Auris Nasus Larynx: Kimitaka Kaga

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ANL-1997; No. of Pages 11

Auris Nasus Larynx xxx (2015) xxxxxx
Contents lists available at ScienceDirect
Auris Nasus Larynx

journal homepage: www.elsevier.com/locate/anl
Auditory nerve disease and auditory neuropathy spectrum disorders

Kimitaka Kaga a,b,*
a
b
National Institute of Sensory Organs, National Tokyo Medical Center, Japan

Center for Speech and Hearing Disorders, International University of Health and Welfare, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 30 April 2015
Accepted 29 June 2015
Available online xxx
In 1996, a new type of bilateral hearing disorder was discerned and published almost simultaneously by
Kaga et al. [1] and Starr et al. [2]. Although the pathophysiology of this disorder as reported by each
author was essentially identical, Kaga used the term auditory nerve disease and Starr used the term
auditory neuropathy.
Auditory neuropathy (AN) in adults is an acquired disorder characterized by mild-to-moderate puretone hearing loss, poor speech discrimination, and absence of the auditory brainstem response (ABR) all
in the presence of normal cochlear outer hair cell function as indicated by normal distortion product
otoacoustic emissions (DPOAEs) and evoked summating potentials (SPs) by electrocochleography
(ECoG). A variety of processes and etiologies are thought to be involved in its pathophysiology including
mutations of the OTOF and/or OPA1 genes. Most of the subsequent reports in the literature discuss the
various auditory proles of patients with AN [3,4] and in this report we present the proles of an
additional 17 cases of adult AN. Cochlear implants are useful for the reacquisition of hearing in adult AN
although hearing aids are ineffective.
In 2008, the new term of Auditory Neuropathy Spectrum Disorders (ANSD) was proposed by the
Colorado Childrens Hospital group following a comprehensive study of newborn hearing test results.
When ABRs were absent and DPOAEs were present in particular cases during newborn screening they
were classied as ANSD. In 2013, our group in the Tokyo Medical Center classied ANSD into three types
by following changes in ABRs and DPOAEs over time with development. In Type I, there is normalization
of hearing over time, Type II shows a change into profound hearing loss and Type III is true auditory
neuropathy (AN). We emphasize that, in adults, ANSD is not the same as AN.
2015 Elsevier Ireland Ltd. All rights reserved.
Keywords:
Auditory nerve disease
Auditory neuropathy
Auditory neuropathy spectrum disorders
DPOAE
ABR
OTOF
OPA1
Part I. Auditory Neuropathy (AN) in Adults (Acquired AN)

1. Introduction
In 1996 a new type of bilateral hearing disorder was discerned
and published almost simultaneously by Kaga et al. [1] and Starr
et al. [2]. Although the pathophysiology of this disorder as reported
by each author was essentially identical, Kaga used the term
auditory nerve disease and Starr used the term auditory
neuropathy. For clarity, the term auditory neuropathy will
subsequently be used in this article.
Auditory neuropathy (AN) in adults is an acquired disorder
characterized by mild-to-moderate pure-tone hearing loss, poor
* Correspondence to: National Institute of Sensory Organs, National Tokyo

Medical Center, 2-5-1 Higashigaoka, Meguro-Ku, Tokyo 152-8902, Japan.
Tel.: +81 3 3411 0111.
E-mail address: kaga@kankakuki.go.jp
speech discrimination and absence of the auditory brainstem

