Background: Auditory neuropathy (AN) is a nosological entity of unknown etiology, which is associated with fluctuations in rates of speech discrimination. Its diagnosis is based on presence of otoacoustic emissions and lack of, or abnormal, brainstem auditory evoked potential. With respect to treatment, we have variable results in the literature about development of speech perception and skills, in children with AN and cochlear implant (CI) rehabilitation. Objectives: Comparatively assessing results recorded for the development of auditory and speech skills in children with auditory neuropathy spectrum disorder (ANSD), who were subjected to cochlear implantation, in comparison to results recorded for children with sensorineural hearing loss associated with other causes was the objective of this study. Method: A systematic literature review with meta-analysis was performed, with studies published from 1975 to 2023. Results: Nineteen studies were included in the systematic review, and eight were selected for the meta-analysis, which showed there was no evidence allowing the conclusion that the two groups were different from each other about results in speech performance after 1 year of CI placement. Conclusion: Therefore, this study shows that CI provides the comparable benefit to children with ANSD in comparison to children with neurosensory hearing loss associated with other causes in their speech development.

Auditory neuropathy (AN) is associated with fluctuations in rates of speech discrimination. With respect to treatment, we have variable results in the literature about development of speech perception and skills, in children with AN and cochlear implant (CI) rehabilitation. To compare their results with sensorineural hearing loss children due to other causes was the objective of this study, which was performed a systematic literature review with meta-analysis that shown there was no evidence allowing the conclusion that the two groups were different from each other about results in speech performance after 1 year of CI placement. So, this study demonstrated that CI provides the comparable benefit to children with auditory neuropathy spectrum disorder in comparison to children with neurosensory hearing loss associated with other causes in their speech development.

Arnold Starr et al., in 1996, identified for the first time hearing loss resulting from disorder of the auditory portion of the vestibulocochlear nerve, called auditory neuropathy (AN), characterized by abnormal neural conduction of acoustic signals in the presence of normal sensory transduction and preserved outer hair cell amplification properties [Colucci, 2020]. It leads to presence of otoacoustic emissions (OAE) and/or cochlear microphonism and absence or abnormal auditory brainstem responses and acoustic reflexes [Starr et al., 1996; Sarankumar et al., 2018]. Although the exact sites of AN lesions remain unknown, studies have suggested sites such as ribbon pre-synapses of inner hair cells; postsynaptic region of unmyelinated dendrites in the auditory nerve; postsynaptic disorders affecting auditory ganglion cells, as well as their myelinated axons and dendrites; and central neural pathway disorders affecting the auditory brainstem [Starr et al., 1996; Colucci, 2020].

The main causes of AN comprise neonatal hyperbilirubinemia; birth asphyxia; prematurity; infectious diseases such as mumps, cytomegalovirus, and meningitis; and genetic factors such as mutations in the OTOF gene – which encodes the otoferlin protein – that indicates one synaptopathy and there is a common cause of clinical auditory neuropathy spectrum disorder (ANSD) [Starr et al., 1996; Humpriss, 2018; Wu et al., 2018; Lin et al., 2022; Nishio et al., 2022; Kurt and Akgul, 2023]. ANSD accounts for approximately 8% of newly identified cases of permanent hearing loss in children [Vlastarakos et al., 2008; Rajput et al., 2019], although prevalence values ranging from 0.54 to 19% have been reported [Humpriss et al., 2013].

It is possible to find thresholds for pure tones that are slightly lowered than normal and incongruously associated with low speech discrimination scores. Speech recognition by patients with AN is worse than the expected for pure tone thresholds, mainly in noise, in comparison to patients with sensorineural hearing loss associated with other causes [Sarankumar et al., 2018].

Auditory rehabilitation based on using hearing aids presents varying outcomes due to loss of neural synchrony, which can significantly impair word comprehension in different contexts. The indication of cochlear implant (CI) for this clinical group comes from the device’s ability to replace auditory sensory cell functions and to directly stimulate the nerve, a fact that benefits neural synchrony and, therefore, contributes to the development of auditory skills [Ching et al., 2013; Fernandes et al., 2015]. Studies have suggested the benefits of using CI in children with ANSD; however, we need more evidence on how, and when, children achieve satisfactory development, as well as on detailed results recorded for auditory detection, discrimination, and speech comprehension performance [Fernandes et al., 2015].

Thus, the aim of the current review was to find scientific evidence available in the literature to answer the following question: “Are there differences in the development of auditory and speech skills between children with ANSD, who were subjected to cochlear implantation, and children with hearing loss associated with other causes?” This systematic review with meta-analysis is going to enrich the guides of surgical CI indications and inform population in general, especially ANSD patient’s about their options for auditory rehabilitation.

Reviewed Databases

The current research started in October 2020 and ended in March 2022. Systematic search was carried out in the following electronic bibliographic databases: ClinicalTrials.gov, MEDLINE, PubMed, Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials [CENTRAL], Cochrane Methodology Register), Scopus, and speechBITE. The gray literature was consulted in Google Scholar, ProQuest, and OpenGrey databases.

In search of the most current evidence, only studies from the 2000s and in English were selected. Systematic reviews, randomized controlled trials, and prospective and retrospective controlled longitudinal observational studies (cohort studies) were included in the current research.

The herein adopted search strategy was based on the combination of the following keywords: cochlear implant, hearing loss AND children (MeSH terms). This combination was added with the following words by applying the OR term: auditory neuropathy, auditory brainstem response, auditory processing disorder and auditory diseases (MeSH terms).

Protocol and Registration

This systematic review followed the criteria recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [Moher et al., 2009] method. Its protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO), under registration number CRD42020205175, on September 29, 2020.

