” was less than 0, indicating that the genetic variant had a worse impact on CI outcomes than the control group.

  • There was no impact if the “standardized mean difference” was between 0 and 0.1 (i.e., the genetic variant had almost little influence on CI outcomes when compared to the control group

  • There was less impact if the effect size was between 0.2 and 0.4, indicating that the genetic variation had minimal impact on CI outcomes when compared to the control group.

  • If the “standardized mean difference” is between 0.5 and 0.7, it indicates a moderate-to-intermediate effect (meaning the genetic variant had a good effect on CI outcomes as compared with the control group).

  • Significant impact if the “standardized mean difference” is between 0.8 and ≥ 1, indicating that the genetic variant had better effect on CI outcomes as compared with the control group according to Hoyt and Del Re [12].

Results

Results of critical appraisal of studies

Five-hundred forty-seven articles on the topic were produced as a result of the review. Of them, 20 papers satisfied the study’s inclusion and exclusion criteria. Either retrospective or prospective cohort studies were used in the investigations. A sizable sample (100 or more) was available for 7 of them. According to the NOS score, the studies had a low risk of bias with the majority of the defects being in the evaluation of hearing aids (no documentation if a hearing aid trial was present before CI) (Table 1).

Table 1 Critical appraisal of studies (RoB assessment)
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Each study’s directness of evidence (DOE) was assessed using the GRADE technique to see how broadly the findings might be applied (Table 2). As a result, it was evident that there were 7 medium-sized DOE studies and 13 high-sized DOE studies.

Table 2 Assessment of quality (directness of evidence—DOE)
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The study results were presented in Tables 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 and subdivided into two main categories: cochlear implant outcomes of genetic mutations in nonsyndromic ANSD (OTOF, GJB2, TMPRSS3, and PJVK) and syndromic ANSD (ATP1A3 and OPA1).

Table 3 Cochlear implantation outcomes in patients with OTOF mutations (DFNB9)
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Table 4 Effect size measure of Cochlear implantation outcomes in patients with OTOF mutations
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Table 5 Comparison between Cochlear outcomes of early and post implantation in OTOF mutations
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Table 6 Cochlear implantation outcomes in patients with GJB2 mutations (DFNB1)
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Table 7 Effect size measure of CI outcomes in patients with GJB2 mutations
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Table 8 Comparison between Cochlear outcomes of early and post implantation/HA in GJB2 mutations
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Table 9 Cochlear implantation outcomes in patients with TMPRSS3 mutations
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Table 10 Effect size measure of cochlear implantation outcomes in patients with TMPRSS3 mutations
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Table 11 Cochlear implantation outcomes in patients with PJVK (DFNB59) mutations
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Table 12 Effect size measure of cochlear implantation outcomes in patients with PJVK (DFNB59) mutations
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Table 13 Cochlear implantation outcomes in patients with ATP1A3 mutations (CAPOS syndrome)
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Table 14 Effect size measure of cochlear implantation outcomes in patients with ATP1A3 mutations
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The outcomes of each genetic mutation were discussed separately with demonstration of its impact on CI outcomes as a primary outcome and the correlation of CI outcomes with timing of CI and hearing aid use among the patients with the same genetic mutation if available.

Cochlear implantation outcomes in non-syndromic ANSD

CI outcomes in OTOF-mutant patients (DFNB9)

Four relevant publications assessing individuals with OTOF mutations were found through database search (Table 3). One study had a medium DoE since it only analyzed a small number of patients, whereas three studies had high DoE. In total, 44 prelingual children with homozygous or compound heterozygous genotypes were assessed across the 4 investigations. Every study had a follow-up period of longer than 3 years.

Table 4 demonstrated that cochlear implantation was successful in treating OTOF mutations when comparing pre- and postimplantation “modified categories of auditory perception (CAP) scores” because Cohen’s d > 1.

Comparing the cochlear nerve deficiency and genetic undetected group’s CI results for OTOF mutations, CI had better outcomes with moderate and significant effects on OTOF mutations, respectively. Additionally, early implantation groups before 2 years had higher CAP scores and, consequently, better CI outcomes than late groups.

At 6 months after implantation, there was a mild impact of early implantation (Cohen’s d/Hedges’ g = 0.54). According to the study by Park et al. [13], the cochlear implantation outcomes for early implantation with OTOF mutations were much better than those for late implantation (Hedges’ g/Cohen’s d = 0.93).