response (ABR) all in the presence of normal cochlear outer hair
cell function as determined by normal distortion product
otoacoustic emissions (DPOAEs) and evoked summating potentials
(SPs) by electrocochleography (ECoG). A variety of processes and
etiologies are thought to be involved in its pathophysiology
including mutations of the OTOF and/or OPA1 genes. Most of the
reports in the literature discuss the various auditory proles of
patients with AN [3,4] and in this review we present the proles of
additional 17 cases of adult AN.
It should be considered that there are differences between
AN and cortical hearing loss. ABR in AN is absent but in
central hearing loss by brain damage is present. However, there
are similarities in AN and hearing loss caused by acoustic
tumor, ABR in AN is absent or wave I only or prolongation of
wave V-Latency. Moreover, Temporal Bone CT scans or MRI
study have demonstrated, no abnormality in our 17 AN cases.
In the literature of AN papers, no abnormal ndings were
reported.
http://dx.doi.org/10.1016/j.anl.2015.06.008
0385-8146/ 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Kaga K. Auditory nerve disease and auditory neuropathy spectrum disorders. Auris Nasus Larynx
(2015), http://dx.doi.org/10.1016/j.anl.2015.06.008
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K. Kaga / Auris Nasus Larynx xxx (2015) xxxxxx
2
Table 1
Prole of 17 adult AN cases.
Case No.
Present age
Onset age
Remarks
16
6
Brain infarction
22
11
Visual
disturbance
22
11
Charcot-Marie-Tooth Disease
27
15
31
6
Viral
cerebellitis
57
15
60
35
72
15
24
22
Visual
disturbance
OPA1
Gene mutation
Case No.
10
11
12
13
14
15
16
17
Present age
Onset age
Remarks
28
10
Temperature-sensitive
61
36
Head trauma
79
64
Head
trauma
42
13
Charcot-Marie-Tooth
Disease Cochlear Implant
20
14
Visual disturbance
25
16
Optic atrophy
44
42
Cochlear implant
Gene mutation
OTOF
28
17
Visual
disturbance
OPA1
OPA1
2. Auditory Proles of the 17 cases of AN in this study

Proles including the present age, onset age, gene mutations
and remarks of our 17 patients with acquired AN are summarized
in Table 1.
In Fig. 1, the DPOAEs, ECoGs and ABRs from both normal hearing
and sensorineural hearing loss and AN patients are illustrated for
comparison.
In Fig. 2, illustrates a typical pure tone audiogram, speech
audiogram, DPOAEs, ECoG and ABR of an AN patient (Case 1).
In Fig. 3, pure tone audiograms of all of our 17 patients are
shown. Low frequency hearing loss and/or mild or moderate
hearing loss are common ndings.
In Fig. 4, speech audiogram scores to monosyllables are shown.
Very poor speech discrimination is also common in most patients
except in Cases 4, 9, 10 and 14.
In Table 2, objective audiometric ndings (DPOAEs, ECoGs and
ABRs) are summarized and are explained as below:
2.1. Otoacoustic emissions (DPOAEs)

All of our patients had normal DPOAEs from both ears.
2.2. ECoGs
ECoGs from all of the 17 patients were classied into three
subtypes.
Type I shows a denite SP, a normal CM and a normal N1.
Type II shows no SP, a normal CM and no N1.
Type III shows no SP, no CM and no N1.
2.3. ABR and ASSR

ABRs and ASSR from all of our patients were absent. In AN, ASSR
as objective audiometry are absent as well as ABRs because ASSR
composes of ABR and MLR.
Fig. 1. Comparison of DPOAEs, electrocochleography (ECoG) and ABRs in normal, sensorineural hearing loss and AN.
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Fig. 2. The original audiological ndings of AN by Kaga et al. (Case 1) [1]. (a) Audiogram, (b) DPOAE, (c) Speech Audiogram, (d) EcoG, (e) ABR.
3. Vestibular function test in AN

There is very little information in the literature regarding the
involvement, if any, of the vestibular system in AN. In light of this,
we administered a vestibular system assessment (ENG and VEMP)
to most of our 17 AN patients.
ENGs were recorded by electrodes at the outer canthi of each
eye. External auditory meati were irrigated with 2 cm3 of ice
water to induce a thermal gradient across the horizontal
semicircular canal. Caloric stimulation provoked normal horizontal nystagmus in only 7 of our 17 patients and abnormal
responses in 10 patients (hypofunction for 5 patients and no
response in 5 patients).
Vestibular evoked myogenic potentials (VEMPs) were
obtained from 14 patients. Acoustic stimulation (200 clicks at
95 dBnHL at 5 Hz) was administered by earphones. Recordings
were taken from the ipsilateral sternocleidomastoid (SCM)
muscle in 100 ms intervals with a bandpass of 202000 Hz. In
5 of the 14 patients VEMPs were abolished but in 9 patients
VEMPs were adequately elicited (Table 3). Vestibular test
recordings (caloric nystagmus and VEMPs) from Case 7 are
shown in Fig. 5.
Hypofunction or loss of caloric induced nystagmus is
consistent with bilaterally impaired horizontal semicircular
canals and/or the superior vestibular nerve. Absence of the
VEMP is probably the result of pathology of the inferior
vestibular nerve or sacculus.
We suggest the use of the terms auditory neuropathy only
in patients with involvement of only the auditory branch of
the VIIIth cranial nerve and auditory vestibular neuropathy
when both the auditory and vestibular branches are involved. This
terminology may give a more pathophysiological categorization
of this disorder. To reiterate we wish to emphasize the existence
of two distinct entities: AN only and combined auditory and

