The term ‘auditory neuropathy spectrum disorder’ (ANSD) encompasses a group of patients with evidence of normal outer hair cell function as reflected by present otoacoustic emissions (OAE) and/or present cochlear microphonics (CM) but absent or abnormal auditory brainstem responses (ABR). Santarelli describes auditory neuropathy as “a hearing disorder characterized by disruption of temporal coding of acoustic signals in auditory nerve fibers resulting in impairment of auditory perception that rely on temporal cues.”¹ Functionally, the disorder may result in hearing thresholds that range from normal in some individuals, to profound in others.² Commonly cited characteristics include speech perception abilities that are poorer than expected for the degree of hearing loss and difficulty hearing in noise.³

Since the first reported cases of auditory neuropathy in the late 1980s and early 1990s, audiologists and other professionals working with these patients have struggled with several complex issues surrounding diagnosis and management. Early reports of auditory neuropathy by Starr and colleagues in 1996 described several patients with perplexing findings that included absent or abnormal ABR and present cochlear microphonics and otoacoustic emissions, implying normal outer hair cell function and altered neural transmission.⁴ The majority of these patients had other peripheral neuropathies, and several were subsequently found to have Charcot-Marie-Tooth disease and other progressive neurologic conditions.⁴ In many cases, the hearing complaints preceded neurologic symptoms by several years.

Prevalence

Over time, as clinical protocols were developed to diagnose ANSD, more children have been identified with this condition. It is now known that ANSD is a relatively common hearing disorder affecting up to 10% of children with permanent hearing loss.² And while the actual prevalence is unknown, it is clear that those who work in settings with a high volume of pediatric patients that employ evidence-based protocols will encounter a substantial number of children with this condition. The prevalence of ANSD in healthy, full-term infants is low, on the order of 1:10,000.⁵ There is a much higher prevalence of ANSD in premature infants and those who have required hospitalization in the neonatal intensive care nursery where histories may have included anoxia, hyperbilirubinemia, low birth weight, or exposure to ototoxic medications.6 In those infants, the prevalence may be as high as 24%.⁷

It has now been nearly 30 years since the earliest case reports and although there is still much to learn, we now have a better understanding of the heterogeneity of the disorder as well as better evidence to guide recommendations for children and families. In particular, discoveries in the areas of genetics, radiologic imaging, and environmental factors have contributed to the role that etiology and site of lesion play in determining outcomes.

Etiology

The etiology of ANSD includes structural abnormalities affecting the auditory system such as an absent or deficient VIII nerve, genetic abnormalities and conditions associated with prematurity, and/or hospitalization in the newborn critical care nursery. Rance and Starr (2015) provide an excellent review of the clinical and pathophysiological features of auditory neuropathy that distinguish site(s) of dysfunction. They emphasize that the diagnosis of auditory neuropathy relies on (1) objective neurophysiological measures of cochlear hair cell and auditory nerve functions; (2) imaging of auditory nerve/brainstem; and (3) behavioural audiological measures. They also describe the diagnostic criteria for presynaptic disorders affecting inner hair cells and ribbon synapses; postsynaptic disorders affecting unmyelinated auditory nerve dendrites; postsynaptic disorders affecting auditory ganglion cells and their myelinated axons and dendrites; and central neural pathway disorders affecting the auditory brainstem.⁸

While it is clear that we now have a variety of radiologic, genetic, and audiologic tools to determine the site of the lesion, complex diagnostic measures are not universally available and, as pointed out by,1 etiologic factors can be identified in only about half of the patients. However, when etiology or site of the lesion can be identified, it may inform clinical decision-making. For example, when genetic evaluation identifies an Otoferlin (OTOF) mutation, a pre-synaptic disorder which disrupts the function of the ribbon synapses, this may predict positive outcomes from cochlear implantation9; whereas radiologic imaging showing an absent or deficient VIIIth nerve may signal a less optimistic prognosis for cochlear implantation and a recommendation for visual communication, with or without a cochlear implant.^10,11

Diagnosis

Well defined, evidence-based clinical protocols are needed to diagnose ANSD. When ABRs are absent or grossly abnormal, testing using single polarity clicks (rarefaction and condensation) at a high-intensity level must be used to determine if auditory neuropathy is present. In addition to ABR, otoacoustic emissions and acoustic immittance measures including the acoustic reflex should be included in the diagnostic test battery. If clinics are using ASSR for diagnostic testing, a click ABR at a high-intensity level with single polarity clicks should be performed in addition to ASSR.

Once an accurate diagnosis is made, families need to be counseled regarding the implications of the diagnosis and the next steps. Inevitably, counseling regarding prognosis at the time of diagnosis will need to be guarded. Apart from the electrophysiologic findings supporting the ANSD diagnosis, little information is available to make predictions regarding expected outcomes until additional clinical data can be obtained. Depending on the medical history of the child and family, this may include imaging of the inner ears (e.g., MRI, CT scans) and referrals for genetics, neurology and ophthalmology. Referral for early intervention services should be made as soon as the diagnosis is confirmed.

