Download Monitoring and Predicting Ototoxic Damage Using Distortion

J Am Acad Audiol 9 : 257-262 (1998)
Monitoring and Predicting Ototoxic
Damage Using Distortion-Product Otoacoustic
Emissions : Pediatric Case Study
Thomas A. Littman*
Amy Magruder*
Douglas R. Strothert
Abstract
Young children undergoing cisplatin chemotherapy are known to be at risk for progressive
sensorineural hearing loss . Early detection of such hearing loss is important for providing
management options . However, in ill and/or young children, behavioral audiometry may not
be sufficiently precise to detect the early stages of hearing loss . This case illustrates that distortion-product otoacoustic emissions (DPOAEs) may be an appropriate cross-check measure
to supplement and confirm pediatric behavioral data . Perhaps more importantly, this study
suggests that DPOAEs may have the potential to predict the earliest stages of progressive
hearing loss before such changes are seen in audiometric thresholds .
Key Words :
Distortion-product otoacoustic emissions, ototoxicity, progressive hearing loss
Abbreviations : DPOAEs = distortion-product otoacoustic emissions, OAEs = otoacoustic
emissions, OHC = outer hair cell, TEOAEs = transient evoked otoacoustic emissions
ensorineural hearing loss has been
reported in 50 percent (Brock et al, 1988)
to 95 percent (Skinner et al, 1990) of children who are undergoing cisplatin chemotherapy. The losses tend to progress from 6000 and
8000 Hz to lower frequencies (Pasic and Dobie,
1991). However, behavioral audiometry in ill
and/or young children may not be sufficiently
precise to detect the initial stages of hearing
loss, particularly at higher frequencies . An objective and accurate cross-check measure is needed
for such monitoring . Otoacoustic emissions
(OAEs) might be appropriate tools for this purpose because (a) cisplatin damages cochlear
outer hair cells (OHCs) (Fleishman et al, 1975);
(b) OAEs are sensitive to cochlear hearing loss
associated with OHC damage (Long and Tubis,
1988 ; Brown et al, 1989 ; Brownell, 1990) ; and
S
(c) OAEs appear to be sensitive to cisplatin ototoxicity in animals (McAlpine and Johnstone,
1990) and humans (Probst et al, 1993 ; Zorowka
et al, 1993) .
For monitoring purposes, distortion-product
otoacoustic emissions (DPOAEs) would seem
preferable to transient evoked otoacoustic emissions (TEOAEs) because DPOAEs provide better results at higher frequencies (Gorga et al,
1993), where cisplatin ototoxicity is first seen in
children (Schell et al, 1989 ; Skinner et al, 1990 ;
Pasic and Dobie, 1991) .
The following case presentation illustrates
the utility of DPOAEs for monitoring cisplatin
ototoxicity in young children . Perhaps more
importantly, this case demonstrates that
DPOAEs may have some ability to "predict" the
progression of hearing loss before the shift in
pure-tone threshold occurs .
CASE REPORT
*Audiology Department, Texas Children's Hospital,
Houston, Texas, tBaylor College of Medicine, Houston,
Texas
Reprint requests : Thomas Littman, Virginia Mason
Medical Center, Section of Otolaryngology/Audiology, 1100
Ninth Ave ., P.O . Box 900, Seattle, WA 98111
he subject of this report was diagnosed with
T medulloblastoma at 41/2 years of age. Total
resection of the tumor was achieved via posterior fossa approach . The patient was subsequently enrolled in a Pediatric Oncology Group
Journal of the American Academy of Audiology/Volume 9, Number 4, August 1998
Table 1
Medulloblastoma Treatment Protocol
Dates
Treatment
9/20/95 to 11/7/95
12/12/95 to 2/2/96
(3 courses)
2/22/96 to 9/20/96
(8 courses)
Radiation
Cisplatin (90 mg/mg2) and
etoposide (300 mg/m2)
Cyclophosphamide (2000 mg/m2) and
vincristine (1 .5 mg/m2)
Total Dose
treatment protocol in the Hematology-Oncology section at Texas Children's Hospital . Doses
of radiation and chemotherapy given to this
patient are summarized in Table 1.