CI outcomes in GJB2-mutant individuals (DFNB1)

Of the 10 selected studies, 1 had a medium DoE, and 9 had high DoE (Table 6). GJB2 mutations in prelingual children with either a homozygote (c.35delG was the most common) or compound heterozygote genotype were assessed in all of the studies. Nine studies had postimplantation follow-up periods longer than a year, one study’s follow-up time reaching 6.5 years, and one study’s follow-up term being as brief as 9 months. Furthermore, it was displayed by Matusiak et al. [14] that distinct gene variations encoding “matrix metalloproteinase MMP9” and “Neurotrophin Brain Derived Neurotrophic Factor (BDNF)” that are involved in synaptic plasticity may be predictors.

GJB2 mutations were found to have favorable cochlear implant results (Table 7). The effect size estimation of GJB2 mutations result, when compared to other groups, ranged from no effect (no worse effect of GJB2 mutations on CI outcomes) to high effect (positive or favorable effect of GJB2 mutations on CI outcomes) (Hedges’ g 0.024–1.2).

Furthermore, there was a significant effect size of GJB2 cochlear implant outcomes when comparing pre-implant and post-implant assessments.

One study by Ozi˛ebło et al. [15] compared early implantation (12–24 months) with very early implantation (< 12 months of age) (Table 8). This comparison displayed a high influence of early implantation (12–24 months) (Hedges’ g = 1.166).

According to hearing aid use, wide hearing aids (free-field responses for at least 250, 500, and 1000 Hz in HAs) produced large effect at time of CI implantation (Hedges’ g = 9.014), when compared with minimal hearing aids (no free-field responses or responses only up to 500 Hz in HAs). At 9 months following implantation, this difference had diminished to a small or negligible effect (Hedges’ g = 0.463).

CI outcomes in individuals with mutations in TMPRSS3

It was noticed in Table 9 that the findings of these studies were somewhat controversial because while TMPRSS3 patients showed improvement, when comparing pre- and post-implant results, it was still less than that of other types of mutations in postimplantation scores, according to Lee et al. [16].

Miyagawa et al. [17] assessed the results of electric acoustic stimulation (EAS) and found significant results. Additionally, Table 10 revealed that a moderate effect (Hedges’ g = 0.819) was seen when comparing CI outcomes in TMPRSS3 mutations with genetic undetected group suggesting positive cochlear implantation outcomes. In this regard, patients utilizing bilateral electric acoustic stimulation showed more positive and greater effect sizes.

In dispute, the research by Eppsteiner et al. [18] showed unfavorable results, i.e., Eppsteiner et al.’s study [18] produced conflicting results, but it showed a detrimental effect (Hedges’ g =  − 2.17) indicating that cochlear implantation outcomes were lower for mutants in TMPRSS3.

Results of cochlear implantation in individuals with mutations in PJVK (DFNB59)

According to Table 11, two studies examining how PJVK mutations affected CI results looked at patients who were prelingual. Because there were only a few patients in each study, the DOE was only medium. PJVK mutations were found in a small fraction of the large cohorts included in both studies. One patient only had follow-up of speech perception scores and showed satisfactory speech perception, but language was poorly developed for the chronological age. Two ANSD patients who had late implantation at ages 5 and 12 were included in the Domínguez-Ruiz et al. study [19], and both patients showed post-CI improvement in pure-tone thresholds. Effect size measurement for this study in the current systematic review was not possible since the other patient did not have follow-up.

Comparing the PJVK effect size measure with other genes, Wu et al. [20] study showed that the effect size measure of PJVK (Hedges’ g < 0) had adverse effect (worse CI outcomes).

Cochlear implantation outcomes in syndromic ANSD

CI outcomes in ATP1A3-mutant patients (CAPOS syndrome)

A medium DoE study by Lee et al. [16] that examined different mutations in 40 patients was recovered. Two adult patients with postlingual hearing loss, heterozygous genotype, and ATP1A3 mutations were identified among them using the targeted exome sequencing method (Table 13). “The Korean version of the Central Institute for the Deaf (K-CID)” and “Spondee and phonetically balanced (PB) word test without visual cues” were administered at different times. Comparing pre- and postimplantation results revealed a significant good impact of ATP1A3 mutations (CAPOS syndrome) (Cohen’s d > 1). Additionally, better cochlear implantation outcomes were demonstrated when comparing ATP1A3 mutation outcomes with outcomes of genetic undetected patients, and there was large effect encountered by Hedges’ g > 1 (Table 14).

