2012 Vol.7 No.

JOURNAL OF SPECIAL PAPER IN CELEBRATION OF PROF.

OTOLOGY YANG'S 50 YEARS CAREER IN MEDICINE

Diagnosis and Treatment of Auditory Neuropathy and Related Research

JI Fei , YANG Shiming

Introduction In 1991, Starr et al [2] reported one case in which

ABRs were missing with moderate low frequency hear-
Deafness is one of the most common otologic diseases ing loss, deteriorated speech discrimination and absent
and a major disease that greatly impacts the Chinese pop- acoustic reflex, but normal CM and OAEs. Psychophysi-
ulation. From the Second National Sample Survey of cal studies showed impaired timing cue perception but
Disabled Persons, it is estimated that there are 27,800, unaffected intensity and frequency cue perceptions. The
000 hearing disabled persons in China, about 2.14% of authors believed that the lesion locations in such cases
the population. Hearing disability continues to increase might include the auditory nerve, synapses, IHCs and, to
at a rate of 30,000 hearing impaired newborns per year a small degree, OHCs. In 1992, GU Rui et al reported
and is at the top of the six major disabilities. In the clinic, 16 cases of bilateral sensorineural hearing loss with un-
different types of hearing loss are treated differently matched speech discrimination and pure tone thresholds,
based upon our understanding of their pathogenic mecha- and absent or abnormal ABRs. Except for the two cases
nisms and hearing-speech loss characteristics, but the in which cerebral atrophy or brainstem tumor were be-
recently noticed auditory neuropathy (AN) lacks thor- lieved to the underlying etiology, there was no evidence
ough research and standard effective management [1]. of neurological pathologies in the rest 14 cases [9]. Starr
AN is a clinically unique disease characterized by deteri- et al conducted follow up studies on similar cases and re-
oration of temporal processing and intact outer hair cell ported 10 cases of seemingly intact cochlear function but
(OHC) functions [2-4]. From the literature, AN may account deteriorated temporal auditory processing in 1996. In 8
for up to 10% of cases of severe or profound hearing of these cases (80% ), there was evidence of auditory
loss [5]. Studies have shown that lesions in AN may involve nerve pathology [1]. Based on these works, Starr et al be-
inner hair cells (IHCs), synapses and auditory nerve lieved that the pathological process in these patients was
trunk, but the main challenge now is the lack of clear similar to that in peripheral sensory neuropathy, includ-
localizing diagnosis which leads to uncertainties in its ing loss of afferent nerve fibers, demyelination and par-
intervention [6]. tial demyelination in surviving nerve fibers, and for the
first time proposed the concept of AN in describing this
Discovery and naming of AN group of patients [1]. The term fitted well in the clinical
observations at the time.
In the 1980s, a few researchers noticed ABR waves Increasing clinical evidence has shown that, among
and thresholds that were not explainable by pure tone patients diagnosed with AN, the rate of accompanying
audiometric results in a small number of patients. For neurological pathologies is significantly lower than that
example, Worthington et al reported 4 cases with reason- in Starr’s initial report [5]. Researchers have later real-
able audiograms but no ABRs or significantly inappropri- ized that lesion sites in these patients are not limited to
ate ABR thresholds [7]. Krause et al reported 7 cases in the auditory nerve, but lesions at IHCs, synapses and the
which audiometry showed normal hearing or moderate auditory nerve trunk can all lead to symptoms in AN and
hearing loss with no history of brainstem injury, but hair cells and synapses are probably more likely to be in-
ABR waves III and V were missing [8]. These cases gen- volved. This adds increased controversy in the naming
erated little interests at the time. of this type of disease. Rapin and Gravel believe that,

Affiliation: Corresponding authors:

Department of Otolaryngology Head and Neck Surgery, YANG Shi-ming, Email:[email protected]
PLA General Hospital, Beijing 100853
PLA Institute of Otolaryngology
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unless there is evidence of auditory nerve damage, the children. It may be diagnosed at newborn times and
term "auditory neuropathy" may not be appropriate. should be suspected in children failing hearing screening
They propose the use of a broader definition of "nerve or deemed at high risk.
conduction disease" [10]. Others have proposed using the Etiologies leading to AN clinical presentations may in-
double meaning term "auditory neuropathy/auditory clude neonatal hyperbilirubinemia, degenerative neural
dys-synchronization (or AN/AD)" [4, 11]. At the Internal diseases, metabolic neural diseases, hereditary motor
Conference on Diagnosis and Intervention of Auditory neuron diseases, demyelination diseases, inflammatory
Neuropathy in Italy in 2008, a guide line for differential neural diseases, ischemic/hypoxic neuropathy, cerebral
diagnosis and intervention of AN in children was pro- edema, cerebral palsy, abnormal release of neurotrans-
posed, which named this class of diseases as"auditory mitters, infectious diseases (e.g. parotiditis), autoim-
neuropathy spectrum disorder"(or ANSD) [12, 13]. The two mune diseases and development retardation. From the
mainstream terms at this time are AN and ANSD. In latest literature, neonatal hyperbilirubinemia and hypox-
consideration of its broad use in the clinic, AN is used in ia are the most important risk factors [18]. Gene mutation
this report to refer to the condition in this group of pa- is another major cause for some AN phenotypes, espe-
tients. cially in AN children with non-syndromic pre-lingual
deafness.
Epidemiology and etiology of AN
AN clinical audiology characteristics and
Summarized in Table 1 are epidemiology reports regard- diagnosis
ing AN in the literature. It shows that the rate of AN is
about 7% to 13.4% (average 10%) among children with Currently, reported clinical characteristics vary greatly
confirmed diagnosis of severe or profound hearing loss [5, among AN patients. Clinically, compromise of auditory
14-19]
, with a matched gender ratio [19, 20]. When the average nerve activities are represented by abnormal or absent
hearing screened newborn population is used, the rate ABRs, absence or elevated thresholds in acoustic reflex
falls blow 1% [17, 20]. Among all age populations or with absent or weak contralateral inhibition, etc. Cochle-
deaf-mute school students, average rate of AN is below ar function indicators such as otoacoustic emissions
3% [21-24]. These data show that AN rate decreases as (OAEs) and cochlear microphonic (CM) are usually nor-
patient age increases. From this, it is speculated that AN mal. There are also unique psychophysical presentations.
may be a condition related to hereditary and/or peri-natal Clinical complaints or functional hearing loss in AN
factors and may be present in about 10% of high risk patients are reflected mainly through psychophysical

Table 1. AN Prevalence in Literature Reports

Year Authors Study Subjects AN/Total n Prevalence (%)

1999 Rance et al [20] Children with severe or profound hearing loss 1/9 11.100
2002 Siniger et al [26] Patients in NIDCD sponsored newborn hearing screening Review 10.00
[21]
2005 Cheng et al Students in US deaf and mute schools 76/777 9.78
2006 Foerst et al [23] Children with severe SNHL 32/379 8.44
2008 Vlastarakos et al [24] Children with confirmed hearing loss Meta-analysis 8.00
[7]
2009 Sanyelbhaa Children with severe or profound hearing loss 15/112 13.40
[8]
2010 Berlin et al Children with hearing loss Review >10.00
[27]
2009 Dowley et al Children with severe SNHL 12/30 40.00
2006 Foerst et al [23] Average newborns 32/3415 0.94

2009 Dowley et al [27] Average newborns 12/45050 0.03

2006 Kumar et al [29] Adult SNHL patients 1/183 0.55

[30]
2004 Tang et al Students in HK deaf and mute schools 3/123 2.44
2007 Lotfi et al [31] Students in deaf and mute schools 13/841 1.55
2001 Lee et al [32] Students in deaf and mute schools 2/81 2.50