Eligibility Criteria

This systematic review was based on the PICOS format as follows:

  • Population: children with ANSD;

  • Interventions: CI;

  • Comparisons: children with neurosensory hearing loss (NSHL) due to other causes (nonauditory neuropathies);

  • Outcomes: development of speech-language and auditory skills after CI implantation measured by speech perception tests;

  • Study designs: systematic reviews, randomized controlled clinical trials, prospective and retrospective cohort studies.

The selected articles should present the following inclusion criteria:

  • Individuals in the age group up to 18 years old, who were subjected to hearing rehabilitation through CI in mean age of 3.5 years.

  • CI functioning assessment based on the electrical response of the cochlear nerve, and auditory pathway assessment based on neurotelemetry (evoked composite action potential [ECAP]) and/or electrical BERA.

  • Assessment of implanted children’s hearing and/or speech skills, after 1 year of CI use.

  • Using speech perception tests in open and closed sets, as well as inventories such as IT-MAIS and MAIS.

Exclusion criteria comprised the following:

  • Articles that did not establish comparisons between groups with ANSD and profound sensorineural hearing loss associated with other causes (NSHL).

  • Studies that did not investigate auditory rehabilitation based on CI.

  • Articles with high risk of bias, according to Joanna Briggs Institute [2014] critical appraisal criteria.

The definition of successful treatment was based on the comparative improvement observed in speech perception tests.

Assessing the Risks of Bias in the Analyzed Studies

Studies that met the inclusion criteria after evaluation from two revisors in the second step were evaluated in compliance with the Joanna Briggs Institute (JBI) risk of bias assessment, through the JBI Critical Appraisal Checklist for Systematic Reviews [Joanna Briggs Institute, 2017a], Randomized Controlled Trials [Joanna Briggs Institute, 2017b], and Cohort Studies [Joanna Briggs Institute, 2017c]. After this assessment procedure was over, studies presenting low risk of bias were subjected to qualitative and quantitative synthesis, whenever it was statistically feasible.

Meta-Analysis

A subsample of articles, which were extracted from the systematic review, was selected for meta-analysis purposes. Random models were used to estimate the relative risk of ECAP, as well as the difference in mean values recorded for open and closed word recognition tests, based on the restricted maximum likelihood method.

Q test was used to identify heterogeneity between studies, whereas I2 statistics were used to measure such heterogeneity. The significance level was set at 5%.

Search and Selection Strategy

The search resulted in the total number of 3,646 articles. The whole article selection process is described in Figure 1, which shows the study-inclusion flowchart, based on PRISMA [Moher et al., 2009] guidelines. No additional studies were found in the reference lists of included articles. In total, nineteen studies, presented in Table 1, have analyzed CI results about the acquisition of auditory abilities assessed through the application of speech perception tests in groups of individuals with ANSD, as well as with NSHL associated with other causes.

Fig. 1.

Articles’ identification and selection diagram adapted from the PRISMA method.

Fig. 1.

Articles’ identification and selection diagram adapted from the PRISMA method.

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Table 1.

