Cochlear implant in Auditory Neuropathy Spectrum Disorders: A systematic review

By Sarfaraz Nawaz Mahaboob, student of

                                     the Master in Clinical Audiology and Hearing Therapy


There is a shortage of literature, and a clear consensus that cochlear implants (CI) benefit the Auditory Neuropathy Spectrum Disorders (ANSD) behavioural and electrophysiological outcomes post CI in the ANSD group. The behavioural outcomes included auditory, speech, and language, academic, social-emotional,  and parental attitude, whereas the electrophysiological result encompassed aided cortical responses pre and post-implantation. Eight articles were shortlisted based on the inclusion and exclusion criteria. In the current review, there was a significant benefit seen in all the domains (auditory skills, verbal skills, quality of life, music perception, and auditory cortex maturation) in implanted ANSD participants in the current review. However, it was noticed that the benefit depended on the age of implantation and the duration of implantation. Therefore, early personalized intervention should be targeted in the ANSD group based on individual needs. However, more studies are required to evaluate the long-term benefits of CI and speech perception in noise among implanted individuals with ANSD.


Keywords: Auditory Neuropathy Spectrum Disorders, cochlear implant, systematic review.


Auditory Neuropathy Spectrum Disorders (ANSD) is an umbrella term referring to hearing dysfunctions demonstrating disrupted signal processing to the auditory nerve by the inner hair cells (IHCs). The past nomenclatures of this disease were auditory dyssynchrony, auditory neuropathy or peri-synaptic audiopathy (Harrison et al., 2015). However, the term ANSD was adopted later due to large heterogeneity across clinical manifestation and aetiology profiles (Hayes & Sininger, 2008; Rance et al., 2014). The diagnostic criteria for this disorder are the presence of otoacoustic emissions or cochlear microphonics, suggesting intact outer hair cells functioning with altered or abnormal auditory brainstem responses (Starr et al., 1996). Individuals with ANSD exhibit significant problems in understanding speech, primarily in background noise, and the speech perception abilities remain disproportionate to their pure-tone hearing thresholds (Fontenot et al., 2017; Kumar & Jayaram, 2005).


ANSD has more frequent occurrences than what was initially anticipated. It has an almost eight per cent incidence in children with hearing loss per year (Madden et al., 2002). Apart from this, it has a prevalence of nearly 0.23 to 0.94 percentage in infants ‘at risk’ for hearing impairment (Rance et al., 1999). The prevalence is also reported as high as 1.96% in NICU babies. These figures are alarming and demonstrate that ANSD must have been underestimated and undertreated in the past. The age of onset of ANSD is reported under two main categories, infancy (early-onset) and adolescence or early adulthood (late-onset) (Rance, 2005). Further, the author also opined that the perceptual disruptions faced by individuals with early-onset and late-onset ANSD are the same or different is yet to establish.


ANSD is reported to have underlying genetic factors and certain cellular, neuronal, and molecular mechanisms leading to acquired or late-onset ANSD. ANSD is also associated with medical conditions such as prematurity, hyperbilirubinemia, jaundice, anoxia and low birth weight. Exchange transfusion, respiratory distress, ototoxic drugs and artificial ventilation also co-occur with the disorder. ANSD is also associated with infectious diseases like mumps and genetic disorders like Friedreich’s ataxia and Charcot Marie Tooth Syndrome (Berlin et al., 2010; Kraus et al., 2000). The genetic origin of ANSD is also documented. OTOF gene abnormalities, leading to abnormal otoferlin protein production, are associated with the DFNB9, resulting in the non-syndromic form of recessive deafness and ANSD. Yasunaga et al. (1999), reported OTOF-related deafness causes problems in releasing neurotransmitters between the inner hair cells, and the auditory nerve is also associated with ANSD. Another irregularity of the DFNB59 gene that codes the protein Pejvakin, which is important for neural conduction along the auditory pathway, is also associated with ANSD (Delmaghani et al., 2006). ANSD occurring transiently with high fever is also documented in the literature(Rance et al., 1999).