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testing. Because psychophysical testing requires cooper- rooms for debate over if AN can be diagnosed based on
ation by the patient, its results are available only from CM linearity data.
older children and adults. Among AN patients reported Simultaneous presence of the two indicators discussed
in the literature, pure tone hearing loss ranges from mild above is a necessary requirement (inclusion criteria) for
to profound, although mild and moderate in most cases. differentiation from other sensorineural hearing loss and
Audiogram patterns are also variable, although dominat- diagnosis of AN. Almost all AN subjects in the reported
ed by ascending patterns [25]. Speech discrimination dis- literature have been identified using these two condi-
orders are the most difficult for AN patients, typically tions [5]. Combined testing of ABRs, CM and OAEs pro-
showing unproportionally poor discrimination contrasted vides information regarding diseases locations along the
to pure tone thresholds, especially in noise [4, 26]. Middle auditory pathways including OHCs, auditory nerve and
ear muscle reflex and olivocochlear reflex are important brainstem, although there still lacks means to identify
to hearing in noise. These are compromised in AN pa- diseases at IHCs and pre- or post-synaptic locations.
tients, i.e. loss of efferent inhibition. This may explain
the poor speech discrimination in noise. Zeng et al Electrophysiological characteristics of AN
found that AN patients had decreased sensitivity to tem-
poral envelop fluctuation and speculated that speech dis- The CM, summiting potential (SP), compound action
crimination difficulties in AN patients might be related potential (CAP) and central auditory evoked potentials
to compromised temporal processing [3]. Compromised (CAEPs) in AN patients all have distinct features that
timing cue perception may affect low frequency discrimi- can be used to differentiate sub-types of AN and facili-
nation, temporal separation perception, timing integra- tate clinical diagnosis and intervention.
tion, temporal modulation perception, forward and back- Starr [29] and Santarelli [30] found that click induced CM
ward masking, signal recognition in noise, binaural beat, in AN children is abnormally large in amplitude. SHI
interaural temporal difference based sound localization, Wei et al [28] concluded that non-linearity in CM I/O
etc. On the other hand, intensity cue perception, such as curve indicates intact OHCs but is insufficient to deter-
intensity discrimination and interaural intensity differ- mine the status of IHCs.
ence based sound localization, is no different in AN pa- Round window electrocochleography (RW ECoG) us-
tients from normal individuals [27]. es transtympanic electrode to record cochlear responses
Among existing diagnostic criteria for AN, the only and provides increased details in information regarding
widely accepted mandatory one is "absent or abnormal the cochlea and VIIIth cranial nerve. Studying the SP
ABRs", which represents disruption to synchronicity in and AP in RW ECoG in conjunction with observation of
activities along the auditory pathway. All patients includ- abnormal positive potential (APP) [30] or dentritic poten-
ed in AN studies so far show this presentation. Abnor- tial (DP) [31] may help locating the AN disease site.
mal ABRs in AN usually refer to inappropriate ABR O'Leary et al were the first to report SP with delayed
morphology or thresholds not anticipated based upon latencies and increased amplitudes (i.e. APP) on RW
pure tone thresholds. This is probably the most distinct ECoG in some children with profound hearing loss [32].
clinical feature in AN. Another necessary presentation is Santarelli [30] and McMahon et al [31] later also recorded
"intact OHC function", as represented by existence of APP in some AN children. Santarelli divided RW ECoG
OAEs or CM or both. It is widely accepted that OAEs findings in AN patients into three groups: 1) presence of
originate from OHCs, but whether CM is solely from both SP and CAP, indicating postsynaptic lesions at prox-
OHCs or may contain contributions from IHCs is still imal auditory nerve endings; 2) presence of SP with
being debated. Because of this, when OAEs are not pres- absence of CAP, indicating pre-synaptic lesions at IHCs;
ent, CM may not be the definite indication of "intact and 3) increased SP amplitude with delayed latencies (or
OHC function". Some believe that the linearity of CM APP) and no CAP, representing pre-synaptic lesions, per-
input/output (I/O) curve reflects the presence of OHCs haps from compromised neurotransmitter release pro-
[28] and that perfect linearity represents loss of OHC cess [30]. McMahon et al [31] believed that APP represent-
compression functions and only contributions from ed pre-synaptic damage, but the mechanisms may be
IHCs. On the other hand, non-linearity in CM I/O similar to that causing increased SP amplitude in pa-
curves indicates intact OHC function, although this does tients with endolymphatic hydrops (i.e. bias shift of IHC
not necessarily provide information on IHCs. Used togeth- cilia toward an "off" position). In their study, SP latency
er with ABR results, OAEs can be an important indicator was normal, followed by a long negative potential, in
of AN. However, linearity measurement has not been some AN patients, which was considered as a DP indicat-
quantified and its relations with OHC function have not ing post-synaptic damage. In general, presence of APP
been confirmed by laboratory or clinical data, leaving appears to indicate pre-synaptic damage or damage to

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the sensory cells, whereas obvious DP may indicate

