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Evaluation of transiently evoked otoacoustic emissions

and auditory brainstem responses in patients with
multiple sclerosis
By Emre Kaytanc, MD; O. Ilkay Ozdamar, MD; Gul Ozbilen Acar, MD;
Muhammet Tekin, MD

Introduction
Multiple sclerosis (MS) is a chronic demyelinating disease, usually occurring in young adults, that affects white
matter of the central nervous system at multiple locations. The course of MS includes remissions and
exacerbations. There is no specific test to diagnose MS. Diagnosis relies on anamnesis and physical examination.
Cerebrospinal fluid findings, magnetic resonance imaging (MRI), and neurophysiologic tests are used to support
the diagnosis.

Previous presentation: This article has been updated and revised from its previous presentation as a poster at
the 29th Politzer Society Meeting; November 14-17, 2013; Antalya, Turkey

Depending on the brainstem involvement of the patient, the following symptoms and findings might be
observed: facial paralysis, hearing loss, tinnitus, unformed auditory hallucinations, vertigo, nystagmus,
internuclear ophthalmoplegia, and other conjugate gaze palsies arising from medial longitudinal fasciculus,
vomiting, facial anesthesia, trigeminal neuralgia and, rarely, stupor and coma.

Structural integrity of the brainstem can be determined by MRI. Sensitivity is reported to be 66% in diagnosis of
MS.1 Functional integrity of the brainstem can be examined through brainstem evoked response audiometry
(BERA). Today, BERA is the most objective way of determining hearing thresholds and auditory pathologies that
are formed along the way from the peripheral sensory organ to the central part of the hearing center in the
cerebrum. BERA is used as an objective examination method in evaluating auditory function in children
(premature infants, newborns, and babies) and adults or children with severe developmental delay who are
uncooperative with conventional audiologic examination methods. It is also an objective method for detecting
neurologic lesions that affect auditory function.

Otoacoustic emissions (OAE) are acoustic signals generated in the inner ear by basilar membrane and vibrating
outer hair cells. These signals reach the outer ear from inside, which is the opposite direction to normal and can,
therefore, be recorded from the external auditory canal.2 OAE can be regarded as a noninvasive and objective
indicator of cochlear function and is utilized in newborn hearing screenings universally. Existence of OAEs
1 de 8 29-10-17 22:21
indicates that hair cells are functioning properly and the hearing threshold is better than 30 to 40 dB; however, it
does not determine the level of hearing threshold.3
 The objective
Evaluation of this study
of transiently is to evaluate
evoked the emis...
otoacoustic changes in the auditory system caused by brainstem involvement
https://www.entjournal.com/print/article/evaluatio...
during the course of MS, through BERA and OAE.

Patients and methods

This study was carried out with the confirmation decree number 56/O of Goztepe Training and Research
Hospital's Ethics Committee, dated April 27, 2009, and was based on the Ministry of Health General Directorate
for Pharmaceuticals and Pharmacy's Guideline for Good Clinical Practice notice number 51748 and its
appendices; on Operational Guidelines for Ethics Committees That Review Biomedical Research published by
WHO in 2000; and the Declaration of Helsinki.

This prospective study was carried out at Goztepe Training and Research Hospital between September 2009 and
May 2010. A total of 160 recordings of BERA and OAE were examined, which were obtained from both ears of 40
participants. Twenty patients, who were referred by the neurology department of our hospital, were definitely
diagnosed as having MS with clinical and MRI findings (MS group). The other 20 participants, who had no
otologic disorders, served as the control group.

Routine ENT examination, pure-tone audiometry, and tympanometry were performed on all patients. BERA and
OAE were performed bilaterally on all participants after the absence of any ear pathology had been verified. The
patients were informed of the tests and their objectives, and their consents were obtained.

BERA recordings were performed with a Medelec Synergy signal averager (VIASYS Healthcare; Conshohocken,
Pa.) and TDH-9 earphones in a sound-insulated environment. VERTEX bimastoid electrode configuration was
used, with patients in the supine position. Patients were questioned as to whether they used any medications
that could affect the test outcomes, and no medication was given during the test.