Apart from these, a subset of patients with ANSD is found to have cochlear nerve deficiency (hypoplasia or aplasia of the eighth nerve) as a comorbid factor (Maris et al., 2011; Zdanski et al., 2006). Both ANSD and cochlear nerve deficiency exhibit poor neural connectivity and conduction. However, in cochlear nerve deficiency, the reduced functional nerve fibres are the root cause of symptoms (Walton et al., 2008; Zdanski et al., 2006). Cochlear nerve deficiency can be typically diagnosed using MRI, and the use of cortical auditory evoked potentials in identifying the disorder is also recommended (Roland et al., 2013).


Individuals with ANSD have severe temporal processing deficits (Zeng et al., 1999). Further, this perceptual deficit is opined to be the result of dyssynchronous neural activity at the level of the auditory nerve. The frequency resolution is normal in individuals with ANSD, the processing contingent on the normal outer hair cells functioning (Rance et al., 2004). Otoacoustic emissions also obtain evidence of the same in this population. Frequency discrimination ability is also severely affected in individuals with ANSD (Rance et al., 2004; Starr et al., 1991). Moreover, the speech understanding ability of individuals with ANSD is correlated with their frequency discrimination abilities (Rance et al., 2004).


The management option for the ANSD population is sparse, and there is no standard treatment documented in literature or at a very preliminary stage. However, the limited benefit of conventional amplification devices is extensively reported in the literature (Deltenre et al., 1999; Rance et al., 2002). There is growing literature on cochlear implantations as a management option for children and adults with ANSD. The assumption behind implantation is that the pulsed electrical stimulation may improve synchronization in the nerve, thereby compensating for the inherent temporal deficits noted in this population (Harrison et al., 2015). Therefore, cochlear implants are rapidly becoming the choice of treatment for this population (Berlin et al., 2003; Peterson et al., 2012; Trautwein, 2002).


The decision about candidacy for cochlear implants is straightforward for infants with SNHL, meeting the auditory thresholds criteria and having no anatomical, social, or mental contra-indications present (Harrison et al., 2015). The author also reported that the candidacy decision for children with ANSD might require additional diagnostic procedures and deliberation. However, some report hearing rehabilitation with cochlear implants is more efficient for those with peri-synaptic disorders (Daniele De Siati et al., 2020). Further, it may be reasonable to consider young children with ANSD having severe to profound hearing loss for implantation since in ‘no’ instance, the speech perception abilities of ANSD are superior to those with SNHL. Hence, currently, those individuals with ANSD having poor speech understanding have cochlear implantation as the most successful treatment option (Rance & Barker, 2009). However, for those individuals with ANSD having a lesser degree of hearing loss, the candidacy of cochlear implantation warrants further research.


However, post evaluation and recommendation of CI in ANSD, there is uncertainty regarding the expected benefits of CI. Several researchers have attempted to review the literature on outcomes related to CI in children with ANSD. Fernandes et al., (2015), systematically reviewed 22 studies and reported comparable post-implantation performance in the ANSD group to implanted children with sensorineural hearing loss (SNHL). Similarly, Humphries et al. (2014), reviewed 27 studies and opined that favourable outcomes were noted in ANSD post-implantation, however with weak evidence. On the other hand, Roush et al. (2011), stated that additional information is needed to comment on the efficacy of CI as a management option for children with ANSD based on the review done on the audiological management of ANSD.


Further, Budenz et al. (2013), reported that those children with ANSD alone had better outcomes than those having comorbidities along with ANSD. Similar findings were also reported by Harrison et al. (2015), that enormous heterogeneity in ANSD and its related comorbidities show inconclusive prognosis with CI. The authors noted that clear prognostic information with CI in this group could be obtained only by subdividing the broad group into discrete disease entities with a wide variety of functional severity.


The prognostic information with CI in ANSD is unclear and requires greater insight into behavioural and electrophysiological outcomes in both children and adults with ANSD. This information would further help counsel the newly diagnosed ANSD cases about CI as a management option. Therefore, there is a need for an extensive systematic review of behavioural and electrophysiological outcomes post cochlear implantation (CI) in children and adults with ANSD. Further, it is necessary to differentiate the benefit of CI among individuals with ANSD alone and comorbidities.

The present systematic review highlights the behavioural and electrophysiological outcomes post CI in children and adults with ANSD. The behavioural outcomes would include auditory, speech and language, academic, social-emotional and parental attitude outcomes, whereas the electrophysiological result encompasses aided cortical responses pre and post-implantation. Further, the present review also attempts to reveal differences in the results across studies and explore the probable reason.

