By Marcello Cherchi, MD PhD
For patients
Hearing loss due to a problem in the hearing-related nerve between the ear and the brain is called an auditory neuropathy. These patients usually have hearing loss on both sides early in life, sometimes beginning in childhood. The diagnosis is usually based on a combination of results from several hearing tests. If your doctor thinks you have auditory neuropathy, then they may suggest that you consult with an audiologist, who may recommend a hearing aid. If hearing aids are inadequate, then the audiologist may refer you to an otolaryngologist to be evaluated for cochlear implantation.
For clinicians
Overview
Auditory neuropathy, sometimes also referred to as “auditory dyssynchrony” or “auditory neuropathy spectrum disorder,” refers to hearing loss due to dysfunction of the auditory nerve rather than to the cochlea. In these patients audiometry shows hearing loss, auditory brainstem evoked responses are abnormal, yet otoacoustic emissions are present. This is difficult to diagnose in older individuals in whom otoacoustic emissions are absent secondary to normal aging. Auditory neuropathy is uncommon, and when present, is often only one part of a broader neuropathic process. There is emerging evidence that some auditory neuropathies (perhaps as high as 40%) may be associated with specific genetic mutations. First-line treatment is with amplification. Cochlear implantation is sometimes attempted.
Introduction
In the early 1990s Starr and colleagues (Starr et al. 1991) and Berlin and colleagues (Berlin et al. 1993) described several patients with subjective hearing loss and a previously unreported pattern of auditory test results. They identified several additional such patients, and in 1996 Starr, Picton, Sininger, Hood and Berlin (Starr et al. 1996) wrote:
“We have identified a group of patients with hearing deficits who have preserved otoacoustic emissions and absent or severely abnormal auditory brainstem responses. Most of the patients complain of difficulty understanding speech, particularly in the presence of noise. Using two particular tests of auditory function, otoacoustic emissions and auditory brainstem potentials, we were able to identify that the function of the VIII nerve was disordered, whereas the function of cochlear outer hair cells was normal” (Starr et al. 1996).
On standard audiometry these patients appeared to have sensorineural hearing loss. In most sensorineural hearing loss (such as presbycusis), the deficit is thought to localize to the cochlear hair cells. But in the patients evaluated by Starr and colleagues, the combination of abnormal auditory brainstem responses yet preserved otoacoustic emissions led these researchers to localize the dysfunction to the auditory nerve, rather than the cochlear hair cells. As they later phrased it, “In auditory neuropathy, the hearing impairment commences downstream from mechanoelectrical transduction and cochlear amplification of outer hair cells” (Moser and Starr 2016).
Also of note, some of the patients originally reported additionally had clinical evidence of a sensorimotor neuropathy (such as reduced myotatic reflexes, impaired proprioception and reduced pallesthesia), and some of the patients also had evidence of vestibular deficits (such as reduced caloric responses). This led the researchers to postulate that, at least in these patients, auditory neuropathy was part of a broader neuropathic problem.
Subsequent research on auditory neuropathy “elucidated the wide range of disease mechanisms, which include loss of inner hair cells (IHCs) or IHC synapses, impaired synaptic transmission to spiral ganglion neurons (SGNs), and disrupted propagation of auditory information along the auditory nerve” (Moser and Starr 2016). In recognition of this range of mechanisms (neuropathy, synaptopathy, spiral ganglionopathy), the literature sometimes refers to this “family” of diseases as “auditory dyssynchrony” or “auditory neuropathy spectrum disorder.”
Demographics
We will discuss below that the auditory test result profile required for a diagnosis of auditory neuropathy often makes it impossible to diagnose in older individuals, so the majority of research on this topic is in younger populations, particularly children with severe hearing impairments. Estimates of the prevalence of auditory neuropathy in this population range over nearly an order of magnitude, from 1.2% (Penido and Isaac 2013) to 8.4% (Foerst et al. 2006).
Diagnosis
In a patient with a clinical history of hearing loss, whose standard audiogram shows poor word recognition and speech perception thresholds out of proportion to performance on pure tone testing, one should check auditory evoked brainstem responses and otoacoustic emissions. If otoacoustic emissions are preserved and brainstem auditory evoked responses are absent or abnormal, then a diagnosis of auditory neuropathy is a reasonable possibility.
