Auditory Neuropathy

Suman Ravi John

Introduction
• Auditory neuropathy is a form of hearing impairment in which cochlear (outer
hair cell) function appears normal but afferent activity in the auditory nerve and
central auditory pathways is disordered
• Auditory neuropathy is a hearing disorder in which the inner ear successfully
detects sound, but has a problem with sending sound from the ear to the brain.
• It can affect people of all ages, from infancy through adulthood.
• When their hearing sensitivity is tested, people with auditory
neuropathy may have normal hearing or hearing loss ranging from
mild to severe.
• They always have poor speech-perception abilities, meaning that they
have trouble understanding speech clearly. People with auditory
neuropathy have greater impairment in speech perception than hearing
health experts would predict based upon their degree of hearing loss
on a hearing test. For example, a person with auditory neuropathy may
be able to hear sounds, but would still have difficulty recognizing
spoken words. Sounds may fade in and out or seem out of sync for
these individuals.
What causes auditory neuropathy?
• Researchers report several causes of auditory neuropathy. In some cases, the
cause may involve damage to the inner hair cells—specialized sensory cells
in the inner ear that transmit information about sounds through the nervous
system to the brain.
• In other cases, the cause may involve damage to the auditory neurons that
transmit sound information from the inner hair cells to the brain. Other
possible causes may include inheriting genes with mutations or suffering
damage to the auditory system, either of which may result in faulty
connections between the inner hair cells and the auditory nerve (the nerve
leading from the inner ear to the brain), or damage to the auditory nerve itself.
• A combination of these problems may occur in some cases.
What are the roles of the outer and inner hair
cells?
• Outer hair cells help amplify sound vibrations entering the inner ear
from the middle ear. When hearing is working normally, the inner hair
cells convert these vibrations into electrical signals that travel as nerve
impulses to the brain, where the brain interprets the impulses as sound.
• Although outer hair cells—hair cells next to and more numerous than
inner hair cells—are generally more prone to damage than inner hair
cells, outer hair cells seem to function normally in people with
auditory neuropathy.
Mechanisms
• A number of mechanisms that could produce the AN result profile have been identified.
Some possible sites of lesion include the cochlear inner hair cells, the synapse between
these cells and Type 1 auditory nerve fibers, and the auditory nerve itself. For a review
see Rance & Starr, 2015.
• Specific damage to the cochlear inner hair cells (IHC) could result in the decrement of the
auditory brainstem response with preservation of preneural (outer hair cell) responses.
• The commonly held notion that the outer hair cells are particularly vulnerable to cochlear
insult and that OHC loss occurs before IHC for most cochlear pathologies argues against
the possibility of measuring OAE and CM responses in ears with significant IHC damage.
• There is, however, evidence from a range of animal models suggesting that certain types
of cochlear insult (notably those caused by prolonged hypoxia) can have a greater effect
on inner than OHC survival (Billet, Thorne, & Gavin, 1989; Bohne, 1976; Shirane &
Harrison, 1987).
• In human subjects a large body of temporal bone work has failed to show specific IHC loss, but
one study (Amatuzzi et al., 2001) has identified 3 babies from a group of NICU nonsurvivors
with this result pattern.
• Furthermore, recent studies using round window electrocochleography to record electrical
activity within the cochlea has suggested the possibility of this “presynaptic” site of lesion in
some individuals with AN (McMahon, Patuzzi, Gibson, & Sanli, 2008). A disorder affecting the
synapse between cochlear IHCs and Type 1 auditory nerve fibers may also produce the AN
result pattern (Starr et al., 1991).
• Mechanisms by which synaptic disruption might occur in the auditory pathway are currently
under investigation, but genetic dysfunction involving the otoferlin (OTOF) protein which
affects neurotransmitter release and is known to result in atrophy and morphological changes
at the IHC/nerve connection, has been identified in subjects with the AN result pattern (Moser
& Starr, 2016).