A systematic review of the literature was undertaken on the outcomes of cochlear implantation in children and adults with ANSD published between January 2016 and December 2021. The studies were selected from databases PUBMED, Google Scholar, ComDisDome, Shodhganga, Web of Science, and SCOPUS. The relevant articles were searched using the keywords’ Auditory Neuropathy Spectrum Disorders’, ‘Auditory Dys-synchrony’, ‘Auditory dyssynchrony’, ‘Auditory Neuropathy’, ‘Cochlear Implants’, ‘Cochlear Implantation’, ‘Electrical stimulation’, ‘Implantable device’ along with appropriate Boolean operators. The article search was done in the major database by combining the keywords with the Boolean operators as represented below:


[Auditory neuropathy spectrum disorder, OR auditory neuropathy, OR auditory dyssynchrony, OR auditory dyssynchrony]




[cochlear implant, OR electrical stimulation, OR implantable device, OR cochlear implantation].


The duplicates were identified and removed from the primary selected articles. Further, RAYYAN (Ouzzani et al., 2016), a free web application, was used for the title and abstract screening. Articles published in peer-reviewed journals and published from 2016 onwards were only selected. The reason behind choosing articles ahead of 2016 was that there were existing systematic reviews for a similar research question until 2015 (Fernandes et al., 2015; Harrison et al., 2015; Humphriss et al., 2013; Roush et al., 2011). The PRISMA flowchart depicting the article selection procedure is displayed in Figure1.


The article inclusion criteria were: a) studies involving human subjects b) experimental studies with children or adults with ANSD as participants, c) articles that examined behavioural (auditory, speech, language, and academic) outcomes post-implantation, d) articles that examined electrophysiological outcomes post-implantation e) articles that examined parental attitude and communication post-implantation.


The article exclusion criteria were: a) studies carried out on animals, b) articles in languages other than English, c) articles before 2016, d) case studies, editorials, letters to editor, and commentaries e) articles comparing outcomes from different surgical procedures f) articles with mixed treatment options such as hearing aid along with CI g) articles published later than March 2022 h) articles where ANSD is suspected but not confirmed by diagnostic tests i) unpublished papers. Further, the research design of the article was not kept as exclusion criteria to derive holistic knowledge of the existing body of evidence.


A total of 264 articles were selected by database searches and handpicking. There were 74 duplicate articles. After the removal of duplicates, the resulting articles were 190 in number. The title and abstract screening was carefully conducted of articles, and on considering the inclusion and exclusion criteria, 72 articles were shortlisted; further among them, 22 articles were published after 2016. Therefore, those 22 articles published after 2016 were winnowed down for full-text screening. The ‘full-text’ screening was conducted to preclude case reports, review articles, commentaries, training outcomes, and letters to editors. Post ‘full-text’ screening, eight research papers were finally shortlisted for review.


The present review focuses on behavioural (auditory, speech and language, academic, social-emotional, and parental attitude or communication) and electrophysiological outcomes post cochlear implantation. The outcomes were broadly pre-defined to include relevant articles. The auditory outcomes may consist of pure-tone, speech unaided and aided detection thresholds, unaided and aided speech recognition thresholds, and unaided and aided speech perception scores. Apart from these, speech in noise, temporal processing, and dichotic listening may also be included under the auditory outcomes. Likewise, the speech and language outcomes may consist of receptive and expressive language skills pre and post-implant and speech intelligibility. The academic outcomes may include reading, writing, spelling abilities and educational performance. Further, another behavioural outcome, social-emotional or parental attitude, may consist of severity rating scales, communication attitude, parental attitude or communication pre and post-implantation. On the other hand, the electrophysiological outcomes include changes in the aided cortical responses post-implantation.


Figure 1

PRISMA Flowchart depicting selection procedure of articles in review


The eight articles selected for the review and their details are illustrated in Table 1. Further, the results of each study under review are elaborately mentioned in Table 2.