The ototoxicity of cisplatin (Schweitzer, 1993)
and, to a lesser extent, vincristine (Mahajan,
1981 ; Lugassy, 1990) is well documented. Furthermore, prior cranial irradiation is known to
potentiate cisplatin ototoxicity (Sexauer et al,
1985 ; Walker et al, 1989 ; Weatherly et al, 1991).
Therefore, pre- and post-treatment audiologic
monitoring was included in the treatment
protocol .
play techniques), an acoustic immittance battery,
and DPOAEs (the cubic distortion product, 2fif2).
Due to patient fatigue, speech audiometry could
not be completed until test 3. DPOAEs were
collected with fl and f2 levels of 65 and 50 dB SPL,
respectively. The frequency ratio of the primaries (f2/fl) was 1.22. Ear canal calibration
data were monitored to ensure that adequate
stimulus energy was present at each frequency.
Absent or reduced amplitude DPOAEs (less
than 5 dB above the two standard deviation
noise floor) were considered to be truly abnormal only if the ear canal sound pressure level of
the primaries was within 5 dB of nominal levels. DPOAEs were accepted as normal if the
primaries were no more than 10 dB below nominal levels and if 2fl-f2 amplitude was 5 dB or
more above the two standard deviation noise
METHOD
A
udiometric evaluations included pure-tone
air- and bone-conduction audiometry (using
BASELINE
250
5320 cGy
270 mg/m2
900 mg/m2
16,000 mg/m2
12 mg/m2
(8-31-95)
RIGHT E AR
500 1 kHz 2 kHz 4 kHz
250
LEFT EAR
500 1 kHz 2 kHz 4 kHz
0
20
J
2
m
a
40
60
20
J
2
m
a
40
Figure 1 Baseline audiometric
test results. Tympanograms and
acoustic reflexes were within normal limits bilaterally. For this and
for subsequent DPOAE plots at the
bottom of Figures 2 and 3, DPOAE
amplitude (circles connected by
lines) is displayed as a function of
frequency. The upper shaded area
represents two standard deviations
above the mean noise floor. DPOAE
collection parameters are detailed
in the Methods section.
60
80
80
100
100
Distortion Product-gram
0.7
258
1
1.5
2
3
kHz (F2)
4
6
8
Predictive Value of DPOAEs/Littman et al
TEST 2 (2-22-96)
250
2
-0
RIGHT EAR
500 1 kHz 2 kHz 4 kHz
250
0
0
20
20
40
J
2
m
60
LEFT EAR
500 1 kHz 2 kHz 4 kHz
40
60
80
80
100
100
Figure 2 Test 2, following treatment radiation, risplatin, and
etoposide . Tympanograms and
acoustic reflexes were within normal limits bilaterally. Bone-conduction thresholds were equivalent
to air-conduction thresholds .
DPOAE collection parameters are
detailed in the Methods section.
Distortion Product-gram
. . . . . . .. . . .: . . . . .. .\. . .. .. . . .:. . .. . . . . . . . . ; .. . . .. . . ;. .. .. .. .. .. .; .. . . .. . .
floor. DPOAEs were not accepted as normal
whenever primary levels exceeded nominal values by more than 5 dB . Emissions were collected using the Otodynamics IL092 system
(software version 4.20B+) .
A baseline audiometric evaluation was completed after surgery but before radiation and
chemotherapy. Test 2 was performed 6 months
later, following radiation and three courses of cisplatin and etoposide . Test 3 was completed 4
months after completion of all therapy (11
months after test 2) .
RESULTS
B
aseline audiometry, shown in Figure 1,
reflects normal sensitivity and normal
DPOAEs bilaterally. In the ear canal, the amplitude of f2 at 6000 Hz for the right ear was 6.8
dB below the nominal level of 50 dB SPL, possibly accounting for the somewhat diminished
emission at that frequency. The amplitude of f2
could not be increased by refitting the probe,
apparently due to idiosyncratic ear canal resonance characteristics . Nonetheless, the 6000-Hz
emission is considered normal by our clinic's
criteria because it exceeds the two standard
deviation noise level by more than 5 dB . Acoustic
immittance findings were normal for this evaluation and for all subsequent retests . The immittance data have been omitted from the figures
to conserve space.
