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Clinical and Audiological Features in Auditory Neuropathy
Colm Madden, FRCSI;
Michael Rutter, FRCS;
Lisa Hilbert, MA;
John H. Greinwald, Jr, MD;
Daniel I. Choo, MD
Arch Otolaryngol Head Neck Surg. 2002;128:1026-1030.
ABSTRACT
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Objective To medically and audiologically characterize a population of children
diagnosed as having auditory neuropathy (AN).
Study Design Retrospective medical chart review.
Setting/Subjects We identified 22 patients from a pediatric otology clinic in a tertiary
care pediatric hospital setting.
Results A genetic factor in AN is suggested by our identification of 3 families
with 2 affected children and 2 other children with family histories that were
positive for hearing loss. Clinical features common among our population included
a history of hyperbilirubinemia (n = 11 [50%]), prematurity (n = 10 [45%]),
ototoxic drug exposure (n = 9 [41%]), family history of hearing loss (n =
8 [36%]), neonatal ventilator dependence (n = 8 [36%]), and cerebral palsy
(n = 2 [9%]). Full clinical and audiological data were available for 18 of
the 22 children, including otoacoustic emissions, auditory brainstem responses
with cochlear microphonics, and age-appropriate audiometric findings. Significantly,
9 of these 18 patients showed improvement in behavioral thresholds over time,
indicating that a subset of children with AN may recover useful hearing levels.
Also significant was the success of cochlear implantation in 4 children.
Conclusions Management of AN in children requires serial clinical and audiometric
evaluations, with a prominent role for behavioral testing. Prematurity, genetics,
and hyperbilirubinemia appear to be significant factors in the development
of AN; hyperbilirubinemia can be associated with spontaneous improvement of
hearing thresholds. For those children not benefiting from amplification or
FM systems, cochlear implantation remains a potentially successful method
of habilitation.
INTRODUCTION
AUDITORY neuropathy (AN) is a hearing disorder characterized by an absent
or severely abnormal auditory brainstem response (ABR), with preservation
of the cochlear microphonics (CM) and otoacoustic emissions (OAEs). Clinically,
AN is defined as (1) hearing loss, usually bilateral, of any degree; (2) normal
outer hair cell function as evidenced by the presence of OAEs and/or CM; (3)
abnormal evoked potentials beginning with wave I of the ABR; (4) poor speech
perception; and (5) absent acoustic reflexes to the ipsilateral and contralateral
tones at a 110-dB hearing level. Starr et al1
described 10 patients, 5 adults and 5 children, who demonstrated these findings
and no other auditory diagnosis on results of clinical, audiological, or radiographic
studies. They coined the term auditory neuropathy.1 The prevalence of AN is not known. Davis and Hirsh2 reported 1 case of AN (0.5%) in 200 patients with
sensorineural hearing loss (SNHL). Other investigators found a higher rate
of prevalence, with Kraus et al3 reporting
a rate of 15% and Rance et al4 of 11% of their
population with permanent hearing loss.
Cases of absent ABRs in the presence of awareness of sound at moderate
or quite low intensities were identified more than 20 years ago.2-3
Some individuals who were diagnosed as having SNHL before OAE testing came
into common use probably had an undetected AN.
Otoacoustic emissions have been used as an objective test of the integrity
of the outer hair cell of the cochlea in patients who are unable to make behavioral
responses (eg, infants) or to confirm behavioral audiometric findings. The
value of the combination of OAEs and measures of neural function at the level
of the eighth cranial nerve and the brainstem has been demonstrated in patients
undergoing clinical assessment for AN.5 Before
the recognition of OAEs, presumptive hair cell function was assessed by recording
CMs generated in response to acoustic signals.
The pathophysiology of AN has been suggested to involve an abnormality
of the peripheral auditory system localized to the inner hair cells, to the
eighth cranial nerve, or to the synapse between them. A disorder at any of
these sites could account for normal OAE findings, loss of ABR potentials,
and disordered speech perception in the presence of relatively preserved pure-tone
thresholds. Based on the finding of normal OAEs, the outer hair cells in the
cochlea are presumed to be normal. The status of the inner hair cells alone
cannot be assessed with any currently available procedure.