Experimental questions


The most common research question evaluated in the shortlisted articles was ‘What are the behavioural auditory and speech outcomes post cochlear implantation in patients with ANSD?’ (Daneshi et al., 2018.; Hu et al., 2022; Sarankumar et al., 2018). Another research question investigated in the selected articles was ‘Does CAEP have a role in determining the outcomes from CI in patients with ANSD?’ (Lee et al., 2021; Saki et al., 2021; Sarankumar et al., 2018). Similarly, another research question was ‘Is there any correlation between the P1 CAEP latency and the speech intelligibility scores?’ (Lee et al., 2021; Saki et al., 2021). Further, a few studies targeted to compare the outcomes post CI based on the intervention time, like early or late implantation and the extent of experience with CI (Lee et al., 2021). A few studies targeted to evaluate the psychoacoustic and music perception abilities of implanted adolescents with ANSD (Yüksel & Çiprut, 2020).


Participant characteristics


Adult participants- Lee et al., (2021) included two adult participants of ages 25 years and 27 years to study the effect of age of implantation and the experience with CI on the behavioural and CAEP responses.


Paediatric participants- Sarankumar et al. (2018) included ten children with ANSD (mean age = 3.8 years) in the study. The age of the children ranged between 1.5 years and six years. Similarly, Lee et al. (2021) included paediatric implanted participants for one month between 10 months and three years. Daneshi et al. (2018) included children implanted with CI lesser than the preschool age or before seven years old. Carvalho et al. (2016) included even adolescent participants and children (2 -16 years) in their study. Similarly, Tokat et al. (2022), included children between 4.3 and 17.3 years old. On the other hand, Yüksel and Çiprut (2020) included twelve adolescents between the ages of 14 and 18 as participants in their study.


Implant Models


The participants in the studies used Medel Pulsar (Sarankumar et al., 2018), Medel Sonata (Daneshi et al., 2018; Hu et al., 2022; Sarankumar et al., 2018),  Advanced Bionics HiRes 90k (Sarankumar et al., 2018), Advanced Bionics Hifocus (Daneshi et al., 2018), Cochlear Nucleus Contour (Daneshi et al., 2018), Cochlear Nucleus 5, 6, and Kanso (Yüksel & Çiprut, 2020).


Experience with CI


In a few studies, the performance with CI was evaluated just after implantation and after one year of rehabilitation (Carvalho et al., 2016; Sarankumar et al., 2018). Similarly, Daneshi et al. (2018) assessed the auditory performance and speech production preoperatively and postoperatively after one year and two years. In a few studies, the auditory and verbal outcomes were evaluated at regular intervals such as 0, 1, 2, 3, 6, 9, and 12 months after CI switched ‘on’ to note the development trend (Hu et al., 2022). Similarly, Saki et al. (2021) noted development in the P1 component of CAEP and speech intelligibility rate pre-implant activation and at 6, 12, and 24-month post-implantation.



Tests assessed


Behavioural Auditory or Speech Perception Tests / Scales


Categories of auditory performance (CAP) that assess a child’s auditory performance post-CI were studied in several research articles (Sarankumar et al., 2018; Daneshi et al., 2018; Lee et al., 2021; Hu et al., 2022). It has scores ranging from 0 to 7 on the hierarchical scale of auditory perceptual ability. Similarly, another scale to measure the benefit of CI, Speech Intelligibility Rate (SIR), is used to quantify the intelligibility of implanted children in everyday spontaneous speech. The SIR scale is also extensively used in various studies as a potential post-CI outcome tool (Sarankumar et al., 2018; Daneshi et al., 2018; Lee et al., 2021; Saki et al., 2021; Hu et al., 2022).


Some questionnaires are administered to parents containing questions based on real-life situations involving the child. The two of them that are frequently used are the Meaningful Auditory Integration Scale (MAIS) and the Meaningful Use of Speech Scale (MUSS) (Sarankumar et al., 2018; Carvalho et al., 2016; Hu et al., 2022).


The Glendonald Auditory Screening Procedure (GASP) is also often utilized to evaluate the speech perception in profoundly deaf children from five years of age (Carvalho et al., 2016).


Speech perception in noise (SPIN) test: In certain studies, the speech perception in noise was evaluated for children greater than three years of age or after one year of rehabilitation. The procedure involved presenting speech and noise at 0 dB signal-to-noise ratio (SNR) or +10 dB SNR and measuring the speech discrimination scores (Sarankumar et al., 2018).


