Key points

Auditory neuropathy (AN), auditory neuropathy/dys-synchrony (AN/AD), and, more recently, auditory neuropathy spectrum disorder (ANSD) are variable terms used to describe an auditory disorder seen in patients ranging in age from infants to adults. With knowledge of the inherent problems presented by each term, ANSD is used here with the understanding that no one term is completely definitive or descriptive.

Overview of characteristics

ANSD is characterized by evidence of intact outer hair cell (OHC) function, shown by the presence of otoacoustic emissions (OAEs) and/or cochlear microphonics (CMs), accompanied by poor eighth nerve–brainstem responses, demonstrated by absent or highly abnormal auditory brainstem responses (ABRs). Further evidence of effects on neural function is demonstrated by absent or elevated middle-ear muscle reflexes (MEMRs) and abnormal medial olivocochlear reflexes (MOCRs). Although understanding of speech in noise is poorer than that observed in sensorineural hearing loss (SNHL), word recognition in quiet is highly variable, and thresholds for pure tones range from normal to profound losses. Most ANSD patients show bilateral characteristics, although function may be asymmetric between ears, and patients with unilateral ANSD have been documented.

Despite fairly similar findings on auditory physiologic measures, patients vary considerably in functional communication abilities. Clinical presentation typically includes difficulty listening in noise, may include fluctuating hearing ability, and, in the case of infants and children, most often involves delays in speech and language development. Patients with ANSD typically demonstrate poor temporal resolution and may have neural deficits in other systems.

Overview of characteristics

ANSD is characterized by evidence of intact outer hair cell (OHC) function, shown by the presence of otoacoustic emissions (OAEs) and/or cochlear microphonics (CMs), accompanied by poor eighth nerve–brainstem responses, demonstrated by absent or highly abnormal auditory brainstem responses (ABRs). Further evidence of effects on neural function is demonstrated by absent or elevated middle-ear muscle reflexes (MEMRs) and abnormal medial olivocochlear reflexes (MOCRs). Although understanding of speech in noise is poorer than that observed in sensorineural hearing loss (SNHL), word recognition in quiet is highly variable, and thresholds for pure tones range from normal to profound losses. Most ANSD patients show bilateral characteristics, although function may be asymmetric between ears, and patients with unilateral ANSD have been documented.

Despite fairly similar findings on auditory physiologic measures, patients vary considerably in functional communication abilities. Clinical presentation typically includes difficulty listening in noise, may include fluctuating hearing ability, and, in the case of infants and children, most often involves delays in speech and language development. Patients with ANSD typically demonstrate poor temporal resolution and may have neural deficits in other systems.

Incidence

ANSD occurs in about 10% of individuals who have a dys-synchronous ABR, or an ABR consistent with an estimate of severe or profound hearing loss. This estimate is based on data from several sources that include screening of more than 1000 children enrolled in schools for the d/Deaf in North America, a similar smaller-scale study in Hong Kong, a hospital-based study of children in Australia, and a multicenter newborn screening study in the United States. A higher incidence of 17.3% and 15.4%, respectively, was reported among children identified with hearing loss following newborn hearing screening. In the neonatal intensive care unit (NICU), rates of ANSD physiologic characteristics ranged from 24% to 40% of infants who failed ABR testing in one or both ears.

Clinical findings

Physiologic measures that assess cochlear active processes related to OHC and mechanical activity and peripheral neural function of the eighth nerve and brainstem pathways most accurately describe patients with ANSD. Cochlear processes are evidenced by the presence of OAEs and CMs. Clinical tests specifically sensitive to auditory nerve dysfunction are the ABR, MEMRs, and the MOCR. Of these measures, OAEs and ABR together form the most sensitive combination. A summary of physiologic and behavioral audiologic test results in patients with ANSD is shown in Table 1 .

Hair Cell Responses: Otoacoustic Emissions and Cochlear Microphonics

OAEs provide a measure of cochlear active processes related to OHC function and cochlear mechanics. The presence of ANSD is typically established based on presence of these responses when peripheral neural responses are absent or significantly reduced. In the absence of middle-ear disorders, OAEs are typically present in patients with ANSD. Because OAEs are low-amplitude acoustic signals, even small middle-ear changes can be sufficient to reduce OAE amplitude or prevent the OAE from being recorded. The effect of even minor middle-ear problems and the high incidence of otitis media in infants and children can confound identification of ANSD.

Cochlear function can also be evaluated using the CM. Because the CM is an electrical response, it does not depend on reverse transmission through the middle ear system. A key factor in distinguishing CM from neural responses is the reversal of the electrical response with presentation of condensation versus rarefaction stimuli. The CM will invert with stimulus polarity reversal, whereas neural responses to clicks typically do not completely invert ( Fig. 1 ).

Auditory brainstem responses to condensation and rarefaction polarity click stimuli in an individual with normal auditory function ( upper ) and an ANSD patient ( lower ). Note the inverting CM in both figures and the lack of a neural response in the lower figure. I, Wave I of the ABR; III, Wave III of the ABR; V, Wave V of the ABR.

Underlying mechanisms

The set of clinical test results observed in patients with ANSD can occur as a result of absence or disruption of inner hair cell (IHC) activity, disorders of the auditory nerve, or abnormalities at the synapses of the IHCs and auditory nerve. IHC abnormalities could result from a lack of development, traumatic insult, or a loss over time. Selective IHC loss was observed in several premature newborns who failed ABR testing. Hypoxia and toxic insults specific to IHCs are other possible explanations. Direct effects on auditory nerve activity have been implicated in patients with concomitant peripheral neuropathies such as Charcot-Marie-Tooth disease, Friedreich ataxia, Mohr-Tranebjaerg syndrome who also display characteristics of ANSD. Study of underlying mechanisms is enhanced through efforts to distinguish presynaptic versus postsynaptic responses using electrocochleography.

Links between ANSD and genetic mutations are well documented with evidence of recessive, dominant, and mitochondrial inheritance patterns, and occurrence in syndromic and nonsyndromic hearing loss (see Ref. for review). An example is the OTOF gene that encodes otoferlin, whose mutations are associated with nonsyndromic recessive ANSD. Otoferlin plays a role in neurotransmitter release at the synapse between the IHCs and the auditory nerve.

In some patients with ANSD, fluctuations in auditory function have been linked to fluctuations in body temperature (as little as 1°C) and an apparent temperature-sensitive form of ANSD. Several reports implicate OTOF gene mutations and other mechanisms, possibly autoimmune disorders, whereby auditory function varies with changes in body temperature. ANSD is also reported in infants with potential risk factors that include hypoxia and hyperbilirubinemia.

Differential diagnosis

Although the test protocols necessary to diagnose ANSD are now well established, dysfunction of the IHCs and their synapses can lead to a hearing disorder that is difficult to distinguish clinically from an auditory nerve disorder. Identifying concomitant peripheral neuropathies or radiologic abnormalities is helpful in distinguishing among various conditions.