Cochlear implantation outcomes of OPA1-mutant patients (dominant optic atrophy)

The OPA1 mutation was examined in two studies. DoE was high in both investigations (Table 15). In one study, OPA1-H (OPA1 haploinsufficiency), which manifested as impaired vision but normal hearing, was studied along with two other types of OPA1 mutations in adult and pediatric patients with postlingual onset of hearing loss, and one patient with congenital onset and eight patients in OPA1-M (missense) underwent cochlear implantation due to hearing loss (Santarelli et al.) [21].

Table 15 Cochlear implantation outcomes in patients with OPA1 mutations (dominant optic atrophy)
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Pre- and post-implant speech recognition scores were evaluated in both quiet and noisy environments by Santarelli et al. [21]. When comparing pre- and post-implant speech recognition scores, OPA1 mutations had a significant impact on both the silent (Cohen’s d = 2.316) and signal-to-noise ratio (S/N ratio + 10) (Cohen’s d = 1.68) (Table 16).

Table 16 Effect size measure of cochlear implantation outcomes in patients with OPA1 mutations
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Discussion

Molecular diagnosis has emerged as a significant component in the evaluation of cochlear implantation and postoperative rehabilitation [22]. In order to collect as many distinct CI outcomes as possible, the search strategy used in the current systematic review was purposefully created and includes multiple studies of diverse genetic variants producing auditory neuropathy in CI candidate populations, either children or adults. The evidence supporting the prediction of CI outcomes was strengthened by restricting this review to high- and medium-quality studies, including cohort studies.

CI outcomes in OTOF-mutant patients (DFNB9)

Regarding the main finding of this systematic review, all of the research (Park et al., 2017, Lin et al., 2022, and Kim et al., 2018) that looked at OTOF mutations showed good outcomes. Good CI outcomes were suggested by this finding for OTOF mutations because this gene mutation is associated with presynaptic ANSD, as reported by Choi et al. [23].

The early cochlear implantation in OTOF mutations was moderately favorable than late implantation which can be explained by the study of Sharma and Cardon [24], which noted that the first 2 years of life are a critical period for correct central auditory development [24]. This data is very significant in that it provides proof of the proper timing of CI in OTOF patients. In this sense, the early implantation in OTOF mutant patients was associated with increased performance; therefore, the better results of early implantation found in this systematic review align with this idea and in agreement with Dean et al. [25].

Cochlear implantation outcomes in patients with GJB2 (DFNB1)

GJB2 mutations may account for half of autosomal-recessive non-syndromic hearing loss in Europeans and people from the Mediterranean region [26]. GJB2 mutations may also result in non-syndromic recessive ANSD. Numerous studies have revealed OAEs in some GJB2/GJB6 deaf patients, which can be identified as auditory neuropathy/dys-synchrony [27, 28].

As a result, the articles that discussed how GJB2 mutations affected cochlear implantations were included in this systematic review. It was important to note that these studies were included in the current systematic review for two reasons, despite the fact that they did not show that OAEs were present in patients. First off, a study by Mostafa et al. [29] revealed that the 35delG mutation of the GJB2 gene is the primary genetic cause of autosomal-recessive non-syndromic hearing loss (ARNSHL) in Egyptian children scheduled for cochlear implantation. This suggests that the GBJ2 mutation is a significant genetic cause in Egypt. Additionally, a number of studies have provided evidence that some ANSD patients eventually had absent OAEs. If the emissions disappear, it may be difficult to diagnose ANSD. However, robust cochlear microphonics can support diagnosis [30].

The results of the 10 studies of GJB2 mutations that were obtained for the current systematic review agreed on improved CI outcomes and larger increases in expressive language. The effect size measure, which ranges from no adverse effect to large favorable effect (Hedges g 0.024–1.2) in all studies comparing the outcomes of GJB2 mutations with other gene mutations. The wide range of effect size may be the result of different variants of the comparing groups’ gene mutations. The fact that GJB2 mutations are one of the presynaptic ANSD mutations that can be bypassed by CI implantation, as described by Del Castillo and Del Castillo [31], may therefore shed light on the positive CI outcome measures.

Early implantation had a significant impact, according to the effect size measure of CI outcomes. These results can be explained by Kawasaki et al. [32], who found that cochlear implant performance is largely affected by higher brain functions — particularly in language development — having a significant impact on cochlear implant performance.

