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Selective Inner Hair Cell Loss in Premature Infants and Cochlea Pathological Patterns From Neonatal Intensive Care Unit Autopsies
Monica G. Amatuzzi, MD;
Clarinda Northrop;
M. Charles Liberman, PhD;
Aaron Thornton, PhD;
Christopher Halpin, PhD;
Barbara Herrmann, PhD;
Luis E. Pinto, MD;
Alberto Saenz, MD;
Alfonso Carranza, MD;
Roland D. Eavey, MD
Arch Otolaryngol Head Neck Surg. 2001;127:629-636.
ABSTRACT
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Background Deafness and handicapping sensorineural hearing impairment occur frequently
in neonatal intensive care unit survivors for unknown reasons.
Patients and Methods Hearing was tested early and repeatedly in neonatal intensive care unit
patients with an auditory brainstem response (ABR) screener. The temporal
bones of 15 nonsurvivors (30 ears) were fixed promptly (average, 5 hours)
after death for histological evaluation.
Results Among these patients, 12 failed the ABR screen bilaterally, 1 passed
unilaterally, and 2 passed bilaterally. Cochlear histopathologic conditions
that could contribute to hearing loss included bilateral selective outer hair
cell loss in 2 patients, bilateral selective inner hair cell loss in 3 (all
premature), and a combination of both outer and inner hair cell loss in 2.
Other hair cell abnormalities were noted; the 2 infants who had passed the
ABR screen demonstrated normal histological features. Neuronal counts were
normal.
Conclusions Auditory brainstem response failure among these neonatal intensive care
unit infants who died was extremely common in part owing to an unexpected
histological alteration, selective inner hair cell loss among premature newborns,
that should be detectable uniquely by the ABR testing method. Additional histological
patterns suggest more than one cause for neonatal intensive care unit hearing
loss. Hair cell loss patterns seem frequently compatible with in utero damage.
INTRODUCTION
HANDICAPPING sensorineural hearing impairment and deafness occur for
unknown reasons in at least 2% to 4% of neonatal intensive care unit (NICU)
survivors, an incidence approximately 50 times greater than in normal newborns.1 This heightened vulnerability of critically ill neonates
is underscored further by the fact that older critically ill pediatric and
adult patients, even those who suffer cardiopulmonary arrest, are unlikely
to develop hearing loss. Retrospective studies have suggested several possible
causes for neonatal hearing loss2, 3, 4, 5, 6, 7
but also have shown that it is impossible to predict which patients will be
affected.8 These neonates depend on early auditory
function to develop speech and language skills. Insight into the peculiar
auditory susceptibility of NICU patients is necessary to optimize appropriate
prenatal and postnatal clinical care intervention and to measure and maintain
hearing function.
Historically, our understanding of the mechanisms of neonatal hearing
loss has been limited by (1) the lack of audiometric data for infants still
in the NICU since for technical reasons hearing tests are typically performed
only on surviving patients near discharge and (2) the lack of temporal bone
tissue in NICU patients from whom correlative audiometric data were available
prior to autopsy. In a previous study, we accomplished a unique prospective
hearing screening on patients while they were still in critical condition
in an NICU, using an automated system designed to measure auditory brainstem
responses (ABRs) in the noisy NICU environment.9
This article summarizes the ear histopathologic findings in 15 of these NICU
patients. The results are relevant not only to the pathophysiology of the
hearing loss but also to possible limitations and interpretations of current
techniques used to test hearing.
SUBJECTS, MATERIALS, AND METHODS
HEARING TESTS
In the NICU, Hospital Nacional de Niños, San Jose, Costa Rica,
92 infants underwent repeated ABR testing before discharge from the hospital
or death. Details of the testing technique have been published previously.9 This study had received institutional review board
approval from both that hospital and the Massachusetts Eye and Ear Infirmary,
Boston. The Hospital Nacional de Niños is a modern 350-bed facility.
The neonatologists received their training in the United States, and the NICU
care was contemporary.