Thirteen-per-second clicks were used as stimuli in both the MS and control groups with the window of analyses of
20 milliseconds (msec). Averaging number and frequency range were chosen as 1,500 and 2,000 Hz to 4000 Hz,
respectively. First, the existence of the waves I, III, and V were searched at 70 dB nHL (normalized hearing level)
intensity, and wave latencies were measured. In addition, I-III, III-V, and I-V interpeak latencies were calculated.
Then, BERA recordings were made at 60, 50, 40, 30, and 20 dB nHL, and intensities were searched at which the
wave V existed. Values obtained at 70 dB nHL were used to compare MS and control groups.

A transient evoked otoacoustic emission (TEOAE) test was performed in a sound-insulated room using a Madsen
Capella Cochlear Emissions Analyzer (GN Otometrics; Taastrup, Denmark) and Madsen earphones, in fast-screen
mode with patients in the supine position. Click stimulus with an acoustic spectrum ranging from 1 to 4 kHz and
peak intensity at 80 5 dB SPL was used. Reproducibility rate over 50% was accepted as the There is
response criterion.

Data were analyzed using the Statistical Package for Social Sciences (SPSS) software (version 15.0 for Windows).
The Student t test was used for comparison of the averages. The data were expressed as average standard
deviation, and p < 0.05 was considered statistically significant.

Results
Forty ears of 20 patients in the MS group (mean age 31.3 4.73 years; 11 females and 9 males) and 40 ears of
20 healthy volunteers in the control group (mean age 30.95 4.83 years; 10 females and 10 males) were
examined in this study (p > 0.05). No statistically significant difference was found when the average ages of MS
and control groups were compared.

Wave latencies and intervals of patients in the MS group, as measured at 70 dB nHL, were compared with the
values of the participants in the control group. Average values for the right ear of the MS group were 2.03 0.27
2msec
de 8 for wave I, 4.36 0.49 msec for wave III, 6.26 0.35 msec for wave V; and 2.33 0.49 msec 29-10-17
for I-III 22:21
interval, 1.90 0.28 msec for III-V interval, and 4.23 0.42 msec for I-V interval.
 In the control
Evaluation group, average
of transiently values
evoked for the right
otoacoustic ear were 1.45
emis... 0.30 msec for the wave I, 3.52 0.31 msec
https://www.entjournal.com/print/article/evaluatio...
for wave III, and 5.38 0.53 msec for wave V; and 2.07 0.44 msec for the I-III interval, 1.85 0.48 msec for
the III-V interval, and 3.92 0.53 msec for the I-V interval.

When right ears were compared between the two groups, the waves I, III, and V peak latencies and I-V interpeak
latency of the MS group were found to be significantly prolonged (p < 0.05) as compared to those in the control
group; a statistically significant difference was not found in terms of I-III and III-V interpeak latencies.

Average values for the left ear in the MS group were found to be 1.86 0.24 msec for wave I, 4.41 0.39 msec
for wave III, and 6.25 msec 0.43 for wave V; and 2.54 0.34 msec for the I-III interval, 1.84 0.20 msec for
the III-V interval, and 4.38 0.43 msec for the I-V interval. Average values of the control group were found to be
1.47 0.24 msec for wave I, 3.40 0.43 msec for wave III, and 5.39 0.46 msec for wave V; and 1.92 0.48
msec for the I-III interval, 1.99 0.53 msec for the III-V interval, and 3.91 0.47 msec for the I-V interval.

When left ears were compared in the two groups, the waves I, III, and V peak latencies and I-III and I-V intervals
were found to be statistically significantly prolonged (p < 0.05) in comparison to the control group; as for III-V
interval no statistically significant difference was found.

The means of waves I, III, V and the I-III, III-V, and I-V intervals belonging to left and right ears of the MS group
were compared (table 1). No statistically significant difference was found when these values for the left and right
ears of patients in the MS group were compared. The means of waves I, III, and V and the I-III, III-V, and I-V
intervals for the left and right ears of the control group were compared (table 2). No statistically significant
difference was found when the means of waves I, III, and V and the I-III, III-V, and I-V intervals for the left and
right ears of the control group were compared.