The effect of hearing aid use prior to implantation was diminished by time regarding postimplantation outcome measures to small or minimal effect. Therefore, even in children who do not respond to HAs (i.e., have no residual hearing), CI can provide appropriate auditory stimulation.

Cochlear implantation outcomes in TMPRSS3-mutant patients

Heterogeneity in CI results was discovered by the current systematic study. Patients with TMPRSS3 gene mutations demonstrated considerably significantly worse post-implant outcome metrics than patients with other genetic abnormalities, according to a study by Eppsteiner et al. [17]. Conversely, Lee et al. [16] found that there was a significant better estimate size measure effect for TMPRSS3 gene mutations when comparing pre- and postimplantation outcomes (Cohen’s d = 1.415) (Table 10) but minimal effect when compared with other genetic undetected group (Hedges g = 0.185). Additionally, three EAS cases, according to Miyagawa et al. [18], demonstrated strong performance, suggesting that EAS is a viable therapeutic alternative.

According to the findings of the research included in the current systematic review, the trials that demonstrated good performance were either observed in patients who had used hearing aids for a longer period of time prior to surgery (Lee et al.) [16] or used electric acoustic stimulation (Miyagawa et al. [18]. This can be explained by the requirement for auditory stimulation, which can preserve low-frequency residual hearing (the disease’s distinctive ski slope audiogram pattern).

Even though the research’ findings were debatable, they had provided significant clinical insights on TMPRSS3 mutations. EAS stimulation was more beneficial for the patients with TMPRSS3. Furthermore, TMPRSS3 patients who had longer follow-ups showed improved postimplantation outcomes, which may suggest that these patients require strong, long-term post-implant rehabilitation in order to progress.

The lengthy duration of hearing loss and the 1-year post-implant improvement in speech perception scores were found to be negatively correlated by Lee et al. [16].

There is still hope for TMPRSS3 patients to gain from CI implantation, but early mutation detection and diagnosis, along with rehabilitation, are critical. Furthermore, neuronal degeneration may be postponed or reduced by earlier spiral ganglion cell neuron stimulation by CI. Human ganglion cells are more resistant to degeneration than animal counterparts, according to research by Liu and his colleagues on the temporal bones of humans [33].

This result could be used to explain various CI results in mutations of the TMPRSS3 gene, which is expressed in spiral ganglion neurons. Moreover, earlier spiral ganglion cell neuron stimulation by CI could delay or decrease the neuronal degeneration [34]. This finding could help explain diverse CI outcomes in TMPRSS3 gene mutations.

Cochlear implantation outcomes in PJVK (DFNB59)-mutant patients

Two research on PJVK mutations were found through this systematic review, and both of them demonstrated worse CI results. Notably, the two earlier studies’ medium level of evidence was mostly caused by their small sample sizes and the loss of certain patients’ follow-up data. Since few patients could be diagnosed with that rare mutation from the huge cohorts in both trials, it was difficult to apply the findings to the general population. Nevertheless, the results of the two studies may still be considered.

The worse CI outcome may be explained by the lesion sites in hair cells, spiral ganglion, and auditory brain stem nuclei in PJVK (formerly DFNB59) [35].

Cochlear implantation outcomes in syndromic ANSD

Cochlear implantation outcomes in ATP1A3-mutant patients

The retrieved study (Lee et al.) [16] displayed that patients with ATP1A3 mutations experienced positive good CI results. The study by Lee et al. [16] revealed something that deserves further attention, even though hearing loss started postlingually, and the period of deafness prior to CI implantation was regarded as short duration because it did not last more than 2 years. This may be reflected in the positive CI results these individuals experienced.

Cochlear implantation outcomes in patients with OPA1 mutations

In the current systematic study, there was consensus regarding satisfactory CI results in OPA1 patients. In this regard, Huang et al. [36] reported that low-amplitude extended negative potentials were detected in transtympanic ECochG recordings of two ANSD patients with OPA1-M mutation, indicating impaired auditory nerve terminal dendritic function. Thus, CI may be able to compensate for the hearing impairment experienced by OPA1-M individuals. At an advanced stage of the OPA1 condition, demyelination and axonal degeneration have been identified as affecting the entire auditory nerve [37].