An automated evoked response infant hearing screener (ALGO-1; Natus
Medical, San Jose, Calif) was used for all tests. This portable, battery-operated
device weighs 3.2 kg and provides a click stimulus with a bandwidth of 750
to 3000 Hz that was modified to increase the output from a 35- to a 40-dB
hearing loss for this study. Recording electrodes (3M, Minneapolis, Minn)
were placed on the vertex of the neonate's head and nape of the neck, and
a separate ground electrode was placed on the chest. Disposable ear couplers
were used. These devices surrounded the auricle and gently adhered to the
side of the head to prevent collapsing ear canals, avoid differences in earphone
placement, and attenuate ambient noise.
Stimuli were provided to the patient at a rate of 37 per second, and
the machine computed a binary averaged response from the electroencephalogram.
At each increment of 500 sweeps, the screener compared the cumulative response
with a normal response template. If the fit was fewer than 4 SDs from chance,
another 500 sweeps were added. If the fit exceeded 4 SDs, it scored a "pass."
The test was terminated and scored as a "refer (fail)" when 15 000 sweeps
had been accumulated without a significant (4 SDs) fit to the template. The
statistical evaluation of the fit was a maximum likelihood test using a Nieman-Pearson
criterion, giving exact control over false-negative error. False-positive
errors were controlled by an artifact rejection algorithm matched to the 15 000-sweep
limit. Because of the myogenic and ambient noise criteria for data acquisition,
testing could be suspended for indeterminate periods. This could lead to an
inability to complete a test within permissible time limits, and the result
was scored as "cannot test." Objective screening results were displayed as
pass, refer (fail), or cannot test based on machine scoring. Waveforms were
not displayed for subjective interpretation. Patients were tested from 1 to
4 times (Table 1).
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Summary of Clinical Audiometric and Histological Data for the 15 Patients
Studied*
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HISTOLOGICAL STUDY
Of the 20 infants who died after being tested, 15 underwent autopsy
for histological evaluation, providing a total of 30 temporal bones for analysis
(Table 1). The bones were promptly
fixed, 1 to 15 hours (average, 5 hours) after death, in neutral-buffered (10%)
formalin solution,decalcified with 5% trichloroacetic acid, and embedded in
celloidin over a period of 12 weeks. The blocks were cut at a thickness of
20 µm in the horizontal plane, and every 10th section was stained with
hematoxylin-eosin and mounted on slides.
The inner ear could be evaluated in all 30 bones. A 2-dimensional projection
technique was used for reconstructing the cochlear spiral and computing the
percentage of distance from the base of each section through the cochlear
duct. Cochlear location was converted to frequency via a mathematical fit
to the cochlear map data provided by Schuknecht10
and Greenwood.11 The number of inner hair cells
(IHCs) and outer hair cells (OHCs) missing in each row was estimated within
each section, and the percentage of hair cell loss was calculated for each
millimeter interval of the organ of Corti. The hair cell counts were performed
with high-powered (x100) phase-contrast objectives. The tissue preservation
was generally excellent and, thus, the cuticular plates and stereociliary
tufts of hair cells were usually clearly visible, adding a valuable histological
marker for hair cell presence that was often used in cases that might have
been otherwise ambiguous (Figure 1).
The condition of the supporting cells, stria vascularis, spiral ligament,
and the Reissner membrane were qualitatively evaluated in each section. The
presence of blood and/or proteinaceous precipitate in the cochlear scalae
was also noted.
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Figure 1. Normal organ of Corti from the
upper middle turn of a cochlea showing excellent preservation. From patient
15, a full-term baby who passed the auditory brainstem response screening
on day 6 and died on day 8. Note stereocilia of the inner hair cell (short
arrow) and outer hair cells (long arrows) (hematoxylin-eosin, original magnification
x250).
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A separate graphic reconstruction was used to evaluate the spiral ganglion.
Cochlear nerve cells (nuclei) were counted in each section with the aid of
an ocular grid. To maintain a close relationship to the sense organ, the spiral
ganglion was divided into 4 contiguous segments from base to apex.12 The ganglion cell populations were determined for
each segment and multiplied by 10 to account for the unmounted sections and
by a factor of 0.61 to compensate for double counting.