Audiometric results following completion
of cisplatin and etoposide treatment are presented in Figure 2. A bilateral high-frequency
sensorineural loss is apparent . DPOAEs were
absent for the right ear at and above 1500 Hz
and were absent or abnormal for the left ear at
and above 2000 Hz . Note that DPOAEs were
abnormal bilaterally at 2000 and 3000 Hz,
despite audiometric thresholds of 10 and 15 dB
HL for those frequencies in both ears . Boneconduction thresholds were consistent with airconduction thresholds but were omitted from
the figures for the sake of clarity.
The results of test 3, following completion
of cyclophosphamide and vincristine therapy,
are presented in Figure 3. The high-frequency
sensorineural loss had progressed in both ears .
Note that the loss now included 2000 and 3000
Hz for both ears (2000 Hz for the left ear was now
15 dB poorer than at baseline). DPOAEs for the
right ear were much the same as for test 2,
although the emission at 1500 Hz appeared to
Journal of the American Academy of Audiology/Volume 9, Number 4, August 1998
TEST 3 ( 1-27 -9 7)
250
RIGH T EAR
500 1 kHz 2 kHz 4 kHz
250
LEFT EAR
500 1 kHz 2 kHz 4 kHz
0
20
=
-°
20
40
60
=
is,
-
a
40
80
80
100
100
0.7
1
1 .5
2
3
kHz (F2)
4
6
8
Figure 3 Test 3, following
treatment with cyclophosphamide and vincristine. Boneconduction thresholds were
equivalent to air-conduction
thresholds . Tympanograms
and acoustic reflexes were
within normal limits bilaterally, except for 4000 Hz, where
contralateral reflexes were
absent for both ears . Diagnostic speech audiometry was
within normal limits bilaterally. DPOAE collection parameters are detailed in the
Methods section.
60
0.7
1
have "recovered" somewhat and was now 3.4 dB
above the noise floor.
The left ear emissions in Figure 3 remained
abnormal for the higher frequencies, while lower
frequency emission amplitude increased, relative to test 2. The left ear DPOAE at 2000 Hz
appeared to have recovered partially and was
now 2.2 dB above the noise floor (this emission
might have been larger, but the noise floor at
2000 Hz was greater at test 2 than at the baseline). This subject's most recent evaluation indicated that the hearing loss was stable, and the
DPOAEs have shown no further recovery.
The relationship between DPOAEs and puretone thresholds at 2000 Hz is shown in Figure
4. This figure clearly indicates that the DPOAE
amplitude dropped into the noise in test 2 before
a significant threshold shift was observed at test
3. Figure 5 reflects a similar pattern at 3000
Hz, where DPOAE amplitude dropped into or
near the noise floor while sensitivity remained
normal during test 2. Sensitivity at 3000 Hz
subsequently declined by 45 and 35 dB for the
right and left ears, respectively, at test 3.
260
1 .5
2
3
kHz (F2)
4
6
8
DISCUSSION
n this case study, DPOAEs were sensitive to
the earliest stages of ototoxicity. DPOAEs
were abnormal for f2 frequencies at which sensorineural hearing loss exceeded 20 dB HL, consistent with group studies in which similar
recording parameters were employed (Gorga et
al, 1993 ; Sun et al, 1996). DPOAEs would therefore seem to be an appropriate cross-check measure for monitoring ototoxicity due to cisplatin
and other agents . Furthermore, after a complete audiometric baseline has been established,
it may be feasible to monitor periodically using
DPOAEs alone. Additional audiometric data
would then be obtained only when DPOAEs
dropped below baseline levels . In this way, monitoring might be more rapid, less expensive, and
less taxing for a patient who often is not feeling
well .