•
• As the term “auditory neuropathy” suggests, the site of lesion in many affected
patients is the nerve itself; 30 to 40% of all AN cases, and ≈80% of all subjects with
symptom onset above the age of 15 years in fact present with generalized neuropathic
conditions and show a range of nonauditory symptoms including muscle weakness and
atrophy, sensory loss, paresthesia (unusual sensations), and dysesthesia (discomfort).

• The site of the disorder affecting the auditory neural pathway may be the myelin
sheath, the neuron, or a combination of both.
• Myelin serves as an electrical insulator in the CNS. Demyelination results in delays in
excitation, reductions in the velocity of action potential propagation, and an increase in
conduction vulnerability (McDonald & Sears, 1970; Rasminsky & Sears, 1972).
• Fibers that are myelinated to differing degrees will therefore conduct neural signals at
different speeds.
• Hence, the synchrony of discharges can be disrupted and processes
dependent on temporal precision (such as the recording of ABRs)
would be affected. Loss of axons can occur as a result of specific
disease processes or as a secondary process in demyelinating
conditions (Rapin & Gravel, 2003).
• An axonal neuropathy in the auditory pathway might not necessarily
affect the timing of neural discharges, but would impact the number
of neural elements available to contribute to the overall response
and, hence, reduce the amplitude of the scalp-recorded ABR to the
point where it is indistinguishable from the overall EEG.
Prevalence
• The prevalence of auditory neuropathy in adult populations is difficult to determine.
• This is primarily because the physiologic test techniques that identify the condition
(ABR/CM/OAE) are not routinely undertaken unless there are specific clinical indicators for retro-
cochlear abnormality such as asymmetric hearing, unusually poor speech perception, or genetic
abnormality associated with synaptic or peripheral neural dysfunction.
• Paediatric populations, on the other hand, do routinely undergo these assessments in both
newborn screening and diagnostic contexts, and the findings from this group suggest that AN is a
relatively high-incidence condition, particularly among babies who have had a difficult neonatal
course.
• Data collected in our laboratory over a 5-year period (1991–1996), for example, found that 0.23%
or 1 in every 423 subjects with risk factors for hearing loss presented with the AN result pattern
(Rance et al., 1999).
• Furthermore, a number of more recent studies have indicated that AN accounts for a significant
proportion (≈10%) of all permanent hearing loss in children (for a review see Rance & Starr, 2011)
Etiology
• While auditory neuropathy can occur in the absence of obvious health
problems, the majority of reported cases (>70%) have presented with
specific medical risk factors (Sininger & Oba, 2001; Rance & Starr,
2015).
• A number of different etiologies have been linked with the condition.
These include transient neonatal insults (in particular involving
hyperbilirubinaemia, hypoxia, and accompanying metabolic acidosis),
infectious processes (such as mumps and meningitis), immune
disorders such as Guillain-Barré syndrome, and genetic
• abnormalities (including mutations of several genes [OTOF, PMP22,
MP2, NDGRGI] important for peripheral nerve function). (For reviews
see Rance, 2005; Rapin & Gravel, 2003; Starr et al., 2003; Starr, Zeng,
Michalewski, & Moser, 2008).
• Congenital disorders such as cochlear nerve insufficiency can also
produce the AN result pattern (Buchman et al., 2006) as can tumors
on the VIIth nerve. Table 6–1 shows a sample of the etiologies
commonly associated with AN and their likely site(s) of lesion.
Behavioral Audiogram
• Hearing threshold levels in individuals with AN vary across the audiometric range. Despite
the fact that all affected subjects show absent or severely distorted auditory brainstem
potentials, sound detection thresholds in both adult and pediatric populations are
reasonably evenly distributed and range from normal to profound levels (Berlin et al., 2010;
Rance et al., 1999; Siniger & Oba, 2001).
• Audiometric pattern varies, but a reasonably high proportion (30–40%) show a low-
frequency configuration with poorest sound detection for stimuli in the 250 Hz to 500 Hz
region (Madden, Rutter, Hilbert, Greinwald, & Choo, 2002; Rance et al., 1999; Sininger &
Oba, 2001).
• Hearing level fluctuations (without a directional trend) have been reported in some cases
but these are relatively rare (Rance et al., 1999; Sininger & Oba, 2001).