Studies included in the systematic review

StudyAuthors/yearStudy typeSample/study groupsDegree of deafnessDiagnostic examsAN diagnosis ageCI placement timeExams performed to assess CIOutcomes
Outcomes of Cochlear Implantation in Children with Auditory Neuropathy Peterson et al., 2003 Prospective cohort 20/10 (ANSD) × 10 (NSHL) Moderate to profound ANSD/NSHL Audiometry, stapedius reflex, OEA, BERA, CT and MRI. Speech tests Not defined 3.84 years (ANSD), 3.48 years (NSHL) Neurotelemetry and speech tests There was no statistically significant difference between the two groups 
Cochlear Implantation in Children with Auditory Neuropathy: Outcomes and Rationale Jeong et al., 2007 Retrospective cohort 16/6 (ANSD) × 10 (NSHL) Moderate to profound ANSD/NSHL Genetic tests (OTOF), audiometry, BERA, OEA, and caloric test. CT and MRI 5–64 months; mean age of 1 year and 7 months At 4 years old, on average Neurotelemetry; stapedius reflex (ESR), BERA, and open-set speech perception tests There was no statistically significant difference between the two groups 
Speech Perception in Children with Auditory Neuropathy/Dyssynchrony Managed with either Hearing Aids or Cochlear Implants Rance and Barker, 2008 Prospective cohort 20/10 (ANSD) × (NSHL) Moderate to profound ANSD/NSHL Not defined Not defined 33.3 months Speech perception tests and BERA ANSD group had worse overall results than in the NSHL group. However, findings in the speech perception test were similar between both groups 
Rate of Neural Recovery in Implanted Children with Auditory Neuropathy Spectrum Disorder Fulmer et al., 2011 Prospective cohort 20/10 (ANSD) × 10 (NSHL) Moderate to profound ANSD/NSHL Not defined Not defined 1.1–14.8 years Audiometry, neurotelemetry, and speech perception tests Both groups had hearing recovery after CI, but the ANSD group showed greater difficulty in noisy environments, although there was not statistically significant difference between groups 
Performance after Cochlear Implantation in Children with Auditory Neuropathy Schramm and Harrison, 2010 Retrospective cohort 95/6 (ANSD) × 89 (NSHL) Severe to profound ANSD Not defined 7.3 months in the ANSD group, and 9.5 months in NSHL, on average Between 11.4 and 11.7 months old Speech perception tests and inventories There was no statistically significant difference between the two groups 
Recovery Function of Electrically Evoked Compound Action Potential in Implanted Children with Auditory Neuropathy: Preliminary Results Kim et al., 2011 Clinical trial 10/6 (ANSD) × 4 (NSHL) Profound ANSD OEA and BERA 1 year and 2 months, on average 3.3–3.5 years old Neurotelemetry and open-set speech perception tests 2 ANSD children did not show satisfactory responses in neurotelemetry or speech perception test. 4 children showed satisfactory responses in both tests, although there was no statistically significant differences between groups 
Cochlear Implantation in Children with Auditory Neuropathy Spectrum Disorder: Long-Term Outcomes Breneman et al., 2012 Retrospective cohort 70/35 (ANSD +CI) × 35 (NSHL +CI) Severe to profound ANSD Audiometry, imitanciometry, OEA, BERA, speech perception test. CT and MRI. Since birth 38.5 months old, on average Neurotelemetry and speech perception test Children with ANSD clearly benefited from cochlear implantation and their long-term outcomes were similar to matched pairs with NSHL. 
Does Cochlear Implantation Improve Speech Recognition in Children with Auditory Neuropathy Spectrum Disorder? A Systematic Review Humphriss et al., 2013 Systematic review 27/(ANSD) × (NSHL) Profound ANSD OEA and BERA Not defined 3.9 months, on average Speech perception test Better evidence is needed. However, lack of robust evidence in this field should not preclude the use of CI in these children 
Outcomes of Cochlear Implantation in Children with Isolated Auditory Neuropathy versus Cochlear Hearing Loss Budenz et al., 2013 Retrospective cohort 34/17 (ANSD) × 17 (NSHL) Profound ANSD Audiometry, BERA, OEA. Ear CT or MRI of the skull 32 months in the NSHL group, and 34 months in the ANSD group, on average 34 months in the ANSD group and 32 months in the NSHL group Speech perception tests There was no statistically significant difference between groups 
A Novel Otoferlin Splice-Site Mutation in Siblings with Auditory Neuropathy Spectrum Disorder Runge et al., 2013 Prospective cohort 2 (ANSD) × 3 (NSHL) Severe to profound ANSD Audiometry, OEA, and BERA 2–9 months 16–18 months old Neurotelemetry, BERA, and speech perception tests There was no statistically significant difference between groups 
Impact of the Presence of Auditory Neuropathy Spectrum Disorder (ANSD) on Outcomes of Children at 3 Years of Age Ching et al., 2013 Population-based cohort study 19 ANSD × NSHL Mild to profound ANSD Not defined Not defined By 3 years of age, 5 were implanted before 12 months of age, and the remaining children were between 14 and 29 months old Speech perception tests There was no significant difference between performance of children with ANSD and children with SNHL 
Performance of Hearing Skills in Children with Auditory Neuropathy Spectrum Disorder Using Cochlear Implant: A Systematic Review Fernandes et al., 2015 Systematic review (2002–2013) 481/(ANSD) × (NSHL) Profound ANSD Not defined Not defined Evaluated CI use time, which ranged from 6 months to 7 years Electrocochleography, MRI, CT, and open set, and inventory speech perception test There was no statistically significant difference between groups 
Auditory Performance and Electrical Stimulation Measures in Cochlear Implant Recipients with Auditory Neuropathy Compared with Severe to Profound Sensorineural Hearing Loss Attias et al., 2017 Prospective cohort 16 (ANSD) × 16 (NSHL) Profound ANSD Audiometry Not defined Younger than 3 years old Neurotelemetry Both groups showed similar development in speech perception tests conducted after CI, both in quiet and noisy environments 
Clinical Role of Electrocochleography in Children with Auditory Neuropathy Spectrum Disorder Fontenot et al., 2017 Prospective cohort 30 (ANSD) × 74 (NSHL) Profound ANSD BERA Not defined Younger than 4 years old Electrocochleography and speech perception tests There was no statistically significant difference in the prevalence of neural activity between groups. Speech perception results were significant in both groups, but the association was stronger in individuals with ANSD. 
Outcomes of Cochlear Implantation in Auditory Neuropathy Spectrum Disorder and the Role of Cortical Auditory Evoked Potentials in Benefit Evaluation Sarankumar et al., 2018 Retrospective cohort 10 (ANSD) X 10 (NSHL) Profound ANSD OEA, BERA CT, and MRI Not defined 1.5–6 years old Neurotelemetry and speech perception tests Comparable benefit of CI between children with ANSD and NSHL. 
Auditory and Speech Performance in Cochlear Implanted ANSD Children Alzhrani et al., 2019 Retrospective cohort 18 (ANSD)× 40 (NSHL) Severe to Profound ANSD OEA, BERA CT, and MRI Minimum of 4 months to a maximum of 37 months 31.3 months (ANSD) and was 32.9 months (NSHL) CAP and SIR Children with ANSD benefit from early cochlear implantation and can reach similar auditory and speech performance results as that achieved by children without ANSD 
Cochlear Implant Behavioral Outcomes for Children with Auditory Neuropathy Spectrum Disorder: A Mini-Systematic Review Myers and Nicholson, 2021 Mini-systematic review The number of participants in each study ranged from 10 to 136 Profound ANSD Not defined Not defined The mean age of implantation across studies ranged from 18.2 to 35.5 months Speech perception tests Children with ANSD fit with CIs can achieve outcomes similar to those of children with sensorineural hearing loss and CIs, despite the heterogeneity of ANSD 
Auditory and Verbal Skills Development Post-Cochlear Implantation in Mandarin Children with Auditory Neuropathy: A Follow-Up Study Hu et al, 2022 Prospective cohort 16 (ANSD) × 124 (NSHL) Profound ANSD and NSHL OEA, BERA, electrocochleogram, tympanometry, bone conduction testing, auditory steady-state response (ASSR), and auditory behavioral assessment. CT and MRI Not defined Not defined Speech perception tests: CAP, SIR, IT-MAIS, LEAQ, MUSS The auditory perception in AN children with CI was rapidly improved during first 3 months. However, the differences in auditory and verbal skills between AN and TD groups increased over time 
Results of Cochlear Implant Surgery in Patients with Auditory Neuropathy Kurt and Akgul, 2023 Prospective cohort 16 (ANSD) × 159 (NSHL) Profound ANSD and NSHL OEA and BERA Not defined The mean implant age was similar between the groups Speech perception tests ANSD patients who do not benefit from hearing aids benefit from CI surgery 