vestibular neuropathy [4,5].
4. Genetic mutations in AN
Various types of gene mutations in AN involving MPZ [6], OTOF
[710], OPA1 [11,12], DMP22 [13,14] have been reported in the
literature. In our genetic evaluations of our AN patients (Table 1) a
mutation of OTOF was detected in Case 10 only and OPA1 was
mutated in Cases 9, 15 and 17 (Fig. 6). The OTOF gene mutation
is thought to give rise to a synaptic disorder involving the inner ear
hair cells. However, an OPA1 gene mutation is thought to underlie
a cochlear nerve disorder coincident with optic nerve involvement. In our patients in spite of routine study of gene mutation, it
should be noted that mutations of other genes are not evident
except OTOF and OPA1.
5. Temperature dependent AN
There is a very rare condition of temperature dependent AN. In
1998, Starr et al. reported transient deafness (AN) in three children
due to a sensitivity to changes in temperature. This was manifest as
a conduction block of the auditory nerve and transient deafness in
the presence of normal cochlear outer hair cell function concurrent
with a rise in their core body temperature [15].
Since then a few case reports have appeared in the literature,
from various countries, of temperature dependent AN in children
(Cianfrone et al. [16] and Marlin et al. [17]) all associated with an
otoferlin mutation. The pathophysiology of transient deafness
due to temperature dependent AN is unknown. A few theories
have been proposed such as a demyelinating disorder [15],
conduction blockage in the synapse between the inner hair
cells and eight nerve bers [16] and temperature sensitive
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Fig. 3. Pure tone audiograms of 17 adult AN cases.
mutations affecting an amino acid conserved in mammalian

otoferlin sequences located in the calcium-binding domain C2F of
the protein [17].
In Fig. 7, the pure-tone and speech audiograms from a 29-yearold man (Case 10) with temperature dependent AN during both
afebrile and febrile states before and after jogging and a hot bath
are illustrated. When his temperature became elevated his hearing
was transiently impaired. His DPOAEs were normal, his ECoGs
showed normal SPs and normal CMs but no N1. His ABRs were
absent. His vestibular assessment showed normal caloric and
VEMP responses. He suffers from transient deafness every time he
takes a bath or hot sauna.
Temperature sensitive AN may be due to temperature
dependent synaptic transmissions in inner ear hair cells.
6. Cochlear implant
Most patients with adult AN can maintain reasonable speech
communication by using their residual hearing and on speaking
face-to-face but they have communication difculty in noisy
environments, meetings and using the telephone. Hearing aids
are useless in AN patients. However, a small number of AN
patients cannot effectively communicate in spite of having only a
mild low tone hearing loss. In these patients, cochlear implantation has been found to be useful for enabling speech and overall
communication and a majority of these patients can achieve
average to above average performance [18,19]. This reacquisition
after implantation may be due to the reintroduction of neural
synchrony by electrical stimulation because the electrical
ABR after cochlear implantation is well elicited. In Table 1, Cases
13 and 16 underwent cochlear implants unilaterally and they can