RESULTS
CLINICAL PROFILE
The population studied consisted of 10 male and 5 female patients, ranging
in age from 1 day to 8 months and in birth weight from 0.9 to 4 kg. Seven
patients were premature (<37 weeks' gestation). The medical conditions
reflected that of a standard NICU patient population (Table 1); the name of each condition reflected the terminology used
in the clinical record.
HISTOLOGICAL FINDINGS
Middle Ear
As summarized in Table 1,
the middle ear cavity contained purulent exudate or eosinophilic precipitate
in 8 patients. In 2 patients, there was a middle ear inflammatory reaction.
In 2 patients, the middle ear cavity appeared to be normal. Because of the
unintentional opening of some middle ears at autopsy, these spaces could not
be evaluated confidently in the remaining 3 patients.
Hair Cell Loss or Damage
As summarized in Table 1,
significant cochlear hair cell loss or damage was seen in 7 of the 15 patients;
the damage was bilateral and was usually symmetrical between ears. In 2 patients
(patients 1 and 2) selective OHC loss was seen. A representative photomicrograph
of a normal organ of Corti in Figure 1
can be compared with OHC loss as shown in Figure 2. The cytocochleograms from patient 1 demonstrate that the
OHCs were missing preponderantly in the basal turn. In patient 2 the hair
cells were missing preponderantly in the apical half of the cochlea. In both
cases the loss was symmetrical (Figure 3).
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Figure 2. Photomicrographs illustrating
expected selective outer hair cell (OHC) loss (long arrows) in 2 patients.
Short arrows in both parts indicate stereocilia on inner hair cells. A, All
3 OHC rows are missing in this section from the basal turn of patient 1, a
full-term baby who failed the auditory brainstem response screening on days
4 and 7 and died on day 8. B, The first 2 rows of OHCs are missing in this
section from the middle turn of patient 2, a full-term baby who failed the
auditory brainstem response screening on days 1, 3, and 15 and died on day
18 (both parts hemoxylin-eosin, original magnification x250).
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Figure 3. Cytocochleograms for left and
right ears in the 2 patients showing selective outer hair cell (OHC) loss.
The 3 OHC rows and 1 inner hair cell (IHC) row are indicated by different
symbols (see key). Each point represents the percentage of missing hair cells
for that row, as averaged across all sections within consecutive 1-mm lengths
of organ of Corti. Cochlear location is converted to frequency via Schuknecht's
map.10 The most critical frequencies for hearing
speech are approximately 0.5 to 4 kHz, similar to the stimulus bandwidth tested
by the auditory brainstem response screener.9
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Selective IHC loss is an extremely rare finding in the temporal bones
of humans or other mammals.10, 11, 12, 13
Nevertheless, selective and widespread loss of IHCs was seen in 3 (patients
3-5) of the 15 patients in this study. Representative photomicrographs from
2 of these infants are shown in Figure 4;
the cytocochleograms are shown in Figure 5. As illustrated by the photomicrographs, tissue preservation was
generally excellent, the patterns of hair cell loss, and particularly this
unique pattern of selective ICH loss, were unambiguous when viewed with high-powered,
phase-contrast objectives. In patient 4 the pattern of hair cell loss was
symmetrical between both ears. In patients 3 and 5 the loss was more extensive
in the left ear than in the right ear (Figure
5). In these infants, concurrent OHC loss was minimal except for
a restricted area in the lower basal turn in patient 5. All 3 patients with
this rare pattern of selective IHC loss were premature (Table 1).
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Figure 4. Photomicrographs illustrating
selective inner hair cell (IHC) loss in 2 premature infants. In both parts,
the absent IHC is indicated by the large arrow, and the outer hair cells are
indicated by the small arrows. A, From the basal turn of patient 3, an infant
of 30 weeks' gestation who failed the hearing test on days 19 and 21 and died
on day 24. B, From the midbasal turn of patient 4, an infant of 31 weeks'
gestation who passed the hearing test on days 2 and 6, failed on days 8 and
10, and died on day 12 (both parts, hematoxylin-eosin, original magnification
x250).