StudyAuthors/yearStudy typeSample/study groupsDegree of deafnessDiagnostic examsAN diagnosis ageCI placement timeExams performed to assess CIOutcomes
Outcomes of Cochlear Implantation in Children with Auditory Neuropathy Peterson et al., 2003 Prospective cohort 20/10 (ANSD) × 10 (NSHL) Moderate to profound ANSD/NSHL Audiometry, stapedius reflex, OEA, BERA, CT and MRI. Speech tests Not defined 3.84 years (ANSD), 3.48 years (NSHL) Neurotelemetry and speech tests There was no statistically significant difference between the two groups 
Cochlear Implantation in Children with Auditory Neuropathy: Outcomes and Rationale Jeong et al., 2007 Retrospective cohort 16/6 (ANSD) × 10 (NSHL) Moderate to profound ANSD/NSHL Genetic tests (OTOF), audiometry, BERA, OEA, and caloric test. CT and MRI 5–64 months; mean age of 1 year and 7 months At 4 years old, on average Neurotelemetry; stapedius reflex (ESR), BERA, and open-set speech perception tests There was no statistically significant difference between the two groups 
Speech Perception in Children with Auditory Neuropathy/Dyssynchrony Managed with either Hearing Aids or Cochlear Implants Rance and Barker, 2008 Prospective cohort 20/10 (ANSD) × (NSHL) Moderate to profound ANSD/NSHL Not defined Not defined 33.3 months Speech perception tests and BERA ANSD group had worse overall results than in the NSHL group. However, findings in the speech perception test were similar between both groups 
Rate of Neural Recovery in Implanted Children with Auditory Neuropathy Spectrum Disorder Fulmer et al., 2011 Prospective cohort 20/10 (ANSD) × 10 (NSHL) Moderate to profound ANSD/NSHL Not defined Not defined 1.1–14.8 years Audiometry, neurotelemetry, and speech perception tests Both groups had hearing recovery after CI, but the ANSD group showed greater difficulty in noisy environments, although there was not statistically significant difference between groups 
Performance after Cochlear Implantation in Children with Auditory Neuropathy Schramm and Harrison, 2010 Retrospective cohort 95/6 (ANSD) × 89 (NSHL) Severe to profound ANSD Not defined 7.3 months in the ANSD group, and 9.5 months in NSHL, on average Between 11.4 and 11.7 months old Speech perception tests and inventories There was no statistically significant difference between the two groups 
Recovery Function of Electrically Evoked Compound Action Potential in Implanted Children with Auditory Neuropathy: Preliminary Results Kim et al., 2011 Clinical trial 10/6 (ANSD) × 4 (NSHL) Profound ANSD OEA and BERA 1 year and 2 months, on average 3.3–3.5 years old Neurotelemetry and open-set speech perception tests 2 ANSD children did not show satisfactory responses in neurotelemetry or speech perception test. 4 children showed satisfactory responses in both tests, although there was no statistically significant differences between groups 
Cochlear Implantation in Children with Auditory Neuropathy Spectrum Disorder: Long-Term Outcomes Breneman et al., 2012 Retrospective cohort 70/35 (ANSD +CI) × 35 (NSHL +CI) Severe to profound ANSD Audiometry, imitanciometry, OEA, BERA, speech perception test. CT and MRI. Since birth 38.5 months old, on average Neurotelemetry and speech perception test Children with ANSD clearly benefited from cochlear implantation and their long-term outcomes were similar to matched pairs with NSHL. 
Does Cochlear Implantation Improve Speech Recognition in Children with Auditory Neuropathy Spectrum Disorder? A Systematic Review Humphriss et al., 2013 Systematic review 27/(ANSD) × (NSHL) Profound ANSD OEA and BERA Not defined 3.9 months, on average Speech perception test Better evidence is needed. However, lack of robust evidence in this field should not preclude the use of CI in these children 
Outcomes of Cochlear Implantation in Children with Isolated Auditory Neuropathy versus Cochlear Hearing Loss Budenz et al., 2013 Retrospective cohort 34/17 (ANSD) × 17 (NSHL) Profound ANSD Audiometry, BERA, OEA. Ear CT or MRI of the skull 32 months in the NSHL group, and 34 months in the ANSD group, on average 34 months in the ANSD group and 32 months in the NSHL group Speech perception tests There was no statistically significant difference between groups 
A Novel Otoferlin Splice-Site Mutation in Siblings with Auditory Neuropathy Spectrum Disorder Runge et al., 2013 Prospective cohort 2 (ANSD) × 3 (NSHL) Severe to profound ANSD Audiometry, OEA, and BERA 2–9 months 16–18 months old Neurotelemetry, BERA, and speech perception tests There was no statistically significant difference between groups 
Impact of the Presence of Auditory Neuropathy Spectrum Disorder (ANSD) on Outcomes of Children at 3 Years of Age Ching et al., 2013 Population-based cohort study 19 ANSD × NSHL Mild to profound ANSD Not defined Not defined By 3 years of age, 5 were implanted before 12 months of age, and the remaining children were between 14 and 29 months old Speech perception tests There was no significant difference between performance of children with ANSD and children with SNHL 
Performance of Hearing Skills in Children with Auditory Neuropathy Spectrum Disorder Using Cochlear Implant: A Systematic Review Fernandes et al., 2015 Systematic review (2002–2013) 481/(ANSD) × (NSHL) Profound ANSD Not defined Not defined Evaluated CI use time, which ranged from 6 months to 7 years Electrocochleography, MRI, CT, and open set, and inventory speech perception test There was no statistically significant difference between groups 
Auditory Performance and Electrical Stimulation Measures in Cochlear Implant Recipients with Auditory Neuropathy Compared with Severe to Profound Sensorineural Hearing Loss Attias et al., 2017 Prospective cohort 16 (ANSD) × 16 (NSHL) Profound ANSD Audiometry Not defined Younger than 3 years old Neurotelemetry Both groups showed similar development in speech perception tests conducted after CI, both in quiet and noisy environments 
Clinical Role of Electrocochleography in Children with Auditory Neuropathy Spectrum Disorder Fontenot et al., 2017 Prospective cohort 30 (ANSD) × 74 (NSHL) Profound ANSD BERA Not defined Younger than 4 years old Electrocochleography and speech perception tests There was no statistically significant difference in the prevalence of neural activity between groups. Speech perception results were significant in both groups, but the association was stronger in individuals with ANSD. 
Outcomes of Cochlear Implantation in Auditory Neuropathy Spectrum Disorder and the Role of Cortical Auditory Evoked Potentials in Benefit Evaluation Sarankumar et al., 2018 Retrospective cohort 10 (ANSD) X 10 (NSHL) Profound ANSD OEA, BERA CT, and MRI Not defined 1.5–6 years old Neurotelemetry and speech perception tests Comparable benefit of CI between children with ANSD and NSHL. 
Auditory and Speech Performance in Cochlear Implanted ANSD Children Alzhrani et al., 2019 Retrospective cohort 18 (ANSD)× 40 (NSHL) Severe to Profound ANSD OEA, BERA CT, and MRI Minimum of 4 months to a maximum of 37 months 31.3 months (ANSD) and was 32.9 months (NSHL) CAP and SIR Children with ANSD benefit from early cochlear implantation and can reach similar auditory and speech performance results as that achieved by children without ANSD 
Cochlear Implant Behavioral Outcomes for Children with Auditory Neuropathy Spectrum Disorder: A Mini-Systematic Review Myers and Nicholson, 2021 Mini-systematic review The number of participants in each study ranged from 10 to 136 Profound ANSD Not defined Not defined The mean age of implantation across studies ranged from 18.2 to 35.5 months Speech perception tests Children with ANSD fit with CIs can achieve outcomes similar to those of children with sensorineural hearing loss and CIs, despite the heterogeneity of ANSD 
Auditory and Verbal Skills Development Post-Cochlear Implantation in Mandarin Children with Auditory Neuropathy: A Follow-Up Study Hu et al, 2022 Prospective cohort 16 (ANSD) × 124 (NSHL) Profound ANSD and NSHL OEA, BERA, electrocochleogram, tympanometry, bone conduction testing, auditory steady-state response (ASSR), and auditory behavioral assessment. CT and MRI Not defined Not defined Speech perception tests: CAP, SIR, IT-MAIS, LEAQ, MUSS The auditory perception in AN children with CI was rapidly improved during first 3 months. However, the differences in auditory and verbal skills between AN and TD groups increased over time 
Results of Cochlear Implant Surgery in Patients with Auditory Neuropathy Kurt and Akgul, 2023 Prospective cohort 16 (ANSD) × 159 (NSHL) Profound ANSD and NSHL OEA and BERA Not defined The mean implant age was similar between the groups Speech perception tests ANSD patients who do not benefit from hearing aids benefit from CI surgery 