communicate well with others.
Part II: Auditory Neuropathy Spectrum Disorders (ANSD) in
newborns
1. Introduction
Auditory neuropathy spectrum disorders (ANSD) is a new
classication which was proposed by the Colorado Childrens
Hospital group in 2008 and dened as normal DPOAEs and absent
ABRs in newborns [20]. The term ANSD is derived from Autism
Spectrum Disorder.
Newborn hearing screening has been conducted in many
countries using Automated ABR (AABR) since Itanos Paper in 1998
[21]. When AABRs are found to be absent in these newborns then
DPOAEs are administered as a second step. If DPOAEs are present with
no evocable AABRs then these newborns are classied as ANSD [22].
In 2013, our group in Tokyo Medical Center classied ANSD into
three types (Table 4). However, we reiterate that AN is not same as
the ANSD.
2. Classication of studies of ANSD
Table 4 presents our classication of typical cases of ANSD in
infants and children with ANSD as a result of our follow up studies.
Type I: Developmental change to normalization of hearing.
There are two subtypes:
Type I-a. At birth DPOAEs are normal and ABRs are initially
completely absent. Over time, DPOAEs remain normal but the
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Fig. 4. Speech audiograms of 17 adult AN cases.
Table 2
Objective audiometry from 17 adult AN cases.
Case No.
DPOAE
ECoG
+
SP
+
SP
+
SP
+
SP
+
SP
+
SP
+
SP
10
11
12
13
14
15
16
17
SP
SP
N1
SP
SP
SP
N1
ABR
( ): absent,
SP:
N1: small compound action potential.
Table 3
Vestibular function tests of 17 adult AN cases.
Case No.
10
11
12
13
14
15
16
17
Caloric
VEMP
N
+
( )
hypo
hypo
+
hypo
( )
hypo
+
N
+
N
+
hypo
+
( )
+
( )
+
( )
+
Caloric test: N; normal function, hypo; hypofunction, ( ); no function.

VEMP: +; normal response, ; no response.
ABR begins to appear and ultimately shows a normal wave

conguration. Patients are able to acquire normal speech and
hearing (Fig. 8).
Type I-b. At birth DPOAEs are normal but the ABRs consist of
only waves I and II. In this subtype the ABR develops a normal
wave conguration over time and patients are able to acquire
normal speech and hearing (Fig. 9).
Type II. Developmental change to profound hearing loss
As newborns, DPOAEs are normal but ABRs are completely
absent. However, as early infants the DPOAE disappears and
patients manifest a profound hearing loss with development
(Fig. 10). Type II cases are good candidates for cochlear implant.
Early cochlear implant is very effective for speech and hearing

acquisition. Type II may be considered a transient ANSD which
changes to a congenital profound hearing loss.
Type III: Congenital AN
Type III newborns have normal DPOAEs and no evocable ABRs.
This prole does not change with the infants development
over time (true AN) and its occurrence rate is the lowest of the
three types. However, within Type III there seems to exist a true
AN and a pseudo AN.
Type III-a (true AN) is a good candidate for cochlear
implantation because of poor ability to acquire speech and
hearing even when aided.
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Fig. 5. Vestibular function tests of an adult AN case (Case 7). (a) Caloric test, (b) VEMP.
Type III-b (pseudo AN) is not a good candidate because children

in this group are able to acquire speech and hearing without a
hearing aid over time.
Fig. 11 shows a typical case of Type III-a. This type is a true
congenital AN. This boys speech and hearing did not develop
even when aided. He underwent a cochlear implant at 3 years of
age and he was then educated in an auditory oral school for the
deaf. Seven years after cochlear implant he is now able to speak
very well and his auditory speech perception test results are
very good. Fig. 12 shows a Type-III-b (pseudo AN). In this type,
children are able to hear and speak well naturally as they
develop although their ABRs are persistently absent in the

presence of normal DPOAEs. Most of these neonates are born
with extremely low body weight, between 400 and 800 g.
Cochlear implants are contraindicated in Type III-b because as
these children develop they can hear and speak well with
improvement of their behavioral audiometry (BOA) thresholds
although their DPOAEs and ABRs do not change over time. ANSD
cases should be followed up by frequent examination of DPOAE
and ABR for observing developmental changes. Therefore, age of
CI should be waited until age of one year at least. We should be
very careful to conduct wrong cochlear implantation.
Fig. 6. Audiological ndings of Case 9 with an OPA1 gene mutation. (a) Audiogram, (b) Speech Audiogram, (c) DPOAE, (d) ABR.
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Fig. 7. Changes in the pure-tone and speech audiograms in Case 10 of temperature-sensitive. AN with an OTOF gene mutation. (a) June 3, 2011. BT: 36.8 8C, (b) June 6, 2011. BT:
37.2 8C, After Jogging & Bathing.
3. Radiological study
Jeong and Kim [26] reported retrospectively in ANSD. Those
radiologic ndings of normal bony cochlear nerve canal and
normal cochlear nerve correlated with excellent speech
perception abilities after CI but a narrow or obliterated bony
cochlear nerve canal and a decient cochlear nerve correlated
with poor speech. However, in this study repetitive measurements of DPOAE and ABR until CI were not shown. In our other
Table 4
Classication of subtypes of ANSD as used by the National Tokyo Medical Center
since 2013.
Type I: Developmental changes to normalization of hearing
I-a
Normalization from absent ABR.
I-b
Normalization from Wave I & II of ABR.
Type II: Developmental changes to profound hearing loss
Disappearance of DPOAE and change to
profound hearing loss.
Cochlear implant candidate.
Type III: Congenital auditory neuropathy
III-a
True auditory neuropathy.
Poor auditory perception.
Cochlear implant candidate.
III-b
Pseudo auditory neuropathy. No indication
of cochlear implant.
case studies, early infants with obliterated bony cochlear nerve