Hence, it is reasonable to infer that a pathological condition of more proximal auditory nerve fibers in the course of the illness may reduce the efficacy of CI stimulation [21]. Accordingly, more research with extended periods of follow-up in early implanted CI candidates in OPA1 patients may be required to evaluate if early cochlear implantation can postpone or even decrease the clinical effect of the process of demyelination of more proximal portions of auditory nerve fibers.

Limitations of this systematic review

The most significant limitation we encountered during this systematic review was the small number of patients, particularly in rare mutations and rare syndromes. As a result, results from studies involving small sample sizes and patients carrying rare mutations should be interpreted cautiously.

Case reports and case series were excluded from this systematic review, which may have preserved some degree of data standardization, but it also resulted in a significant reduction in the number of studies, particularly in rare gene mutations.

Unfortunately, we were not able to analyze the impact of many syndromes as Charcot–Marie–Tooth (CMT) disease, Mohr–Tranebjaerg syndrome (MTS), Refsum’s disease, and mitochondrial disease, due to unavailable studies which investigated both the syndrome and genetic evaluation and follow-up of cochlear implant outcomes.

For hearing aids and CIs candidates, there was a requirement for studies to display results of electrophysiological measures (i.e., cortical evoked potentials, electrocochleography, and ABR).

Furthermore, in some mutations as PJVK, additional studies were required to evaluate the impact of early implantation on the CI outcomes.

Conclusion

Because the results of cochlear implantation in ANSD patients exhibit greater variability than in cochlear SNHI patients, cochlear implantation requires special consideration. The current systematic study showed that patients with ANSD who had mutations in the genes OTOF, GJB2, ATPA3, and OPA1 had good CI outcomes. Some genetic variants had effects similar to TMPRSS3, but they also produced greater results when HA and/or EAS were used for longer periods of time. A genetic etiology-based optimal window time for CI timing may be provided by the genetic testing in order to achieve a satisfying result.

Recommendations

Many ANSD patients may not receive an early diagnosis in neonatal screening programs if just OAEs are used. Therefore, their diagnosis might not be made until they are in preschool or school age. These patients might not receive early rehabilitation because of the delayed diagnosis. In this regard, automated ABR for neonatal screening may be preferable if at all possible. It is important to remember that postponing diagnosis can result in less successful CI outcomes.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

CI:

Cochlear implantation

ANSD:

Auditory neuropathy spectrum disorder

NOS score:

Newcastle–Ottawa quality assessment scale

ROB:

Risk of bias

DOE:

Directness of evidence

CAP scores:

Categories of auditory perception

References

  1. Rajput K, Saeed M, Ahmed J, Chung M (2019) Findings from aetiological investigation of auditory neuropathy spectrum disorder in children referred to cochlear implant programs. Int J Pediatr Otorhinolaryngol 116:79–83

    Article  CAS  PubMed  Google Scholar 

  2. Amati-Bonneau P, Guichet A, Olichon A, Chevrollier A et al (2005) OPA1 R445H mutation in optic atrophy associated with sensorineural deafness’. Ann Neurol 58(6):958–963

    Article  CAS  PubMed  Google Scholar 

  3. Mizutari K, Matsunaga M, Inoue Y, Kaneko H, Yagi H, Namba K et al (2010) Vestibular dysfunction in a Japanese patient with a mutation in the gene OPA1. J Neurol Sci 293(1–2):23–28

    Article  CAS  PubMed  Google Scholar 

  4. Roux I, Safieddine S, Nouvian R, Grati M, Simmler MC, Bahloul A et al (2006) Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell 127:277–289

    Article  CAS  PubMed  Google Scholar 

  5. Shearer AE, Hansen MR (2019) Auditory synaptopathy, auditory neuropathy, and cochlear implantation. Laryngoscope Investigative Otolaryngology 4:429–440. https://doi.org/10.1002/lio2.288

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rance G, Starr A (2015) Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy. Brain 138:3141–3158

    Article  PubMed  Google Scholar 

  7. Pelosi S, Wanna G, Hayes C, Sunderhaus L et al (2013) Cochlear implantation versus hearing amplification in patients with auditory neuropathy spectrum disorder. Otolaryngol Head Neck Surg 148(5):815–821

    Article  PubMed  Google Scholar 

  8. Harrison RV, Gordon KA, Papsin BC, Negandhi J, James AL (2015) Auditory neuropathy spectrum disorder (ANSD) and cochlear implantation. Int J Pediatricotorhinolaryngol 79(12):1980–1987