• On occasion fluctuations have been observed in individuals with a temperature-sensitive
form of AN associated with OTOF-related synaptic abnormality (Starr et al., 1998).
• Interestingly, auditory perceptual ability (in particular the perception of speech signals) is
not strongly correlated with the behavioral audiogram in the AN population (Rance et al.,
2002; Zeng, Oba, & Starr, 2001).
Speech Perception
• Difficulties with speech understanding are a consistently reported feature of AN. Most affected
adults report perceptual deficits far greater than would be predicted from their audiometric
results (Rance et al., 2008, 2010a; Starr et al., 1996; Starr, Sininger, & Pratt, 2000; Zeng et al.,
2001).
• A high proportion of children with AN also show only limited capacity to understand speech,
even in favorable (quiet) listening conditions. Figure 6–2 shows openset speech perception
scores plotted against average hearing level for 336 children who have been presented in the
literature.
• As can be seen from this data, approximately 50% of cases show perceptual ability poorer than
the expected minimum for sensory hearing loss of equivalent degree. In addition to these
perceptual limitations in quiet, speech understanding in noise is also a particular problem for
listeners with AN-type hearing loss.
• This may in some cases reflect the fact that their perceptual ability is so poor to begin with that
any loss of information in noise has a dramatic effect on overall speech understanding.
• However, a number of studies have presented subjects who could score at 100% on speech
perception tasks in quiet, but who showed little or no perceptual ability even in relatively low
levels of background noise (Kraus et al., 2000; Rance et al., 2007, 2012a; Shallop, 2002)
Auditory Processing
• The fact that understanding of speech is severely disrupted by AN
despite adequate detection of sound (in many cases) suggests that signal
distortion is a limiting factor to perceptual ability.
• In these subjects, who all show evidence of neural code disruption, it is
useful to consider the “building blocks” of auditory perception and how
these basic processes are affected by AN.
• Various perceptual abilities that underpin the perception of complex
auditory signals (including speech) have been studied in subjects with
normal acuity and subjects with sensory hearing loss.
• Some of these include: frequency resolution, intensityrelated
perception, temporal processing, and frequency discrimination.
Frequency Resolution
• Frequency resolution is the ability of the auditory system to separate components in a complex sound.
• For example, to identify or “resolve” the formant peaks in a vowel sound. Spectral processing of this sort
occurs at the level of the cochlea and is mediated by the active processes of the OHCs, which amplify and
sharpen the peaks of basilar membrane movement (Yates, Johnstone, Patuzzi, & 0 20 40 60 80 100 0 20 40
60 80 100 3-Frequency Average (dBHL) O p e n - S e t S p e e c h S c o r e ( % ) Word score Sentence score
Figure 6–2.
• Open-set speech perception score/average hearing level comparisons for the 336 children with AN-type
hearing loss who had appeared in the literature up to April 2017.
• The filled data points represent findings from open-set word tests, and the open points show open-set
sentence test results.
• The dashed line represents the minimum expected score for ears with sensory hearing loss (Yellin, Jerger, &
Fifer, 1989). Robertson, 1992).
• As OHC function (reflected by the presence of OAE and/or CM responses) is “normal” in ears with AN­type
hearing loss, it is not surprising to find that frequency resolution measured both physiologically (through
the generation of OAE suppression tuning curves [Abdala, Sininger, & Starr, 2000]), and psychophysically
(Cacace, Satya­Murti, & Grimes, 1983; Rance et al., 2004) have been normal in most reported cases.
Intensity-Related Perception
• Discrimination of intensity cues is typically normal in subjects with AN. Zeng,
Kong, Michaelewski, and Starr (2005), for example, found that intensity difference
limen (the smallest perceivable level difference between stimuli) for a group of
AN subjects were similar to those obtained for normally hearing controls.
• Subjects in both groups in this study were able to consistently detect intensity
differences of as little as 2 to 3 dB when stimuli were presented at reasonable
sensation levels (≥50 dB).
• Furthermore, these authors also found that binaural intensity processing was
normal in their cohort of AN subjects.