canal or decient cochlear nerve investigated by CT and MRI
demonstrated profound hearing loss with absent of DPOAE. Thus,
outcome of following up DPOAE and ABR are critical problems at
present. Our classication of subtypes of ANSD is expected to
solve this issue.
4. Genetic mutation
Matsunaga et al. [10] studied deafness genes in Japanese infants
presenting with ANSD and found a high incidence of mutation in
the GJB2 and OTOF genes and suggested that there may be a
mixture of congenital deafness and true AN and a genetic
evaluation of these infants can contribute to a more precise
diagnosis of ANSD.
Finally, we emphasize that ANSD infants should be carefully
followed and repeatedly examined by DPOAEs, ABRs and
behavioral audiometry before considering a cochlear implant.
Pediatric cochlear implantation in the presence of profound
hearing loss (Type II) and true congenital AN (Type III-a) is very
effective for the development of speech and hearing [2325]. Type
I-a, Type I-b and Type III-b are not good candidates for cochlear
implants because of these childrens ability to develop good speech
and hearing. In infants with detectable ANSD we should very
carefully and serially monitor with DPOAEs, ABRs and behavioral
audiometry and wait for their possible development of relatively
normal speech and hearing.
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Fig. 8. Type I-a. Normalization of an absent ABR in a 640 g birth weight female.
Fig. 9. Type I-b. Normalization of only Wave I and II of the ABR in a-3-year-old female. (a) DPOAE, (b) ABR.
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Fig. 10. Type II. Developmental change to profound hearing loss. DPOAEs disappear with development (A well baby). (a) DPOAE, (b) ABR, (c) PTA.
Fig. 11. Type III-a. Congenital auditory neuropathy with speech and hearing problems. Audiological ndings of pre and post CI (Preoperative: a-3-year-old boy, (a) COR, (b)
ABR, (c) DPOAE; Postoperative: a 11-year-old, (a) DPOAE, (b) Perception of monosyllables).
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10
Fig. 12. Type III-b. Pseudo auditory neuropathy without speech and hearing problem (a well baby). (a) DPOAE (9 days after birth), (b) ABR (9 days after birth), (c) Changes of COR.
Conclusion of adult AN and ANSD in newborns

ANSD in newborns is not the same as AN in adults (acquired
type). Various hypotheses of the pathophysiology of AN are
proposed: presynaptic or postsynaptic disorders of synapses
between inner hair cells and the cochlear nerve, desynchronization
within the cochlear nerve, demyelination or axonal atrophy of the
cochlear nerve. Genetic mutations in AN involving OTOF, OPA1 and
other genes have been reported [27,28]. However, there is the
possibility of unknown mutations because the reported gene
mutations are not commonly detected.
Cochlear implantation in adult AN patients and in infants with
ANSD, which progresses into profound hearing loss or does not
progress with development (true congenital AN) is very effective
in the reacquisition of good speech and hearing. The essential
pathophysiology of AN can be either pre- or postsynaptic and
involve pathology between the inner ear hair cells and the
cochlear nerve.
Conict of interest
The authors report no conicts of interest.
Acknowledgements
This research is supported by the Health and Labor Sciences
Research Grants for Comprehensive Research on Persons with
Disabilities from Japan Agency for Medical Research and Development, AMED. I thank Ms. Kayoko Sekiguchi for her unlimited
secretarial effort and Dr. Dominic Hughes, Ph.D. for his scientic
advice and English language editing.
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ANL-1997; No. of Pages 11

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