Electrophysiological Measures


Some studies have evaluated the benefit of CI using an electrophysiological tool such as Cortical Auditory Evoked Potential (CAEP). The benefit of CAEP is that it does not require behavioural cooperation from the child, it can determine cortical maturation, and predicts behavioural outcomes in children with ANSD. The P1 component of CAEP is a biomarker to assess cortical maturity (Sarankumar et al., 2018). The aided CAEP (with CIs) are also utilized in the studies to evaluate the benefit of CI. The latency of the P1 CAEP was analyzed in many articles considered for the present review (Sarankumar et al., 2018; Lee et al., 2021; Saki et al., 2021).


Quality of life/ Subjective assessment


In many studies, the subjective rating with cochlear implantation was also considered an outcome measure. For this purpose, some studies utilized a Likert scale ranging from 0 to 10, wherein ‘0’ indicates that the user regrets the intervention, whereas ’10’ indicates the user is completely satisfied with the work and recommends it (Carvalho et al., 2016). In one of the study, Parents’ Perspective Questionnaire was used to analyse the quality of life of cochlear implanted children with ANSD (Tokat et al., 2019).


Psychoacoustic and Music perception abilities


Music perception and psychoacoustic abilities also play a significant role in determining the benefit of CI (Yüksel & Çiprut, 2020). The knowledge of the same in the present review of the ANSD implanted population can help determine whether the music perception and psychoacoustic perception of the ANSD implanted individuals are similar to the SNHL implanted individuals. Music perception, especially tasks like melody recognition, requires both auditory and non-auditory skills and long persisting ANSD, which may affect the same. Hence, it is necessary to evaluate the music perception abilities of implanted individuals with ANSD.


Table 1. Study characteristics of articles under review

In the present review article, several outcome measures post-CI were studied, and the results are discussed in detail in this section based on the outcome measure. As mentioned prior, the study evaluated outcomes with CI in the ANSD population in a wide age range, including children, adolescents, and even adults. The behavioural outcomes were also correlated with the electrophysiological outcome in some studies. The findings of the present review on benefit evaluation with CI are further discussed in light of existing literature.


Auditory Perception


The present review showed a significant improvement in the auditory abilities of implanted ANSD participants determined by CAP, IT-MAIS, LEAQ, and GASP scores (Carvalho et al., 2016; Daneshi et al., 2018; Hu et al., 2022; Sarankumar et al., 2018). These findings relate well with the existing literature(Jeong et al., 2007; Kontorinis et al., 2014)  .Further, in the present study, the developmental trajectory of the auditory abilities in the ANSD group was similar to the typically developing children, which is also already reported (Breneman et al., 2012). However, the ANSD group lagged behind the typically developing children’s overall auditory performance (Hu et al., 2022). Further, the hearing perception of implanted children with ANSD was comparable with those with profound sensorineural hearing loss at one-year post-implant (Sarankumar et al., 2018). These findings also direct CI as a potential management option for the auditory development of children with ANSD.


It was also noted that the children with ANSD having residual hearing had greater benefit with CI when compared with those having no residual hearing (Hu et al., 2022). These findings are synchronous to the existing study by McCreery et al. (2015), reporting higher LEAQ results in those hearing aid users with ANSD having residual hearing. In the present review, slow growth was noticed in the first year of switch-on, followed by rapid growth in the second year and stable saturation was witnessed in the third and fourth years of switch-on in the ANSD population. The findings of this study are in line with the research done on the effects of age on cochlear implantation in children with pre-lingual deafness (Lyu et al., 2019).


Speech perception in noise (SPIN) test performance improved in ANSD participants post-CI, with 63% and 80% scores at 0dB and +10dB SNR, respectively (Sarankumar et al., 2018). Further research is warranted to compare the post CI performance of ANSD participants to that of profound SNHL participants. Overall the CI proved to be an effective procedure for the management and rebuilding of the auditory pathway of the ANSD population based on the current review.