The risk factors for the development of AN are only speculative. Perinatal
risk factors such as perinatal intracranial hemorrhage, asphyxia, and hyperbilirubinemia
have been implicated.3 Coincidentally, these
factors have also been implicated in other central neurological pathologies.
Genetic factors may also be involved in the pathogenesis of AN. Bonfils et
al6 reported on a kindred with a dominant inheritance
pattern of a progressive hearing loss with characteristics similar to those
of AN.
This report describes the relatively large single-institution experience
of the Children's Hospital Medical Center, Cincinnati, Ohio, with children
with AN.We herein present the clinical, audiological, and radiographic findings
of this distinct population of patients with AN and describe the treatment
paradigms used based on the natural history of the disorder.
PATIENTS AND METHODS
We performed a medical chart review of the hospital's hearing loss database
for an 8-year period. Criteria for inclusion in the study were as follows:
(1) permanent SNHL, (2) the presence of a CM with a severely abnormal or absent
ABR waveform, and (3) the presence of a transient evoked or distortion-product
OAE at the initial presentation. Complete reviews were made of the otologic
and audiological charts to confirm all database information. All patients
underwent computed tomography of the temporal bones and a comprehensive laboratory
and medical evaluation. The latter included ophthalmologic and genetics consultations,
electrocardiography, renal and thyroid panels, urinalysis, and measurement
of the sedimentation rate and the levels of glucose, syphilis IgG and IgM,
cholesterol, and triglycerides.
Age-specific pure-tone audiometry for the standard frequencies from
250 to 8000 Hz was performed for all children using conventional, play, or
behavioral means. Tympanometry was also performed at the time of testing.
Click-evoked distortion-product OAEs were measured at click levels of
65- and 55-dB peak sound pressure for the f1 and f2 components. The noise
floor for the distortion-product OAEs was 8 dB, with waveform reproducibility
in at least 3 octave bands of more than 75%.
Auditory brainstem evoked potentials were recorded in a single-electrode
configuration, in a channel running from the forehead to the ipsilateral ear
using a band-pass filter between 100 and 3000 Hz. Click stimuli consisted
of 1 run of condensation followed by 1 run of rarefaction clicks presented
monaurally at rates of 21.1 per second and at intensities of 80-dB and when
necessary at 95-dB HL.7 Two averages were made
at each test signal, and the presence of reproducible components were defined.
Patients underwent assessment in a sound-treated room, in a state of natural
or chloral hydrate–induced sleep.
Audiometric thresholds were analyzed at 500, 1000, 2000, and 4000 Hz
individually and for a pure-tone average at these frequencies. Statistical
analysis comparing audiometric improvements between patients with and without
hyperbilirubinemia was performed using the Wilcoxon rank sum test.
RESULTS
PATIENT DEMOGRAPHICS AND STATISTICS
From our database of 428 children with hearing loss, 22 had a diagnosis
of AN. In 20, the diagnosis was based on positive OAE findings with an absent
ABR finding or with only a CM on ABR findings. Two additional patients were
identified with an obvious CM on ABR findings, but they failed to demonstrate
robust OAEs. Full data were available on 18 of the 22 children with AN; the
remaining 4 children had received a recent diagnosis.
The mean age at presentation was 17 months (range, 1-60 months), with
9 male and 13 female children. The mean age at diagnosis of hearing impairment
was 4.5 months (range, 3 days to 19 months). The racial demographic data showed
18 white and 4 African American patients. The overall prevalence of AN in
our population with known SNHL is 5.1%. All but 1 patient with AN had received
the diagnosis after OAEs began to be routinely used in our institution, in
1996, so a more useful gauge to the frequency of this disorder was to evaluate
this time period. Since 1996, the incidence of the diagnosis of AN was approximately
10% per year in our population with SNHL.
RISK INDICATORS
Predisposing factors associated with AN were varied and often found
in combination. Overall, 15 children with AN (68%) had a complicated perinatal
course. This included hyperbilirubinemia in 11, prematurity in 10, the use
of gentamicin sulfate or other ototoxic medications in 9, and the need for
mechanical ventilation in 8 children. Cerebral palsy was noted in 2 patients.
A genetic influence appeared to be a factor in the development of AN in up
to 8 patients (36%) in our series. A recessive inheritance pattern can be
hypothesized because of the presence of 2 sets of sibling pairs and 1 set
of twins. The other 2 patients had remote family histories of idiopathic hearing
loss without any formal genetic pattern. All 8 of these patients had a severe
or profound hearing loss and had no evidence of improvement compared with
the remainder of our study population.