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Figure 5. Cytocochleograms for right and
left ears in the 3 infants showing selective inner hair cell (IHC) loss. All
other conventions for data display are as described in the legend to Figure
3.
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In patients 6 and 7 there was total loss of both IHCs and OHCs in the
basal cochlear regions. Patient 6 was a newborn with trisomy 13 syndrome.
In patients 8 through 11 there were significant abnormalities in many
of the hair cells remaining in the cochleae. These abnormalities consisted
of (1) swollen OHCs, common in all of these patients or (2) herniation of
the IHC contents into the scala media, which was common in patients 8 and
10. It is difficult to determine whether these abnormalities represent incomplete
premortem damage or postmortem autolysis; however, these ears had acceptably
short postmortem fixation times ranging from 2 to 11 hours (Table 1), making autolysis less likely.
In all of the 4 remaining patients (patients 12-15), the cochleae were
well preserved, as illustrated by the photomicrograph in Figure 1; there was no significant hair cell abnormality. Visual
inspection of the spiral ganglion in these 4 patients showed a high density
of neurons throughout the Rosenthal canal, and neuronal counts in these 8
ears were among the highest of the 30 ears in the study (see "Neuronal Loss"
subsection of the "Results" section).
Neuronal Status
Qualitative analysis of the spiral ganglion region in all patients suggested
there was no neuronal loss. The Rosenthal canal, where the cell bodies are
found, appeared full of neurons, without the empty spaces seen in cases of
clear-cut neuronal loss.13
For more quantitative analysis, the number of spiral ganglion cells
was counted and total cell counts were estimated (see "Subjects, Materials,
and Methods" section). As seen in Figure 6, when these counts are compared with those obtained, using identical
techniques, from older human temporal bones (aged, 1-10 years), these data
suggest that (1) neonatal ears have fewer spiral ganglion cells than in the
adult ears and (2) the number of ganglion cells increases systematically during
this immediately postnatal period. The same conclusion was reached when data
were plotted separately for each of the 4 longitudinal segments of the ganglion
(data not shown).
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Figure 6. Spiral ganglion cell counts in
each ear from 14 of 15 patients in the present study plotted as a function
of postconceptional age. (Data from patient 6 with trisomy 13 is not included).
The cell counts are expressed as a percentage of the mean neuronal counts
found in a study of temporal bones from older patients (adapted from Otte
et al12).
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Other Abnormalities of the Cochlear Duct
Congenital middle and inner ear malformations were seen only in 1 patient
(patient 6) with trisomy 13 syndrome who demonstrated the shortest cochlear
duct (24 mm); most ducts ranged from 30 to 32 mm. In patients 3 and 4 the
Reissner membrane was contacting the organ of Corti. It may be significant
that both of these infants also showed hydrocephaly; an association has been
suggested between the increased intracranial pressure of hydrocephaly and
the collapse of the Reissner membrane.14
Patients 2, 9, and 12 showed basophilic deposits in the stria vascularis
bilaterally. In infants 6 through 8, there were cells extruding from the surface
of the stria vascularis and also swollen OHCs. Blood or proteinaceous precipitate
was frequently noted but did not correlate with the condition of the organ
of Corti (data not shown).
COMPARISON OF HEARING TESTS AND HISTOLOGICAL FINDINGS
Patients 14 and 15 passed the hearing tests bilaterally. Neither infant
had significant hair cell loss, and both sets of cochleae were extremely well
preserved. Patient 15 had blood in the perilymphatic spaces bilaterally, and
both patients 14 and 15 had a fluid-filled middle ear bilaterally.
Patient 5 passed the test unilaterally. This patient also showed selective
IHC loss that was extensive on both sides (Figure 5). The right ear, however, passed the screening test, and
the right ear also had less IHC loss than the left ear.