Since it is not possible to make predictions of estimated hearing thresholds from ABR or ASSR, the determination of functional hearing status must be deferred until behavioral audiometry can be reliably performed. While reliable behavioral thresholds can be established for typically developing infants by 6–9 months of age, children with developmental delays, including many premature infants at risk for ANSD, may need to be older before this can be accomplished. Indeed, a small percentage of children with more severe developmental disabilities may never be able to provide reliable behavioral thresholds. Cortical evoked potentials are being investigated for use in these cases and should be considered when the behavioural assessment is unsuccessful.^13,14

Management

For many years, recommendations for or against cochlear implantation or hearing aids as well as communication methodology have been made based on single case reports or studies with a small number of subjects.¹⁵ In recent years, clinical researchers have expanded the knowledge base and there are now several studies demonstrating that some children will benefit from acoustic amplification^16,17 while others, despite adequate audibility of speech, will receive greater benefit from cochlear implantation.11,18,19 We have also learned that for some children, neither technology is sufficient and supplemental visual communication is needed.

Many children with ANSD will have hearing thresholds in the severe or profound range and will meet the criteria for cochlear implantation based on the degree of hearing loss alone. For these children, cochlear implantation should be offered unless there are medical or radiologic contraindications.

It should also be noted that a small percentage of children with ANSD will have behavioral hearing thresholds that are within normal limits bilaterally. These children should be carefully monitored with behavioral audiometry including age-appropriate speech perception measures in quiet and in noise until functional hearing status can be determined. Consideration should also be given to the use of remote microphone technology in the classroom and, if indicated, for personal use. Many children with ANSD and normal hearing thresholds will develop speech and language on a normal trajectory with little or no functional communication difficulty; however, there have been reports of children with ANSD and normal hearing thresholds who have significantly impaired auditory function. These children will require a comprehensive assessment by an interdisciplinary team.

Perhaps the most challenging group of children with ANSD from a treatment perspective, are those whose hearing thresholds are in the mild or moderate range. While most children with typical sensory (cochlear) impairment and hearing thresholds in this range are excellent candidates for amplification, outcomes for children with ANSD in this category are more variable. For some children with ANSD, the acoustic signal provided by conventional amplification may be severely disrupted even though the audibility of the signal is adequate and prescriptive targets are matching well. Once reliable estimates of behavioral thresholds are obtained, most clinical protocols recommend a trial with acoustic amplification using evidence-based hearing aid fitting protocols.^20-23 However, ongoing monitoring by speech-language pathologists, teachers of the deaf, and other intervention professionals combined with early aided speech perception measures are needed to ensure that the child is making age-appropriate progress with communication development, and if not, referral should be made for cochlear implant evaluation.

Finally, since a diagnosis of auditory neuropathy in early infancy may be a biomarker of other neurologic conditions such as mitochondrial and metabolic disorders, it is critically important that audiologists and other professionals working with infants diagnosed with ANSD consider referrals to other medical specialists (e.g., pediatric genetics and neurology) especially when an infant presents with no other risk factors for auditory neuropathy.

Summary

ANSD is a hearing disorder characterized by disruption of temporal coding. It varies in degree and severity, and its impact on speech perception. It is relatively common among children who are deaf or hard of hearing, with some estimates as high as 10% of children with permanent sensorineural hearing loss. Infants with complicated birth histories are at greatest risk. The diagnosis requires a combination of electrophysiologic and behavioral methods, the latter being inevitably delayed until behavioral measures can be reliably obtained. Some children with ANSD obtain benefit from acoustic amplification and others are candidates for cochlear implantation; a small percentage do not appear to benefit from either technology. Not surprisingly, parents of young children with ANSD are often confused at the time of diagnosis, making it essential for clinicians to provide information that is accurate and based on scientific evidence but delivered in a manner that is comprehendible for parents and caretakers. The British Columbia Early Hearing Program has developed a video and brochure for families that we have found to be helpful in this regard.²⁴ Future research aimed at better understanding the nature, etiology, and sub-classification of ANSD will continue to inform and refine our ability to provide optimal clinical management and intervention.

References

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20. American Academy of Audiology. Clinical practice guidelines: Pediatric amplification. Reston, VA: 2013.
21. Ontario Ministry of Children Community, and Social Services. Ontario Infant Hearing Program Protocol for the Provision of Amplification. Ontario: Author; 2019. Available at: https://www.uwo.ca/nca/pdfs/clinical_protocols/IHP_Amplification%20Protocol_2019.01.pdf
22. Year 2019 Position Statement: Principles and Guidelines for Early Hearing Detection and Intervention Programs. J Early Hear Detect Intervent 4(2):1–44. DOI: 10.15142/fptk-b748
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24. British Columbia Early Hearing Program, Provincial Health Services Authority, Auditory Neuropathy Spectrum Disorder. 2016. Available at: https://www.youtube.com/watch?v=ZZFERUP15wE&list=PLcE0nANeV5MqiIMHTFSNCEQksrl0-pYlT&index=25&t=1s