    Article  Google Scholar 

  9. Page MJ, McKenzie JE, Bossuyt PM, Boutron I et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev 10:89. https://doi.org/10.1186/s13643-021-01626-4

    Article  PubMed  PubMed Central  Google Scholar 

  10. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605. https://doi.org/10.1007/s10654-010-9491-z. (Epub 2010 Jul 22 PMID: 20652370)

    Article  PubMed  Google Scholar 

  11. Guyatt GH, Oxman AD, Vist GE, Kunz R et al (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336(7650):924–926

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hoyt WT, Del Re AC (2017) Effect size calculation in meta-analyses of psychotherapy outcome research. Psychother Res 28(3):379–388

    Article  PubMed  Google Scholar 

  13. Park JH, Kim AR, Han JH, Kim SD, Kim SH, Koo JW, Oh SH, Choi BY (2017) Outcome of cochlear implantation in prelingually deafened children according to molecular genetic etiology. Ear Hear 38(5):e316–e324. https://doi.org/10.1097/AUD.0000000000000437. (PMID: 28841141)

    Article  PubMed  Google Scholar 

  14. Matusiak M, Oziębło D, Obrycka A, Ołdak M, Kaczmarek L, Skarżyński P, Skarżyński H (2021) Functional polymorphism of MMP9 and BDNF as potential biomarker of auditory neuroplasticity in prelingual deafness treatment with cochlear implantation-a retrospective cohort analysis. Trends Hear 25:23312165211002140. https://doi.org/10.1177/23312165211002140. (PMID:33787399;PMCID:PMC8020743)

    Article  PubMed  PubMed Central  Google Scholar 

  15. Oziebło D, Obrycka A, Lorens A, Skarzynski H, Ołdak M (2020) Cochlear implantation outcome in children with DFNB1 locus pathogenic variants. J Clin Med 9:228. https://doi.org/10.3390/jcm9010228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee SY, Shim YJ, Han JH, Song JJ, Koo JW, Oh SH, Lee S, Oh DY, Choi BY (2020) The molecular etiology of deafness and auditory performance in the postlingually deafened cochlear implantees. Sci Rep 10(1):5768. https://doi.org/10.1038/s41598-020-62647-y. (PMID: 32238869; PMCID: PMC7113281)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Miyagawa M, Nishio SY, Sakurai Y, Hattori M, Tsukada K, Moteki H, Kojima H, Usami S. (2015) The patients associated with TMPRSS3 mutations are good candidates for electric acoustic stimulation. Ann Otol Rhinol Laryngol. 124 Suppl 1:193S-204S. https://doi.org/10.1177/0003489415575056. Epub 2015 Mar 13. PMID: 25770132.

  18. Eppsteiner RW, Shearer AE, Hildebrand MS, Deluca AP, Ji H, Dunn CC, Black-Ziegelbein EA, Casavant TL, Braun TA, Scheetz TE, Scherer SE, Hansen MR, Gantz BJ, Smith RJ. (2012) Prediction of cochlear implant performance by genetic mutation: the spiral ganglion hypothesis. Hear Res 292(1–2):51–8. https://doi.org/10.1016/j.heares.2012.08.007. Epub 2012 Aug 28. PMID: 22975204; PMCID: PMC3461332.

  19. Domínguez-Ruiz M, Rodríguez-Ballesteros M, Gandía M, Gómez-Rosas E et al (2022) Novel pathogenic variants in PJVK, the gene encoding pejvakin, in subjects with autosomal recessive non-syndromic hearing impairment and auditory neuropathy spectrum disorder. Genes 13:149. https://doi.org/10.3390/genes13010149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu CC, Lin YH, Liu TC, Lin KN, Yang WS, Hsu CJ, Chen PL, Wu CM (2015) Identifying children with poor cochlear implantation outcomes using massively parallel sequencing. Medicine (Baltimore) 94(27):e1073. https://doi.org/10.1097/MD.0000000000001073. (PMID: 26166082; PMCID: PMC4504554)

    Article  PubMed  Google Scholar 

  21. Santarelli R, Rossi R, Scimemi P, Cama E et al (2015) OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation. Brain 138(3):563–576

    Article  PubMed  PubMed Central  Google Scholar 

  22. Molina-Ramirez LP, Bruce IA., Black GCM. Cochlear implantation in the era of genomic medicine. Cochlear Implants Int, 2020;21(2):117–120. https://doi.org/10.1080/14670100.2019.1678895