Of the 12 patients who failed the hearing tests bilaterally, 2 (patients
1 and 2) had selective OHC loss, 2 (patients 3 and 4) had selective IHC loss,
and 2 (patients 6 and 7) had total loss of IHCs and OHCs in the basal cochlear
regions. The remaining 6 (patients 8-13) had no significant loss of hair cells,
although 4 (patients 8-11) did demonstrate hair cell abnormalities. Of these
12 patients, 2 (patients 2 and 9) showed a middle ear space that appeared
to be free of fluid at the time of death.
COMMENT
The patients described in this article are from a larger study using
prospective ABR screening to test auditory function in critically ill NICU
infants.9 The conventional rate of ABR screening
failure among study survivors was 6%, an expected result. However, since premortem
ABR results had never been collected by anyone, the failure rate of 25 of
30 ears in nonsurvivors was unexpectedly high. To gain anatomic insight into
the cause of neonatal hearing loss, systematic autopsy recovery and analysis
of temporal bones were necessary.
Generally, inner ear histopathologic features were heterogeneous among
these patients, suggesting more than 1 cause for hearing loss. Therefore,
hearing loss is not analogous to neonatal vision loss, in which a single postnatal
treatment variable of oxygen toxicity has been able to be modified with great
success to diminish the incidence of retinopathy of prematurity.15
In the cochlea, 2 patients showed loss of both OHCs and IHCs, 2 showed selective
loss of OHCs, and 3 showed selective loss of IHCs. Additionally, these hair
cell losses usually appeared to reflect fully resolved degeneration, with
phalangeal scars resealing the reticular lamina, reinforcing a previous impression
that hair cell loss occurred in utero.9 One
implication of these findings is that hearing loss might be better considered
a coexisting medical condition rather than an adverse effect of necessary
NICU treatment. Another implication is that an effort to improve hearing in
most NICU survivors via postnatal treatment modification will be fruitless.
Passing the final ABR screen bilaterally was noted for 2 patients who
also had normal and well-preserved cochlear tissues. Patient 5 unilaterally
passed the final ABR screen, despite a significant selective IHC lesion (right
ear), indicating that fewer than half of the normal number of IHCs are sufficient
to generate a detectable ABR. Selective IHC loss in this model does not greatly
shift the threshold for evoked electrical responses until that loss exceeds
70% theoretically; a 50% loss of neuronal elements can be compensated by a
200% (6-dB) increase in stimulus intensity.
Important and unsuspected, the selective and widespread loss of IHCs
seen in 3 infants in this study is not found in the cochleae of older patients.
Platinum antineoplastic agents produce widespread and selective IHC loss in
some animals16, 17; but such medications
are not used in the NICU. High doses of some ototoxic antibiotic agents have
also been reported to produce a restricted region in the cochlear apex in
guinea pigs where only IHCs are destroyed; however, in all such cases there
was also a much larger area of the basal, and sometimes middle tums, in which
all OHCs were destroyed.18 To our knowledge,
there is only one other histological report of selective IHC loss in a human
cochlea of any age and that patient was also a premature infant.19
Given that all 3 patients with selective IHC loss in this study were premature,
and that 1 of the other 2 premature patients showed widespread herniation
of the IHCs, the clear implication is that selective IHC damage is significant
and common in the temporal bones of premature infants. This distinctly remarkable
finding provides some explanation for the higher incidence of hearing impairment
specific to an NICU population.
The loss of OHCs is expected to account for hearing loss; either combined
loss of OHCs and IHCs or selective OHC loss is a common cause for sensorineural
hearing loss in older patients. However, the OHC patterns in the other infants
distinct from the premature infants were atypical and did not explain fully
the causes of hearing loss in those patients.
The loss of hair cells in this study was not associated with a significant
secondary loss of cochlear neurons as a cause for hearing loss. Significant
neuronal degeneration is not expected with OHC loss because 90% to 95% of
the auditory nerve fibers contact IHCs only.13
Following IHC loss, significant loss of cochlear neurons is demonstrable within
a few months,20, 21 first visible
as a degeneration of the peripheral axon within the osseous spiral lamina,
followed later by degeneration of the cell body in the spiral ganglion. Thus,
given the young age of these NICU patients, it is expected that even IHC loss
was not accompanied by significant neural degeneration.