• In this case, the sound lateralization percepts produced by the simultaneous
presentation of stimuli at different levels in each ear were equivalent for the
normal and AN subject groups (Zeng et al., 2005)
• Processing of Temporal Cues Apart from a reduction in signal
audibility, disruption of timing-related information is the major way in
which auditory perception is affected in subjects with AN. Profound
deficits have been reported in this population for a range of monaural
and binaural processing abilities.
Temporal Resolution
• Temporal resolution is the ability to perceive changes in auditory
signals over time. The limit of the auditory system’s ability to
accurately encode or “resolve” rapid stimulus changes has most
commonly been measured using “gap detection” tasks where the
shortest detectable silent period in a burst of noise or a pure tone is
determined. Gap detection ability in subjects with AN is significantly
poorer than for normally hearing listeners (Michalewski et al., 2005;
Rance et al., 2010a; Starr et al., 1991, 1996; Wynne et al. 2013; Zeng,
Oba, Garde, Sininger, & Starr, 1999; Zeng et al., 2005). Where normal
subjects typically can perceive gaps of
Binaural Temporal Processing
• As well as demonstrating monaural temporal processing limitations, individuals with AN also show an
impaired ability to integrate binaural temporal cues.
• Abnormal Masking Level Difference (MLD) results, for example, are a consistently reported finding
(Berlin, Hood, Cecola, Jackson, & Szabo, 1993; Hood, 1999; Starr et al., 1991; Starr et al., 1996).
• MLD assessment measures the release from masking obtained when a signal or noise is presented out
of phase with a competing signal in the contralateral ear. Normal subjects typically show a masking level
difference (with dichotic phase inversion) of ≈10 dB indicating that phase information from each ear has
been accurately represented at the level of the lower brainstem (Licklider, 1948).
• AN subjects in contrast typically show little or no masking release suggesting an inability to combine the
neural code from each ear. Localization based upon binaural timing cues is also impaired in AN patients.
• Despite the fact that affected individuals can use interaural intensity differences to make lateralization
judgments (Zeng et al., 2005) a number of studies have found that even gross timing differences
(between ears) are not interpreted as changes in sound direction (Starr et al., 1991; Kaga et al., 1996;
Zeng et al., 2005). Zeng et al. (2005), for example, found that in their normally hearing cohort, interaural
timing differences of
Frequency Discrimination
• Frequency discrimination is the ability to perceive changes in the pitch of a single stimulus over
time, or across individual stimuli.
• High frequency discrimination (≥4 kHz) is thought to be dependent on the arrangement of spatial
excitation along the basilar membrane (Sek & Moore, 1995). Discrimination of lower frequency
sounds is similarly influenced by this tonotopic cochlear representation, but is also enhanced by
temporal information (Sek & Moore, 1995).
• In particular it has been hypothesized that “phase locking” (where neural firing patterns reflect
the stimulus waveform) can fine-tune discrimination in this frequency range. (Neural refractory
limitations prevent phase locking for high frequency signals.)
• Phase locking requires a high degree of temporal precision and so, not surprisingly, individuals
with AN show a reduced ability to use these cues and can demonstrate severely impaired
frequency discrimination (Rance et al., 2004; Rance et al., 2010a; Zeng et al., 2005). Frequency
discrimination deficits have been reported for AN subjects at all frequencies in the audiometric
range, but low frequency perception is most affected, typically showing difference limen more
than 10 times greater than those of normally hearing subjects.
Temporal Processing and Neural Conduction
Disorder
• The precise mechanisms by which temporal cues are disrupted in the auditory
pathway of AN patients are unclear.
• The absence or severe distortion of the ABR does, however, point to a
dyssynchrony of neural firing in the peripheral auditory system.
• The degree to which neural precision is affected in individual cases is difficult to
determine and may vary significantly across the AN population.
• Disruption of averaged potentials from the brainstem would suggest a temporal
distortion of at least 0.5 msec (Kraus et al., 2000; Sininger, Hood, Starr, Berlin &
Picton, 1995; Starr et al., 1991) and some patients, perhaps those with only
mildly depressed psychophysics results and reasonable speech perception (see
Figure 6–2), may suffer a temporal disruption close to this limit.