A subgroup of eight studies was selected from the larger group for meta-analysis purposes. This subgroup was used to evaluate CI results in two different stages: the first one was focused on intraoperative ECAP performance, whereas the second stage focused on the application of speech perception tests, in open or closed sets or inventories, after 1-year CI use.

Quality of Studies

All nineteen articles included in the qualitative synthesis have shown high quality and low risk of bias, based on the JBI critical appraisal checklist, as we can see in Table 2 (JBI checklist for cohort studies), Table 3 (JBI checklist for randomized controlled trials), and Table 4 (JBI checklist for systematic reviews). In the JBI critical appraisal checklist, each question must be answered using four options: yes (Y), no (N), unclear (U), and not applicable (NA). The calculation of the risk of bias percentage is done by the amount of “S” that was selected in the checklist. When the answer “NA” was selected, the question was not considered in the calculation, in accordance with the guidelines of the Joanna Briggs Institute. Up to 49% are considered to be at high risk of bias. From 50–70%, the risk is moderate, and above 70%, the risk of bias is low [Joanna Briggs Institute, 2014].

Table 2.

JBI checklist for cohort studies

Jeong et al, 2007Rance and Barker, 2008Fulmer et al., 2011Schramm and Harrison, 2010Breneman et al., 2012Budenz et al., 2013Peterson et al., 2003Ching et al., 2013Attias et al., 2017Sarankumar et al., 2018Fontenot et al., 2017Runge et al., 2013Alzhrani et al., 2019Hu et al., 2022Kurt and Akgul, 2023
1. Were the two groups similar and recruited from the same population? 
2. Were the exposures similarly measured to assign people to both exposed and nonexposed groups? 
3. Was the exposure measured in a valid and reliable way? 
4. Were the confounding factors identified? 
5. Were strategies to deal with confounding factors stated? 
6. Were the groups/participants free from the investigated outcome at study implementation or at exposure time? 
7. Were the outcomes measured in a valid and reliable way? 
8. Was the follow-up time reported and long enough for outcomes to take place? 
9. Was the follow-up complete, and if not, were the reasons for follow-up loss described and explored? 
10. Were strategies to address incomplete follow-up used? NA NA NA NA NA NA 
11. Was appropriate statistical analysis performed?  
Jeong et al, 2007Rance and Barker, 2008Fulmer et al., 2011Schramm and Harrison, 2010Breneman et al., 2012Budenz et al., 2013Peterson et al., 2003Ching et al., 2013Attias et al., 2017Sarankumar et al., 2018Fontenot et al., 2017Runge et al., 2013Alzhrani et al., 2019Hu et al., 2022Kurt and Akgul, 2023
1. Were the two groups similar and recruited from the same population? 
2. Were the exposures similarly measured to assign people to both exposed and nonexposed groups? 
3. Was the exposure measured in a valid and reliable way? 
4. Were the confounding factors identified? 
5. Were strategies to deal with confounding factors stated? 
6. Were the groups/participants free from the investigated outcome at study implementation or at exposure time? 
7. Were the outcomes measured in a valid and reliable way? 
8. Was the follow-up time reported and long enough for outcomes to take place? 
9. Was the follow-up complete, and if not, were the reasons for follow-up loss described and explored? 
10. Were strategies to address incomplete follow-up used? NA NA NA NA NA NA 
11. Was appropriate statistical analysis performed?  
Table 3.