  23. Choi BY, Ahmed ZM, Riazuddin S, Bhinder MA, Shahzad M, Husnain T, Friedman TB (2009) Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan. Clin Genet 75(3):237–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sharma A, Cardon G (2015) Cortical development and neuroplasticity in auditory neuropathy spectrum disorder. Hear Res 330:221–232. https://doi.org/10.1016/j.heares.2015.06.001

    Article  PubMed  PubMed Central  Google Scholar 

  25. Dean C, Felder G, Kim AH (2013) Analysis of speech perception outcomes among patients receiving cochlear implants with auditory neuropathy spectrum disorder. Otol Neurotol 34(9):1610–1614

    Article  PubMed  Google Scholar 

  26. Kenneson A, Van Naarden BK, Boyle C (2002) GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: HUGE review. Genet Med 4:258–274

    Article  CAS  PubMed  Google Scholar 

  27. Engel-Yeger B, Zaaroura S, Zlotogora J, Shalev S (2003) Otoacoustic emissions and brainstem evoked potentials in compound carriers of connexin 26 mutations. Hear Res 175:140–151

    Article  CAS  PubMed  Google Scholar 

  28. Cheng X, Li L, Brashears S, Morlet T et al (2005) Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf. Am J Med Genet A 139(1):13–18

    Article  PubMed  Google Scholar 

  29. Mostafa BE, El Sawi MA, Sabri SM, Hassan DA, Safik MR (2021) Genetic screening for 35delG mutation in Egyptian patients with profound SNHL scheduled for cochlear implantation: a population based study. ORL 83:181–186. https://doi.org/10.1159/000513752

    Article  CAS  PubMed  Google Scholar 

  30. Deltenre P, Mansbach AL, Bozet C, Christiaens F (1999) Auditory neuropathy with preserved cochlear microphonics and secondary loss of otoacoustic emissions. Audiology 38:187–195

    Article  CAS  PubMed  Google Scholar 

  31. Del Castillo FJ, Del Castillo I (2012) Genetics of isolated auditory neuropathies. Front Biosci (Landmark Ed). 17(4):1251–1265. https://doi.org/10.2741/3984. (PMID: 22201801)

    Article  PubMed  Google Scholar 

  32. Kawasaki A, Fukushima K, Kataoka Y, Fukuda S, Nishizaki K (2006) Using assessment of higher brain functions of children with GJB2-associated deafness and cochlear implants as a procedure to evaluate language development. Int J Pediatr Otorhinolaryngol 70(8):1343–9. https://doi.org/10.1016/j.ijporl.2006.01.010. (Epub 2006 Mar 23. PMID: 16549217)

    Article  PubMed  Google Scholar 

  33. Liu W, Edin F, Atturo F, Reiger G et al (2015) The pre- and post-somatic segments of the human type I spiral ganglion neurons—structural and functional considerations related to cochlear implantation. Neuroscience 284:470–482

    Article  CAS  PubMed  Google Scholar 

  34. Chung J, Park SM, Chang SO, Chung T, Lee KY, Kim AR, Choi BY (2014) A novel mutation of TMPRSS3 related to milder auditory phenotype in Korean postlingual deafness: a possible future implication for a personalized auditory rehabilitation. J Mol Med 92:651–663

    Article  CAS  PubMed  Google Scholar 

  35. Usami SI, Nishio SY, Moteki H, Miyagawa M, Yoshimura H (2020) Cochlear implantation from the perspective of genetic background. Anat Rec 303(3):563–593

    Article  Google Scholar 

  36. Huang R, Santarelli A, Starr A (2009) Mutation of OPA1 gene causes deafness by affecting function of auditory nerve terminals. Brain Res 1300:97–104

    Article  CAS  PubMed  Google Scholar 

  37. Kjer P, Jensen OA, Klinken L (1983) Histopathology of eye, opticnerve and brain in a case of dominant optic atrophy. Acta Ophthalmol (Copenh) 61:300–312

    Article  CAS  PubMed  Google Scholar 

  38. Kim BJ, Jang JH, Han JH, Park H, Oh DY, Lee S, Choi BY (2018) Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics. J Transl Med 16:1–13. https://doi.org/10.1186/s12967-018-1708-z

    Article  CAS  Google Scholar 

  39. Wu CC, Hsu CJ, Huang FL, Lin YH et al (2018) Timing of cochlear implantation in auditory neuropathy patients with OTOF mutations: our experience with 10 patients. Clin Otolaryngol 43(1):352–357. https://doi.org/10.1111/coa.12949