Speech Comprehension and Expression


A gradual improvement in the verbal development was seen in the ANSD group post CI and with hearing age (Carvalho et al., 2016; Daneshi et al., 2018; Hu et al., 2022; Sarankumar et al., 2018). However, the verbal skills of the AN group lagged behind the typically developing group at 12 months of age post CI because of slow development (Hu et al., 2022). Similar findings were also reported by Cardon and Sharma (2013) on speech discrimination tasks. On the other hand, Alzhrani et al. (2019) reported contradictory results of the similar auditory and verbal performance of ANSD and typically developing groups. The difference in the present study’s findings can be attributed to the heterogonous type ANSD population. In addition, the speech outcomes of the ANSD group post-one-year of the implant are also reported to be comparable to those with cochlear hearing loss (Sarankumar et al., 2018). Hence, CI again can be understood as a potential management option for speech development in children with ANSD.


There was larger individual variation, and the individual scores were more scattered in the ANSD group when compared to the typically developing group, which could be attributed to varied aetiology, site of lesion, and their clinical manifestations. However, there was a trend of improvement noted in the verbal skills of the ANSD group post nine months of CI (Hu et al., 2022).


Music Perception/Psychoacoustic abilities


The individuals with ANSD derived benefit from CI also in terms of music perception and betterment of psychoacoustic abilities. The improvement of implanted individuals with ANSD was also comparable to those with sensorineural hearing loss (Yüksel & Çiprut, 2020). However, the individuals with ANSD significantly performed poorer and lagged behind the SNHL group on the melody recognition task (Yüksel & Çiprut, 2020).


The finding of similar performance of implanted individuals with ANSD and implanted individuals with SNHL contradicts the finding by He et al. (2016), who reported that the SNHL group had significantly better music perception than the ANSD group post-CI. The difference in the finding could be attributed to the difference in the participants involved in both the studies. He et al. (2016) included participants even with cochlear nerve deficiency and those of much lesser age. Because temporal auditory processing becomes adult-like by the age of 11 years in normal-hearing individuals, participants over 12 years should be included.


Quality of Life


Cochlear implantation improves auditory and language development in children with ANSD and enhances their quality of life (Tokat et al., 2019). The parents reported that with the advent of CI, there was an improvement in the education and communication abilities of children with ANSD, thereby increasing their self-confidence and social relation. Further, even the duration of implant usage positively affected the self-confidence and social relationships of implanted children with ANSD.


CAEP maturation


CAEP is an important tool in assessing the cortical maturity post CI in the ANSD group. In the present review, several studies demonstrated a negative correlation between the P1 latency and the SIR, MUSS, MAIS, and CAP scores(Lee et al., 2021; Saki et al., 2021; Sarankumar et al., 2018). The correlation between the P1 latency and speech scores is well documented in the literature(Alvarenga et al., 2012; Guo et al., 2016). Hence, CAEP can even predict the speech perception of implanted children with ANSD. Saki et al. (2021) also propounded that the children with ANSD having better P1 CAEP responses had higher speech intelligibility scores than those who had abnormal or absent P1 CAEP responses. CAEP, an objective measure, has an advantage in that it evades inter-tester variability. It can also be used for difficult test populations to evaluate the cortical maturation for speech perception.

There is limited literature, and clear consensus regarding the benefit of CI in the ANSD population is lacking. Hence, the present review targeted to review the behavioural and electrophysiological outcomes post CI in the ANSD group. The current review showed a significant benefit in all the domains (auditory skills, verbal skills, quality of life, music perception, and auditory cortex maturation) in implanted ANSD participants. Therefore, CI is an effective management option for auditory and verbal development in children with ANSD. In addition, the implanted individuals with ANSD have similar music perception abilities as that of implanted SNHL individuals. However, more studies are required to evaluate the long term benefits of CI and speech performance in the noise among implanted individuals with ANSD. In a nutshell, CI improves communication abilities and music perception and enhances the quality of life of individuals with ANSD.


The appropriate age to undergo cochlear implantation for the ANSD group has been reported to be two years, considering the sensitive period (British Society of Audiology, 2019). In the present review, the majority of the studies reported benefits with CI in various domains (Sarankumar et al., 2018; Hu et al., 2022; de Carvalho et al., 2016; Daneshi et al., 2018). However, a few studies demonstrated a delay in certain development aspects and included children with a median age greater than two years (Hu et al., 2022; Daneshi et al., 2018). Therefore, early personalized intervention should be targeted for the ANSD group based on individual needs (Hu et al., 2022). In addition, in the current review, it was noted that the listening performance and the speech production were also influenced by the age of implantation and also the duration of postoperative follow-up.



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