Results of electrocardiography, comprehensive laboratory analysis, and
ophthalmologic and genetic evaluations were all unremarkable in these patients,
except in the affected sibling pairs. Radiological evaluation, including computed
tomography of the temporal bone or magnetic resonance imaging, revealed no
evidence of dysplasia of the inner ear or internal auditory canal. We found
no historical or clinical evidence of peripheral neuropathy in any of our
patients, and peripheral neuropathy has not developed in any child to date.
CHANGES IN TEST RESULTS OVER TIME
Of the 18 children with full audiological data, the initial mean of
the pure-tone average at 500 Hz and 1, 2, and 4 kHz was 101 dB, and the final
mean threshold was 67 dB (Figure 1).
The initial audiogram showed that most children (16/18 [89%]) presented with
a severe or profound loss (Figure 2).
The final audiogram from our follow-up of these children shows a more even
distribution, with 11 (61%) of the 18 children with a severe or profound loss
(>75 dB), 1 (6%) with a moderate impairment (41-74 dB), and 6 (33%) with mild
to borderline hearing (20-40 dB). All audiograms had a flat configuration,
and none of our patients had a unilateral SNHL. Two patients (a pair of siblings)
lost their OAEs after undergoing amplification during a 2-year period. Their
CMs remained unchanged. No patient had any discernible pattern on their ABRs,
and this did not change with time. Results of tympanometry showed normal middle
ear pressures.
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Figure 1. Mean pure-tone thresholds at presentation
(top) and the last audiogram (bottom). Mean initial hearing loss was 101 dB;
current, 67 dB.
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Figure 2. Tendency to spontaneous resolution
in patients with auditory neuropathy, initial vs final audiogram. Data are
expressed as number of children.
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Overall, 9 (50%) of the 18 children with severe or profound hearing
loss showed audiological evidence of a spontaneous improvement in their hearing
(Figure 2). This occurred 1 to 15
months after their diagnosis, with a mean improvement time of 5.8 months.
In 3 of the 9 patients with spontaneous improvement, the audiograms showed
only a low-frequency gain initially. We compared improvement rates in children
with (10/18 [56%]) and without (8/18 [44%]) neonatal hyperbilirubinemia. The
children with jaundice were more likely to have a more profound initial hearing
loss but showed a greater tendency to improve spontaneously and to end with
a better hearing outcome (Figure 3A).
When analysis of the frequency-specific data was performed, a statistically
significant difference between children with and without jaundice was observed
at the following frequencies: 500 Hz (P = .02), 1
kHz (P = .04), and 2 kHz (P
= 0.04) (Figure 3B). Children achieved
a stable audiogram by a mean age of 18 months (range, 11-25 months), with
clinically meaningful improvement (ie, the decision for cochlear implantation)
occurring by a mean age of 12 months.
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Figure 3. Comparison of improvements of
the hearing outcomes in children with and without hyperbilirubinemia. A, Mean
values for hearing level are expressed in decibels. B, Change in hearing level
for each frequency. Asterisk indicates statistical significance (Wilcoxon
rank sum test).
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The audiological improvements in these children were better than would
be predicted on the basis of development. Of these 9 children, the initial
ABR test results corresponded to abnormal findings on behavioral audiometry.
Initial behavioral audiometric testing was not performed until at least 6
months of age. We found no significant difference in the timing of the initial
audiogram between patients with and those without hyperbilirubinemia. The
mean age at initial testing for children with hyperbilirubinemia was 8.8 months,
(range, 6-23 months); for those without, 10.4 months (range, 6-20 months).
Total bilirubin levels in those affected ranged from 12.3 to 40.0 mg/dL
(210-684 µmol/L), with a mean level of 19.4 mg/dL (332 µmol/L).
Hyperbilirubinemia lasted 4 to 10 days, with a mean of 6.8 days in duration.
Hyperbilirubinemia was noted on postpartum day 2 or 3, and the therapeutic
intervention was appropriate to the level of bilirubin, ranging from no intervention
to phototherapy to exchange transfusion when needed. No correlation of the
bilirubin levels and the extent of improvement of the audiogram was noted.