    Article  CAS  PubMed  Google Scholar 

  40. Lin P-H, Wu H-P, Wu C-M, Chiang Y-T et al (2022) Cochlear implantation outcomes in patients with auditory neuropathy spectrum disorder of genetic and non-genetic etiologies a multicenter study. Biomedicines 10:1523. https://doi.org/10.3390/biomedicines10071523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Popov TM, Stancheva I, Kachakova DL, Rangachev J, Konov D, Varbanova S, Mitev VI, Kaneva RP, Popova DP (2014) Auditory outcome after cochlear implantation in patients with congenital nonsyndromic hearing loss: influence of the GJB2 status. Otol Neurotol 35(8):1361–5. https://doi.org/10.1097/MAO.0000000000000348. (PMID: 24691507)

    Article  PubMed  Google Scholar 

  42. Davcheva-Chakar M, Sukarova-Stefanovska E, Ivanovska V, Lazarevska V, Filipche I, Zafirovska B (2014) Speech perception outcomes after cochlear implantation in children with GJB2/DFNB1 associated deafness. Balkan Med J 31(1):60–63. https://doi.org/10.5152/balkanmedj.2014.9535. (Epub 2014 Mar 1. PMID: 25207169; PMCID: PMC4116006)

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wu C, Ko H, Tsou Y, Lin Y, Lin JL, Chen CK, Chen PL, Wu CC (2015) Long-term cochlear implant outcomes in children with GJB2 and SLC26A4 mutations. PLoS ONE 10(9):e0138575. https://doi.org/10.1371/journal.pone.0138575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Daneshi A, Hassanzadeh S, Emamdjomeh H, Mohammadi SH, Arzhangi S, Farhadi M, Najmabadi H (2012) Prevalence of GJB2-associated deafness and outcomes of cochlear implantation in Iran. J Laryngol Otol 2011;125(5):455–459. https://doi.org/10.1017/S0022215110002999. (Epub 2011 Jan 31 PMID: 21281533)

    Article  Google Scholar 

  45. Angeli SI, Suarez H, Lopez A, Balkany TJ, Liu XZ (2011) Influence of DFNB1 status on expressive language in deaf children with cochlear implants. Otol Neurotol. 32(9):1437–1443. https://doi.org/10.1097/MAO.0b013e31823387f9. (PMID: 21956600; PMCID: PMC3219822)

    Article  PubMed  PubMed Central  Google Scholar 

  46. Reinert J, Honegger F, Gürtler N (2010) High homogeneity in auditory outcome of pediatric CI-patients with mutations in Gap-Junction-Protein Beta2. Int J Pediatr Otorhinolaryngol 74:791–795

    Article  PubMed  Google Scholar 

  47. Varga L, Kabatova Z, Masindova I, Nechodomova D, Gašperíková D, Klimeš I, Profant M (2014) Is deafness etiology important for prediction of functional outcomes in pediatric cochlear implantation? Acta Otolaryngol 134:571–578. https://doi.org/10.3109/00016489.2014.894253

    Article  PubMed  Google Scholar 

  48. Karamert R, Bayazit YA, Altinyay S, Yılmaz A, Menevse A, Gokdogan O, Ant A (2011) Association of GJB2 gene mutation with cochlear implant performance in genetic non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol 75(12):1572–1575

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Audiovestibular Medicine Unit, ENT Department, Faculty of Medicine (Girls), Al-Azhar University, Cairo, Egypt

    Naema Mohamed Ismail & Reda Mohamed Behairy

  2. Public Health Department, Faculty of Medicine (Girls), Al-Azhar University, Cairo, Egypt

    Salma Badreldin Galal

  3. Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

    Rasha Mohamed Sabry

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RMS and RMB performed the independent systematic titles and abstracts search based on the selection criteria, collected independently the study data, and analyzed these data. SBG and RMS independently assessed the risk of bias of the recruited studies and interpreted the data. NMI was a major contributor in writing the manuscript. All the authors read and approved the final manuscript.

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Ismail, N.M., Galal, S.B., Behairy, R.M. et al. Systematic review of outcomes of cochlear implantation of different genotypes in patients with auditory neuropathy spectrum disorder. Egypt J Otolaryngol 40, 102 (2024). https://doi.org/10.1186/s43163-024-00677-3

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