Perhaps of greater interest, this case study
suggests that DPOAEs may be more sensitive
to incipient cochlear damage than behavioral
thresholds. The striking pattern in Figures 4 and
Predictive Value of DPOAEs/Littman et al
2000 Hz - RIGHT EAR]
25
a
10
5
~
t1
O
0 Z
O
__Z] ~
~
F
-5
C
rn
.10 w
Q
O
40
Baseline
Test 2
`- Pure-Tone Threshold
-~J -20
a
0
Test 3
J
10
15 v
O
20
3000 Hz - RIGHT EAR I- 2s
0
J
20 a
In
20
0
L
d
t
30
H
N
40
H
tit
50
d
60
70
Baseline
e DPOAE Signal-to-Noise Redo
Pure-Tone Threshold
Test 2
Test 3
D DP.- Signal-to-Noise. Ratio
2000 Hz - LEFT EAR
Pure Tone Threshold
DDPOAE Signal-to-Noise Ratio
1
Pure-Tone Threshold
r3 DPOAE Signal-to-Noise Ratio
Figure 4 The relationship between pure-tone thresholds at 2000 Hz and DPOAEs for f2 = 2000 Hz . DPOAE
amplitude is displayed in terms of signal-to-noise ratio
(amplitude of the emission above the two standard deviation line of the noise floor) . Note that the DPOAE
dropped into the noise floor at test 2, while no significant
change was seen in the pure-tone threshold for the right
(a) and left (b) ear. The DPOAE for the left ear "recovered"
somewhat at test 3 and is now 2.4 dB above the noise floor.
Figure 5 The relationship between pure-tone thresholds at 3000 Hz and DPOAEs for f2 = 3000 Hz . DPOAE
amplitude is displayed in terms of signal-to-noise ratio
(amplitude of the emission above the two standard deviation line of the noise floor) . Note that the DPOAE
dropped into the noise floor at test 2, while no significant
change was seen in the pure-tone threshold for the right
ear (a). For the left ear (b), the DPOAE dropped to within
2 .6 dB of the noise (a drop of 18 .2 dB from baseline), with
no significant change in pure-tone sensitivity.
5 is that DPOAE amplitudes fell into or near the
noise floor before behavioral threshold changes
were noted at corresponding frequencies. In this
sense, the DPOAEs may be predictive, foretelling a substantial threshold shift for a given
frequency prior to a measurable sensitivity loss .
Because 11 months elapsed between monitoring
sessions, we cannot speculate on how much time
actually elapsed between the DPOAE drop and
a pure-tone sensitivity shift.
Warning of impending hearing loss could be
useful for the oncologist, who might have the
option of adjusting the chemotherapy to a potentially less ototoxic regimen. Likewise, early indicators of threshold shift would be useful for
planning audiologic management and counseling.
We speculate that the "predictive" drop in
the DPOAE reflects the progression of hair cell
damage . Thus, at the initial stage of toxicity, the
chemotherapy agents may only damage one or
two rows of OHCs, affecting DPOAEs but not
threshold sensitivity. Subsequently, as the drugs
damage the remaining OHCs in that f2 frequency
region, pure-tone sensitivity is reduced.
A limitation of this case study is that only
two postbaseline measures were obtained . As a
result, we do not have a clear picture of the
time course of this phenomenon . We cannot
determine the temporal interval by which the
DPOAE drop precedes the sensitivity change .
Similarly, we cannot comment on whether the
DPOAE and pure-tone changes were gradual or
precipitous .
The case described herein is not an isolated
one. We now have similar data from 14 children (9 undergoing cisplatin chemotherapy and
Journal of the American Academy of Audiology/ Volume 9, Number 4, August 1998
5 with congenital cytomegalovirus infection),
demonstrating the predictive ability of DPOAEs .
It therefore seems that DPOAEs may have the
potential to predict the earliest stages of progressive cochlear hearing loss .
Mahajan SL . (1981). Acute acoustic nerve palsy associated with vincristine therapy. Cancer 47 :2404 .
Acknowledgment . This work was presented, in part, at
the Twentieth Midwinter Research Meeting of the Association for Research in Otolaryngology, St . Petersburg
Beach, FL, February 2, 1997 .
Probst R, Harris FP, Hauser R. (1993) . Clinical monitoring using otoacoustic emissions. Br JAudiol 27 :85-90 .
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