Note that this test result profile requires preserved otoacoustic emissions. Since otoacoustic emissions degrade with age, and are often nearly absent by the 6th or 7th decade of life, an older person may have a dysfunctional auditory nerve yet not meet criteria for auditory neuropathy because otoacoustic emissions are absent. This is unfortunate, because some of these patients may go through numerous attempts at amplification with hearing aids and find them all unsatisfactory.
Since these criteria effectively make it impossible to diagnose auditory neuropathy in the elderly, most of the research on this topic is in younger individuals, typically in children with severe hearing loss.
Treatment
Even when the diagnosis seems secure, treatment of auditory neuropathy is difficult (Giraudet and Avan 2012). Practically, in a patient with auditory neuropathy most audiologists will attempt amplification with a hearing aid since this approach has little medical risk, it is noninvasive and it is reversible. Cochlear implantation is sometimes attempted on the logic that a weakened (but not completely dead) auditory nerve may still be able to transmit the electrically augmented signals driven by a cochlear implant.
However, it is important to recognize that since dysfunction in auditory neuropathy localizes to the auditory nerve itself, interventions at the auditory nerve (such as a cochlear implant) or “upstream” from the auditory nerve (such as hearing aids) are likely to be inadequate if not completely ineffective. Rather, a strategy to bypass the auditory nerve is needed, such as auditory brainstem implants (Wong et al. 2019), though this approach is certainly much more invasive and risky.
It has been estimated that approximately 40% of cases of auditory neuropathy are attributable to genetic mutations (Burdo et al. 2021), and a broad range of genes has been implicated (Del Castillo and Del Castillo 2012), including over 90 mutations in OTOF which encodes otoferlin; DFNB1 which encodes connexins; locus DFNA25 in the SLC17A8 gene which encodes vesicular glutamate transporter 3; DFNB9 in “deafness, nonsyndromic autosomal recessive 9;” CACNA1D which encodes an alpha-1 subunit on the CaV1.3 calcium channel; MPZ gene that encodes myelin protein zero in Schwann cells; DFNB59 which encodes pejvakin; DIAPH3. Consequently, the advent of gene therapy may eventually provide opportunities for intervention in these patients.
References
Berlin CI, Hood LJ, Cecola RP, Jackson DF, Szabo P (1993) Does type I afferent neuron dysfunction reveal itself through lack of efferent suppression? Hear Res 65: 40-50. doi: 10.1016/0378-5955(93)90199-b
Burdo S, Di Berardino F, Bruno G (2021) Is auditory neuropathy an appropriate term? A systematic literature review on its aetiology and pathogenesis. Acta Otorhinolaryngol Ital 41: 496-506. doi: 10.14639/0392-100X-N0932
Del Castillo FJ, Del Castillo I (2012) Genetics of isolated auditory neuropathies. Front Biosci (Landmark Ed) 17: 1251-65. doi: 10.2741/3984
Foerst A, Beutner D, Lang-Roth R, Huttenbrink KB, von Wedel H, Walger M (2006) Prevalence of auditory neuropathy/synaptopathy in a population of children with profound hearing loss. Int J Pediatr Otorhinolaryngol 70: 1415-22. doi: 10.1016/j.ijporl.2006.02.010
Giraudet F, Avan P (2012) Auditory neuropathies: understanding their pathogenesis to illuminate intervention strategies. Curr Opin Neurol 25: 50-6. doi: 10.1097/WCO.0b013e32834f0351
Moser T, Starr A (2016) Auditory neuropathy–neural and synaptic mechanisms. Nat Rev Neurol 12: 135-49. doi: 10.1038/nrneurol.2016.10
Penido RC, Isaac ML (2013) Prevalence of auditory neuropathy spectrum disorder in an auditory health care service. Braz J Otorhinolaryngol 79: 429-33. doi: 10.5935/1808-8694.20130077
Starr A, McPherson D, Patterson J, Don M, Luxford W, Shannon R, Sininger Y, Tonakawa L, Waring M (1991) Absence of both auditory evoked potentials and auditory percepts dependent on timing cues. Brain 114 ( Pt 3): 1157-80. doi: 10.1093/brain/114.3.1157
Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI (1996) Auditory neuropathy. Brain 119 ( Pt 3): 741-53. doi: 10.1093/brain/119.3.741
Wong K, Kozin ED, Kanumuri VV, Vachicouras N, Miller J, Lacour S, Brown MC, Lee DJ (2019) Auditory Brainstem Implants: Recent Progress and Future Perspectives. Front Neurosci 13: 10. doi: 10.3389/fnins.2019.00010