post-synaptic damage or damage to the auditory nerve.
Therefore, RW ECoG wave analysis may help formulating
audiological intervention strategies for AN patients. The
14 AN children in McMahon's report all received cochlear
implant [31]. Electrically evoked ABR (EABR) waves were
poorly differentiated in children with SP + DP, showing
that neural synchronization was not improved by electrical
stimulation. EABRs, however, were normal in children
withAPP. Gibson and Sanli[33] reported similar findings.
Auditory evoked potentials originating from the thala-
mus and cerebral cortex may provide hearing capabili-
ties in AN patients. The P1-N1-P2 components in
CAEPs arise from primary auditory cortex in the trans-
verse temporal gyrus. The important CAEP mismatch
negativity (MMN) comes from the planum temporale
outside the auditory cortex and from the lateral posterior
temporal gyrus and can be viewed as an indicator of
pre-cortical hearing discrimination. MMN in AN chil-
dren indicates retained coding of auditory information at Figure 1. Left: Schematic representation of connection
a cortical level. Such CAEP testing may provide objec- of afferent auditory nerve fibers to an IHC via synapses.
tive means in evaluating auditory threshold and speech Upper right: Temporal responses of a number of audito-
discrimination capability in AN patients, especially in ry nerve fibers to a stimulation signal. Black arrows -
children who are unable to cooperate or use hearing aids normal responses; gray arrows - abnormal nerve fiber re-
or cochlear implants. Current research data support the sponses. Bottom right: Gross auditory nerve response to
notion that presence of CAEPs (including MMN) is cor- the transient stimulus. Abnormal nerve fiber responses
related to speech discrimination in AN children. Rance include: a) greatly variable discharge latencies, i.e. poor
et al [34] reported CAEP testing in 18 AN patients, show- synchronicity; and b) reduced number of responding
ing that normal CAEPs were correlated to better speech nerve fibers, i.e. decreased neural discharges [6].
discrimination than those with poor CAEPs. Speech dis-
crimination scores in AN children with positive MMN al-
The accuracy of auditory temporal coding is main-
so seem to be superior over those without. Pearce et al
[35] tained by multiple physiological mechanisms. IHCs are
applied CAEP testing in 2 infants diagnosed with AN.
the cells that provide sound information to the central
Hearing aids were chosen for the one with positive
nervous system. Each IHC synapses with multiple inde-
CAEPs and cochlear implant for the one in whom
pendent afferent nerve fibers and each synapse is able to
CAEPs could not be induced with or without assistance.
release glutamate to activate rapid depolarization. Gluta-
Despite the above mentioned electrophysiology tests,
mate released in the process quickly opens the post-syn-
the sensitivity and specificity of these tests remain to be
aptic AMPA glutamate receptor. The excitatory post-syn-
further studied for hopefully their utility as an objective
aptic currents (EPSCs) at the nerve ending show rapid
means in evaluating hearing and speech discrimination
rising and falling, allowing fast repetitive discharges in
capability in young AN children and in predicting inter-
short time. Similar nerve sizes mean similar transduc-
vention outcomes.
tion velocity, leading to optimal synchronization in dis-
charges. As it approaches the node of Ranvier, signal
Pathophysiological mechanisms of AN
conduction assumes a saltatory (jumping) pattern, great-
ly increasing the speed of conduction. Under normal cir-
Possible lesion sites in AN include IHCs, IHC ribbon
cumstances, all nerve fibers fire in a very short period of
synapses and auditory nerve trunk. Damage at these lo-
time with in a very coherent manner. If neurotransmitter
cations may lead to two neurophysiology consequences
[27] release is disrupted by IHC lesions, or if the number or
: 1) loss of synchronization of neural discharges from
sensitivity of receptors is compromised by synaptic le-
auditory nerve demyelination and/or synaptic dysfunc-
sions, or if conduction velocity is impeded by nerve fi-
tion between the auditory nerve and IHCs; and 2) de-
ber lesions, then the discharge synchronicity and number
crease in neural discharges due to loss of receptors or ax-
of discharging nerve fibers will be impaired and timing
ons (Figure 1).
pattern and magnitude of large scale discharge altered.
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Particular pathological changes that can potentially dis- grossly abnormal while OAEs are present. Auditory
rupt or lower neural conduction synchronicity include pathway dysfunction related to this gene involves only
mechanical changes in hair cells, metabolic changes loss of the spiral ganglion, with no peripheral or cranial
within hair cells, compromised release and re-uptake of nerve neuropathy.
neurotransmitters, decrease in receptor sensitivity and These animal models have served to guide clinical
impaired discharge initiation at nerve endings, as well as treatment for AN, i.e. cochlear implant can be expected
pathologies involving neurotransmitters, axons and my- to produce good results in patients with presentations
elin sheath. corresponding to animal models of IHC and synaptic le-
At this time, the best evidence to support existence of sions, whereas it usually fails in those with presentations
AN is presence of accompanying peripheral or cranial corresponding to models of auditory nerve or central au-
nerve neuropathy. If such neuropathy is absent and there ditory pathway damages.
is clear auditory responses to electrical stimulation,
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