JBI checklist for randomized controlled trials

Kim et al., 2011
1. Was true randomization used to assign participants to treatment groups? 
2. Was participants’ allocation to treatment groups concealed? 
3. Were treatment groups similar at baseline? 
4. Were participants blind to treatment assignment? 
5. Were those delivering treatment blind to treatment assignment? 
6. Were outcome appraisers blind to treatment assignment? 
7. Were treatment groups treated identically other than the intervention of interest? 
8. Was the follow-up complete, and if not, were the differences in follow-up between groups properly described and analyzed? 
9. Were participants analyzed in the groups they were randomized to? 
10. Were outcomes measured in the same way for all treatment groups? 
11. Were outcomes measured in a reliable way? 
12. Was appropriate statistical analysis used? 
13. Was the trial design appropriate, and was any deviation from the standard RCT design (individual randomization, parallel groups) accounted for in trial performance and analysis? 
Kim et al., 2011
1. Was true randomization used to assign participants to treatment groups? 
2. Was participants’ allocation to treatment groups concealed? 
3. Were treatment groups similar at baseline? 
4. Were participants blind to treatment assignment? 
5. Were those delivering treatment blind to treatment assignment? 
6. Were outcome appraisers blind to treatment assignment? 
7. Were treatment groups treated identically other than the intervention of interest? 
8. Was the follow-up complete, and if not, were the differences in follow-up between groups properly described and analyzed? 
9. Were participants analyzed in the groups they were randomized to? 
10. Were outcomes measured in the same way for all treatment groups? 
11. Were outcomes measured in a reliable way? 
12. Was appropriate statistical analysis used? 
13. Was the trial design appropriate, and was any deviation from the standard RCT design (individual randomization, parallel groups) accounted for in trial performance and analysis? 
Table 4.

JBI checklist for systematic reviews

Humphriss et al., 2013Fernandes et al., 2015Myers and Nicholson, 2021
1. Is the review question clearly and explicitly stated? 
2. Were the inclusion criteria appropriate for the review question? 
3. Was the adopted search strategy appropriate? 
4. Were the sources and resources used to search for studies adequate? 
5. Were the criteria adopted to appraise studies appropriate? 
6. Was critical appraisal independently conducted by two, or more, reviewers? 
7. Were there methods to minimize data extraction errors? 
8. Were the methods used to combine studies appropriate? 
9. Was the likelihood of publication bias assessed? 
10. Were recommendations for policy and/or practice supported by reported data? 
11. Were the specific directives for new research appropriate? 
Humphriss et al., 2013Fernandes et al., 2015Myers and Nicholson, 2021
1. Is the review question clearly and explicitly stated? 
2. Were the inclusion criteria appropriate for the review question? 
3. Was the adopted search strategy appropriate? 
4. Were the sources and resources used to search for studies adequate? 
5. Were the criteria adopted to appraise studies appropriate? 
6. Was critical appraisal independently conducted by two, or more, reviewers? 
7. Were there methods to minimize data extraction errors? 
8. Were the methods used to combine studies appropriate? 
9. Was the likelihood of publication bias assessed? 
10. Were recommendations for policy and/or practice supported by reported data? 
11. Were the specific directives for new research appropriate? 

Meta-Analysis Results

Eight studies conducted with 239 children, in total – 103 children from the ANSD group and 136 from the NSHL group – were selected for neurotelemetry purposes, as presented in Figure 2. Relative risk measure was used to compare groups based on neurotelemetry; the estimated value was 0.91 at 95% confidence interval (0.76–1.10). Consequently, there was no evidence to allow the conclusion that the two investigated groups differed from each other in neurotelemetry, since both groups have shown neural response to CI stimulus. There was high heterogeneity among articles (I2 = 79%; p value <0.001).

Fig. 2.

Forest plot of neurotelemetry proportion.

Fig. 2.

Forest plot of neurotelemetry proportion.

Close modal

Two studies conducted with 27 children, in total – 13 children from the ANSD group and 14 from the NSHL group – were selected to assess the difference in mean values recorded for open-set word recognition, as shown in Figure 3. The mean difference between the two groups was −3.27, at 95% CI (−9.08; 2.53). Therefore, there was no evidence allowing the conclusion that the two investigated groups were different from each other. There was low heterogeneity between articles (I2 = 0%; p value = 0.92).

Fig. 3.

Forest plot of open-set word recognition means.

Fig. 3.

Forest plot of open-set word recognition means.

Close modal

Two studies conducted with 13 children from each group (ANSD and NSHL) were selected to assess the difference in mean values recorded for closed-set word recognition, as presented in Figure 4. The mean difference between the two groups was 0.19, at 95% CI (−2.21; 2.60); therefore, there was no evidence allowing the conclusion that the two groups were different from each other. There was low heterogeneity between articles (I2 = 0%; p value = 0.32).

Fig. 4.

Forest plot of closed-set word recognition means.

Fig. 4.

Forest plot of closed-set word recognition means.