• In summary, the findings presented in this case study demonstrate that the
perceptual profile typical of subjects with AN is quite different to that seen for
sensory hearing loss.
• Subjects in the latter group, as a result of their abnormal cochlear function, show
impaired frequency resolution and frequency discrimination but relatively normal
temporal processing.
• Individuals with AN on the other hand, typically present with normal cochlear
processing and hence normal frequency resolution, but as a consequence of their
neural transmission deficiencies, show severe disruption of timing cues.
• Both types of hearing loss affect speech understanding (although probably in
different ways) and both result in difficulties in background noise, but overall the
perceptual disruption caused by AN is far more pronounced
Management of AN
• As the pattern of perceptual deficits in AN is fundamentally different
from that associated with sensory loss, different management
approaches are required. The application of AN-specific habilitation
strategies in this population is yet to be thoroughly investigated.
Optimization of the input provided to affected ears has, however,
been considered
Remote Microphone (FM) Listening Systems
• The use of remote microphone (FM) listening devices and sound-field
amplification systems to improve speech understanding in
background noise has been explored in listeners with sensory hearing
loss (Hawkins, 1984) and CAPD (Johnstone, John, Hall, & Crandell,
2009). A recent study (Rance et al., 2010b) has also demonstrated
significant benefits in a group of children and adults with AN (due to
the neurodegenerative disease, Friedreich ataxia). In this case,
assessment of 10 subjects fit with personal remote microphone
devices revealed aided open-set speech perception improvements
and substantial (self-reported) listening and communication benefits
over the course of a 6-week device trial (Figure 6–9).
Amplification
• The provision of hearing aids to individuals with AN (particularly children) has
been a controversial issue.
• There are two main arguments against amplification in this population.
• The first is that highlevel inputs may damage the cochleae in these ears with
normal OHC function.
• The second is that conventional amplification will not overcome the temporal
distortion introduced into the system by the APD.
• That is, the listener will be presented with a louder, but equally disrupted signal.
• The potential benefit offered by amplification relates to the subjects’ improved
access to sound. As many affected individuals have significantly elevated hearing
thresholds, they simply cannot detect speech and other signals at normal levels.
Cochlear Implants
• Cochlear implantation is currently the intervention option of choice for AN patients with severe auditory
processing difficulties.
• Many reported cases have shown normal device function, significant perceptual benefits, and language
development rates consistent with their implanted peers with sensory loss (Madden et al., 2002; Mason, De
Michelle, Stevens, Ruth, & Hashisaki, 2003; Shallop, 2002; Teagle, Roush, & Woodward, 2010; Trautwein,
Shallop, Fabry, & Friedman, 2001; Zeng & Liu, 2006).
• However, approximately 25% of implantees with AN fail to achieve open-set speech perception and show no
improvement on their preoperative listening ability (Teagle et al., 2010; Roush et al., 2011).
• The efficacy of cochlear implantation appears to be closely related to the site(s) of lesion in individuals with AN.
• The CI electrically stimulates the auditory neural structures up to the level of the spiral ganglion neurons (SGN).
As such, patients with etiologies involving a pathological locus prior to the SGN (i.e., those with a history of
hypoxia, OTOF abnormality, OPA1 mutation) typically show excellent outcomes as their pathology is bypassed
by the CI signal.
• In contrast, those with aetiologies with pathological sites at or proximal to the SGN (i.e., those who have
suffered kernicterus or show auditory nerve/brainstem disorder) obtain variable results as the signal provided
by the implant must still pass through a disordered neural system (Rance & Starr, 2015).
Summary
• AN is a clear example of a “bottom-up” type processing disorder.
• Affected individuals show physiologic evidence of neural transmission
disorder in the auditory brainstem that results in a unique pattern of
perceptual deficits.
References
• Geffner, D. (2017). Auditory processing
disorders : Assessment, management, and
treatment, third edition. Plural Publishing,
Incorporated.

• Additional Reading
• What Is Auditory Neuropathy? — Causes &
Treatment | NIDCD (nih.gov)
THANK YOU