SENSORY AIDS
Hearing aids and/or an FM system were used in 16 (73%) of the 22 children.
Four children (18%) needed cochlear implants. Four children (18%) were observed
and did not require any amplification because of spontaneous improvement.
Two of our most recent patients younger than 6 months are undergoing observation,
but their need for auditory assistance cannot be determined at this time.
The 4 patients who needed cochlear implants included a pair of siblings.
They all presented with a bilateral profound SNHL, and no evidence of a spontaneous
resolution was noted during a 1-year follow-up. They received no benefit from
our standard amplification with or without FM assistance. Our patients undergoing
cochlear implantation were aged 1 to 3 years, with a mean age of 2 years.
All 4 patients tolerated the implantation procedure well, with no complications
noted. Our first 2 patients have documented significant improvement in their
auditory and communicative skills after implantation, with age-appropriate
open-set speech discrimination scores of better than 70%. The next 2 patients
underwent implantation within the past 6 months, and their preliminary data
so far suggest a potential for similar improvement.
COMMENT
Patients with AN have normal outer hair cell function as measured by
OAE findings and the presence of a CM on results of ABR testing, but a lack
of neural synchrony as demonstrated by absent ABR waveforms. Although the
population with presumed AN is heterogenous, they consistently exhibit a constellation
of findings that suggest that the outer hair cell function is normal and that
the inner hair cell and/or eighth cranial nerve functions are impaired. Findings
on pure-tone audiograms in these patients range from normal to profoundly
impaired. Most of the patients complain of difficulty understanding speech,
particularly in the presence of noise. Patients diagnosed as having AN tend
to have word recognition abilities that are disproportionately poorer than
would be predicted by audiometric thresholds.1, 3
Speech intelligibility scores in retrocochlear disorders (ie, acoustic neuromas)
are reduced beyond what would be expected for the loss of sensitivity. The
hearing loss may be stable or may fluctuate over time. A variety of audiograms
have been described with no clear predominating shape and pattern.1-5
Our study confirms the heterogeneous clinical findings in AN. The medical
impact of the hearing loss on these patients remains significant. Patients
in our study with significant and persistent hearing loss have responded well
to conventional rehabilitation with amplification and cochlear implantation.
OTHER PERIPHERAL NEUROPATHY
Some of the patients initially diagnosed as having AN in other studies
demonstrated indications of a peripheral neuropathy, or these indications
developed.1, 8 Patients with similar
audiometric findings have been diagnosed as having hereditary motor sensory
neuropathy (Charcot-Marie-Tooth disease type 1),1, 9
Friedreich ataxia,10 or Guillain-Barré
syndrome.11 Therefore, a neuropathic process
may also affect the auditory nerves and thus account for the hearing disorder,
which developed in patients before the clinical neuropathy.8
Spoendlin12 described the temporal bones of
2 individuals with Friedreich ataxia. He noted that the organ of Corti was
normal, but that damage to the spiral ganglion cells had occurred in these
patients. Hallpike et al13 also found normal
hair cells with degeneration of spiral ganglion cells and auditory nerve fibers
in a patient with hereditary hearing loss, poor speech comprehension, and
peripheral neuropathy. No patient in our study had any clinical evidence of
a neuropathy. Neuropathy was excluded by results of routine developmental
evaluation by the pediatrician or the neurologist. The mean follow-up for
these patients is 32 months, and the oldest child is now aged 10 years. Rance
et al4 found no evidence of neuropathy in their
study of 20 children with AN. However, in long-term follow-up studies, Starr
et al8 demonstrated peripheral neuropathies
in 80% of children with AN who were older than 15 years. None of these children
exhibited evidence of a peripheral neuropathy at younger than 5 years. Longitudinal
studies in our cohort will be required to examine the prevalence of any neurological
conditions.
GENETICS
Roma (gypsy) families have demonstrated hereditary auditory, vestibular,
motor, and sensory neuropathies in a number of reports.9, 14
Results of sural nerve biopsies on some adults showed systemic demyelinization
and also the loss of a number of axons. The locus of the gene in these cases
of a demyelinative neuropathy was located on the long arm of chromosome 8
(8q24). In our study, several families had 2 offspring with AN and no other
apparent clinical disease. A genetic sensitivity to clinically low levels
of bilirubin and AN has been postulated (C. I. Berlin, PhD, oral communication,
February 5, 2000). This may explain why our patients with a history of hyperbilirubinemia
had higher or worse initial hearing thresholds but did better than children
without hyperbilirubinemia, with better thresholds overall. Further studies
in our families will be required to better delineate these genetic factors.