Close modal

Six [Kim et al., 2011; Humphriss et al., 2013; Runge et al., 2013; Attias et al., 2017; Fontenot et al., 2017; Kurt and Akgul, 2023] of the nineteen studies included in the current systematic review have used pure tone and vocal audiometry, BERA, and/or OAE as complementary methods for ANSD diagnosis. However, the adopted ANSD diagnostic tests were not defined by six authors [Rance and Barker, 2008; Schramm and Harrison, 2010; Fernandes et al., 2015; Fulmer et al., 2011; Ching et al., 2013; Myers and Nicholson, 2021]. Seven [Peterson et al., 2003; Jeong et al., 2007; Breneman et al., 2012; Budenz et al., 2013; Sarankumar et al., 2018; Alzhrani et al., 2019; Hu et al., 2022] among the six studies using audiometry and BERA as diagnostic method, completed the study using other tests, such as ear computed tomography, cranial magnetic resonance, in order to provide more information on patients’ clinical condition.

Major risk factors to acquire AN are as follows: prematurity, neonatal hyperbilirubinemia, birth asphyxia, infectious diseases (TORCHS), and genetic factors such as mutations in the OTOF gene. According to Kurt and Akgul, 2023, “among the patients included in this study, 31% of them had the risk factor of prematurity, 19% had the risk factor of hyperbilirubinemia, and 19% had both prematurity and hyperbilirubinemia.”

Based on the nineteen articles subjected to the systematic review, the mean ANSD diagnosis age was 11 months; results have evidenced the presence of OAE, absent or abnormal auditory brainstem responses with cochlear microphonism. Although, based on both the clinical practice and the literature, OAE can physiologically disappear during individuals’ first year of life, this not yet fully understood, fact may result from the underestimated prevalence of AN [Korver et al., 2012]. One hypothesis is that the loss or decrease in outer hair cells’ function may result from either afferent or efferent auditory nerve damage, resulting from lack of trophic factors directed to these cells, which are neuromodulated by the olivocochlear efferent pathway [Starr et al., 1996; Jeong et al., 2007; James et al., 2018].

Imaging test results of most patients were normal. In some cases, it was possible visualizing auditory nerve aplasia or hypoplasia. According to Harrison et al. [2015], “aplasia of the cochlear nerve can also present characteristics of ANSD,” which, according to Fernandes et al. [2015], are correlated to poor speech perception findings after CI use.

Therefore, imaging tests are reliable predictors of post-CI speech perception results. Harrison et al. [2018] suggested the inclusion of exams, such as MRI of the skull in parasagittal sections and CT of the ears in axial sections, in preoperative CI protocols to measure the diameter of the cochlear nerve, which is mostly formed by afferent fibers, although it has traces of efferent fibers. Such features reinforce the hypothesis that cochlear efferent fibers in children with ANSD, who show cochlear nerve hypoplasia/aplasia in imaging tests, account for efferent auditory responses to contralateral stimulus [Harrison et al., 2015]. Hypoplasia of cochlear nerve results in a poor prognosis of speech development in all patients (ANSD or NSHL) after CI, according to Lin et al., 2022, so the presence of nerve and its diameter in image exams are critical factors for prognosis and this should be discussed with patient’s parents before the CI surgery to manage expectations with speech development [Nishio et al., 2022].

With respect to auditory rehabilitation in all nineteen articles included in the systematic review had CI insertion, in both groups (neuropaths and individuals with NSHL associated with other causes) at the age of 3.5 years, on average. On the other hand, only ten studies [Jeong et al., 2007; Rance and Barker, 2008; Carvalho et al., 2011; Breneman et al., 2012; Budenz et al., 2013; Ching et al., 2013; Runge et al., 2013; Attias et al., 2017; Alzhrani et al., 2019; Kurt and Akgul, 2023] started with hearing aids and patients got adapted to them in their first year of life. According to Sharma et al. [2002], until 3.5 years old, the human central auditory system remains maximally plastic; otherwise, after 7 years old, cerebral plasticity reduces greatly. So, we have maximum benefit in children with CI implantation until 3.5 years [Sharma et al., 2002].

According to Sarankumar et al. [2018], children with ANSD, who were subjected to CI, have shown significantly improved auditory perception and speech outcomes, 1 year after the procedure. Furthermore, post-CI benefits in hearing and speech outcomes in children with ANSD were comparable to those observed in children with NSHL associated with other causes.

Neural response to electrical stimulation can be observed through BERA and electrically ECAP, also known as neurotelemetry. Kim et al. [2011] have suggested that CI users’ ability to understand the speech may depend on their auditory system’s ability to process temporal information. Therefore, favorable CI outcomes are associated with improved neural activity synchrony in the auditory pathway, since it restores individuals’ ability to process temporal auditory information. Ten of the fifteen analyzed studies assessed neural response through neurotelemetry [Peterson et al., 2003; Jeong et al., 2007; Carvalho et al., 2011; Fulmer et al., 2011; Kim et al., 2011; Breneman et al., 2012; Runge et al., 2013; Attias et al., 2017; Fontenot et al., 2017; Sarankumar et al., 2018], and eight [Peterson et al., 2003; Jeong et al., 2007; Fulmer et al., 2011; Kim et al., 2011; Runge et al., 2013; Attias et al., 2017; Fontenot et al., 2017; Sarankumar et al., 2018] of them were included in the meta-analysis and showed that most patients presented robust neural responses, although there was no statistically significant difference between the ANSD and NSHL groups.

A wide variety of speech perception and language skills tests were used in the analyzed studies to assess groups with ANSD and NSHL after CI. Seven studies applied open-set speech perception tests; five applied closed-set speech perception tests, and three applied the auditory integration scales (IT-MAIS and MAIS); some of them combined tests and inventories to better assess their patients [Peterson et al., 2003; Ching et al., 2013; Sarankumar et al., 2018; Alzhrani et al., 2019; Myers and Nicholson, 2021; Hu et al., 2022; Kurt and Akgul, 2023].