Excellent correlation (96% agreement) has been demonstrated for detection
of sensorineural hearing loss with the ABR screener used in this study compared
with complete ABR testing in NICU survivors.22, 23, 24, 25, 26
The ABR screener was set to fail those with more than a 40-dB hearing loss.
The widespread presence of fluid in the middle ear in the infants of this
study could have complicated the interpretation of how much hearing loss was
sensorineural (and permanent) and how much was conductive (and reversible).
Middle ear status did not influence testing results in this study since the
presence or absence of middle ear fluid did not correlate with pass or fail
results.
In older populations, a theoretical auditory neuropathy of the eighth
cranial nerve has been postulated based on the clinical finding of normal
otoacoustic emissions (OAEs), a complementary audiometic measurement, in the
presence of highly abnormal or absent responses measured via ABR.27 Data from this study, documenting the unexpectedly
high frequency of selective IHC lesions in NICU patients, suggest an alternate
interpretation as a primary loss of IHCs rather than a primary disorder of
the auditory nerve.
Also germane is the question of whether the screening results in this
study might have differed significantly if OAEs had been used rather than
ABRs. This speculation is especially relevant given the recent development
of universal hearing screening programs for millions of normal newborns.23 These programs use ABR and OAEs either as single
or as complementary techniques. The production of normal OAEs requires normal
OHCs but is unaffected by even complete loss of IHCs.17
An ABR, however, requires functional OHCs, IHCs, cochlear neurons, and an
intact central auditory pathway. If the selective IHC loss reflected in the
cytocochleograms in cases 3 through 5 (Figure
5) represents the only cochlear dysfunction, OAEs in these cases
would have been completely normal and would not have detected the hearing
loss. Potential relevance of these findings for the recently legislated universal
hearing screening programs of the normal neonate population needs to be determined
as huge populations are being tested.
AUTHOR INFORMATION
Accepted for publication November 14, 2000.
This investigation was supported by grant RO1 DC 00188 from the National
Institutes of Health, Bethesda, Md, and a Brazilian CAPES grant (Dr Amatuzzi).
Presented in part at the American Society of Pediatric Otolaryngology
meeting, Orlando, Fla, May 9, 1996.
We are grateful to the staff of the Department of Pathology and the
Neonatal Intensive Care Unit at the Hospital Nacional de Niños. L.
Antonio Bonilla and G. Guido Rodriguez deserve a special thanks for their
expert and efficient job of acquiring the temporal bones and E. Jorge Piza,
MD, for performing autopsies. At the Massachusetts Eye and Ear Infirmary,
Harold F. Schuknecht, MD, gave invaluable instructions about cochlear reconstructions
and reviewed slides with us. Joseph B. Nadol, MD, provided insightful manuscript
review. We thank Richard Cortese, for his excellent photographic work. Betty
Treanor superbly facilitated communication among us and assisted with manuscript
preparation.
From the Departments of Otolaryngology (Drs Amatuzzi, Liberman, and
Eavey and Ms Northrop) and Audiology (Drs Thornton, Halpin, and Herrmann),
Massachusetts Eye and Ear Infirmary, Boston; Department of Otology and Laryngology,
Harvard Medical School, Boston, (Drs Liberman, Thornton, Halpin, Herrmann,
and Eavey); Departments of Pediatrics (Drs Pinto and Saenz) and Pathology
(Dr Carranza and Ms Northrop), Hospital Nacional de Niños, Escuela
Autonomade Ciencias Medicas, Universidad Autonoma de Centro America, San Jose,
Costa Rica; and Department of Otorhinolaryngology, Universidade de Sâo
Paulo, Sâo Paulo, Brazil (Dr Amatuzzi).
Corresponding author: Roland D. Eavey, MD, Massachusetts Eye and
Ear Infirmary, 243 Charles St, Boston, MA 02114.
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