HYPERBILIRUBINEMIA AND OTHER RISK INDICATORS
Hyperbilirubinemia occurred in 50% of our population. Infants and children
who demonstrate paradoxical audiological findings have been well described
in the literature with hyperbilirubinemia3, 5
or have been described with AN.4 In a study
of 13 neonates with hearing loss due to hyperbilirubinemia, Chisin et al15 found CMs in 9 of the 13 children with absent or
disordered ABRs, suggesting sparing of the hair cells. This finding suggests
an association between hyperbilirubinemia and the occurrence of this unique
form of hearing impairment, particularly in premature and low-birth-weight
infants. Prematurity and perinatal anoxia predisposes infants to bilirubin
encephalopathy (kernicterus),15-16
and both conditions were present in 7 (64%) of our 11 patients with hyperbilirubinemia.
Severe SNHL and central nervous system deficits such as choreoathetotic cerebral
palsy, seizures, and mental retardation were once relatively common sequelae
of hyperbilirubinemia. Improvements in medical therapy have significantly
reduced the occurrence and severity of kernicterus in full-term infants. The
toxic effects of low and moderate levels of bilirubin on the central nervous
system of premature and low-birth-weight infants may account for these cases
of AN. In premature and low-birth-weight infants, the risk for kernicterus
and permanent sequelae may be much higher at serum bilirubin levels below
those thought to be safe for term infants.5
Successful treatment before the development of kernicterus may account for
the "spontaneous" improvement in these children's hearing thresholds. Children
with neonatal hyperbilirubinemia appear to represent a unique subpopulation
of patients with AN. Because of the common incidence of milder forms of hyperbilirubinemia,
future studies may examine the presence of AN in a large-scale, otherwise
healthy, newborn population.
IMPLICATIONS FOR NEWBORN HEARING SCREENING
This study illustrates the value of the combined use of OAEs and ABRs
in hearing loss screening. We recommend routine OAE testing in all children
diagnosed as having SNHL. Absent OAEs require clinical evaluation of the patient's
middle ear status, followed by tympanometry and measurement of the middle
ear muscle reflexes to rule out a hidden middle ear disease. Checks of ABR
and/or CM should be considered in high-risk newborns who undergo OAE testing
as their primary screening tool. Physicians and audiologists should include
AN in their differential diagnosis of SNHL in children. A subset of these
patients with a history of hyperbilirubinemia shows distinct audiological
improvement during the first year of life. Although the appropriate treatment
strategies have yet to be confirmed, selective amplification and cochlear
implantation appear to be successful.
AUTHOR INFORMATION
Accepted for publication February 13, 2002.
This study was presented at the annual meeting of the American Society
of Pediatric Otolaryngology, Scottsdale, Ariz, May 10, 2001.
We thank Stacy Poe and Judy Bean, PhD, of the Department of Biostatistics
at Children's Hospital Medical Center, Cincinnati, Ohio, for their statistical
analysis of the data.
Corresponding author and reprints: John H. Greinwald, Jr, MD, Center
for Hearing and Deafness Research, Department of Pediatric Otolaryngology,
Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229
(e-mail: John.Greinwald{at}chmcc.org).
From the Center for Hearing and Deafness Research, Departments of Pediatric
Otolaryngology (Drs Madden, Rutter, Greinwald, and Choo) and Audiology (Ms
Hilbert), Children's Hospital Medical Center, Cincinnati, Ohio.
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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Causation of Permanent Unilateral and Mild Bilateral Hearing Loss in Children
Tharpe and Sladen
TRENDS AMPLIF 2008;12:17-25.
ABSTRACT
Newborn Hearing Screening in the NICU: Profile of Failed Auditory Brainstem Response/Passed Otoacoustic Emission
Berg et al.
Pediatrics 2005;116:933-938.
ABSTRACT
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A gene responsible for autosomal dominant auditory neuropathy (AUNA1) maps to 13q14-21
Kim et al.
J. Med. Genet. 2004;41:872-876.
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