According to the meta-analysis, after the assessed studies proved CI efficiency in transmitting electrical signals through the auditory pathway, based on neurotelemetry (ECAP), they also assessed the difference in mean values recorded for speech perception in open- and closed-set tests between the ANSD and NSHL groups. There was low heterogeneity between groups, since both recorded similar results for the development of auditory skills in individuals subjected to CI. This finding proves that CI indication is beneficial to children with ANSD, compared to what is already a consensus in relation to non-neuropaths.

According to Jeong et al. [2007], there was no statistically significant difference in results observed for neurotelemetry amplitude and speech perception tests between groups of individuals with ANSD and NSHL, who showed good performance after CI. These data were corroborated by twelve other [Peterson et al., 2003; Fulmer et al., 2011; Kim et al., 2011; Ching et al., 2013; Runge et al., 2013; Attias et al., 2017; Fontenot et al., 2017; Sarankumar et al., 2018; Alzhrani et al., 2019; Myers and Nicholson, 2021; Hu et al., 2022; Kurt and Akgul, 2023] studies included in the systematic review; thus, despite the heterogeneity, all children evaluated in these studies benefited from the use of CI.

According to Kim et al. [2011], neurotelemetry can be a useful index to predict results in children with ANSD who were subjected to cochlear implantation. It is so because, since neurotelemetry is the technique used to measure neural potential, patients with ANSD (due to pre-synaptic lesions) present robust post-CI measurements and satisfactory auditory performance. On the other hand, patients with postsynaptic lesions often showed no/low neurotelemetry results and poor performance in speech perception tests.

Rance and Barker [2008] and Runge et al. [2013] showed that neuropaths had worse outcomes than their peers with NSHL associated with other causes, in both quiet and noisy environments. According to Runge et al. [2008], ANSD is a neural pathway conduction disorder, according to which, transmission signals can be interrupted by either electrical (by the CI) or acoustic stimuli. It likely happens due to the effects of neonatal conditions and complications that directly affect auditory pathway. However, this factor was not observed in the current meta-analysis, which did not evidence statistically significant difference or heterogeneity in post-CI speech perception tests between the two assessed groups.

According to Fontenot et al. [2017], results of neural response and speech perception tests did not show statistically significant difference between groups, although the electrocochleography (ECohG) waveform amplitude and the association of speech perception acquisition were higher and stronger in the ANSD group, respectively. It happened because hair cells in the cochlear basal turn, which account for the great magnitude of ECohG responses, as well as for cochlear microphonism, are initially preserved in individuals with ANSD.

Hu et al. [2022] demonstrated that ANSD cochlear implanted children have a rapid improvement in their auditory perception development in first 3 months and verbal skills after 9 months of CI use, but with passing time, the study shows great differences in auditory and verbal skills between ANSD and NSHL. However, this does not contraindicate a CI in this population. Humphriss et al. [2011] did not reach conclusions about CI benefit to children with ANSD; however, they stated that lack of robust evidence in this field should not be used to discourage CI use, since current evidence is consistent with the benefit provided by it.

Hearing rehabilitation based on CI has revolutionized the treatment provided to children with profound sensorineural hearing loss. There is sufficient scientific evidence in the literature to prove benefits of CI to auditory perception skills, as well as to language and speech development. However, there are variable results in the literature about the real benefit provided by CI to children with ANSD due to the wide diversity of likely responses to this auditory rehabilitation type, which is likely associated with the fact that the pathophysiology of this disease is not yet fully understood [Sarankumar et al., 2018].

The current study has shown that children with ANSD, who were subjected to CI, recorded significant improvement in hearing perception and speech outcomes, 1 year after they started using the investigated device. It has also been emphasized that the post-CI benefits in hearing and speech outcomes observed for children with ANSD were comparable to those observed for children with profound sensorineural losses associated with other causes.

Although the current study found three systematic reviews [Humphriss et al., 2013, Fernandes et al., 2015; Myers and Nicholson, 2021] on the investigated subject, there was no consensus between first two5,7 about how and when children achieve satisfactory language development or about detailed results concerning the auditory performance of children with ANSD, i.e., their sound detection, discrimination, recognition, and listening comprehension skills, since results of these studies were presented in a more general way [Vlastarakos et al., 2008]. The last one [Myers and Nicholson, 2021] evaluated a small number of articles, only four, which reduces the reliability of its results.

Thus, according to existing reviews in the literature, there was still no ideal rehabilitation strategy for children with ANSD, until this moment, with this study were demonstrated similar results in the auditory skills of neuropaths and non-neuropaths when using CIs. Therefore, the current study enabled confirming the benefits deriving from using CI in children with ANSD, in the acquisition of auditory skills and in language development, in comparison to what is consensus in the literature for patients with sensorineural hearing loss associated with other reasons.

An ethics statement is not applicable because this study is based exclusively on published literature. This systematic review followed the criteria recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method and for which the protocol was registered on September 29, 2020, in the International Prospective Register of Systematic Reviews (PROSPERO) database under registration number CRD42020205175. This study is part of a larger study entitled: “evaluation of diagnosis, treatment and rehabilitation in otology,” with approval by the Research Ethics Committee, CAAE: 36929420.1.0000.5082. This study is a systematic review, and therefore, consent forms are not required.

The authors have no conflicts of interest to declare.

The author’s own resources were used. No funding was received to perform this study.

Marina Bernardes: research, writing, formatting, review. Claudiney Costa and Hugo Ramos: coordination and guidance. Rodolfo Almeida, Fayez Bahmad Junior, and Pauliana Lamounier: guidance and review. Débora Gobbo: research and review. Natália Carasek: formatting and proofreading.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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