Table 1. The mean peak latencies of waves and

intervals for the left and right ears of patients in the
MS group
Right Left

Mean (msec) SD Mean (msec) SD p Value

I 2.03 0.27 1.86 0.24 >0.05

III 4.36 0.49 4.41 0.39 >0.05

V 6.26 0.35 6.25 0.43 >0.05

I-III 2.33 0.49 2.54 0.34 >0.05

III-V 1.90 0.28 1.84 0.20 >0.05

I-V 4.23 0.42 4.38 0.43 >0.05

Key: msec = milliseconds; SD = standard deviation.

Table 2. The mean peak latencies of waves and

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Evaluation of transiently evoked otoacoustic emis...
intervals for the left and right https://www.entjournal.com/print/article/evaluatio...
ears of patients in the
control group
Right Left

Mean (msec) SD Mean (msec) SD p Value

I 1.45 0.30 1.47 0.24 >0.05

III 3.52 0.31 3.40 0.43 >0.05

V 5.38 0.53 5.39 0.46 >0.05

I-III 2.07 0.44 1.92 0.48 >0.05

III-V 1.85 0.48 1.99 0.53 >0.05

I-V 3.92 0.53 3.91 0.47 >0.05

Key: msec = milliseconds; SD = standard deviation.

The means of the interaural differences of wave V and the I-III, III-V, and I-V intervals pertaining to the MS and
control groups were compared (table 3). When the means of the interaural differences of the MS group were
compared with those of the control group, the mean interaural difference of the I-V interval of the MS group was
found to be statistically significantly more prolonged (p < 0.05) than that of the control group. No statistically
significant difference was found when the means of wave V and the I-III and III-V intervals were compared.

Table 3. Means of interaural differences pertaining to

MS and control groups
MS group Control group

Mean (msec) SD Mean (msec) SD p Value

V 0.40 0.46 0.15 0.12 >0.05

I-III 0.35 0.24 0.34 0.35 >0.05

III-V 0.49 0.46 0.27 0.30 >0.05

I-V 0.40 0.48 0.19 0.16 <0.05

Key: msec = milliseconds; SD = standard deviation.

TEOAE was performed on all ears that were included in the study, and the reproducibility rate was found to be
more than 50% in both the MS and control groups. No statistically significant difference was found between the
4MS
deand
8 control groups. 29-10-17 22:21
Evaluation of transiently evoked otoacoustic emis... https://www.entjournal.com/print/article/evaluatio...
Discussion
Although MRI is the most reliable method for diagnosis, it may not always show the inactive plaques in the
central nervous system. BERA, acoustic reflex, and decay tests have been used by many researchers either to
demonstrate the changes caused by demyelination or as a diagnostic method. Brainstem involvement occurs at
the most in 15% of cases while hearing loss is seen in 1 to 3%.4

Stockard et al reported 53% BERA abnormality in possible MS cases with no symptoms and findings of brainstem
involvement, and 93% and 60% BERA abnormality in two different studies with MS-diagnosed patients.5 La
Mantia et al pointed out silent brainstem lesions determined by 60% BERA in possible MS patients and 44% in
diagnosed MS patients.6

Jerger et al showed that MS is more common in females and that acoustic reflex, BERA, and all of the speech
tests were abnormal in 10% of MS patients while only one of them was abnormal in 40 to 50% of the cases.7
They reported that there was not any relation between abnormality, severity, and duration of the disease. They
suggested that MS patients had hearing loss at high frequencies and that this was more distinct in males.7

Chiappa found 57% BERA abnormality in diagnosed MS patients with brainstem involvement.8 Taking the results
of many studies into account, this author reported an abnormal BERA rate of 67% in patients diagnosed with MS.
Chiappa also determined the main BERA changes as abnormalities in width and absolute latency of the V wave,
loss at the IV and V wave, and prolongation in the III-V interval. Chiappa further reported that there was no
relation between MS localization and BERA changes.

Fischer et al found BERA abnormality in 67% of the 33 diagnosed MS cases and reported that 4 of them had
internuclear ophthalmoplegia.9 Antonelli et al suggested that BERA abnormality rate is higher in diagnosed MS
patients.10 They also pointed out the frequency of BERA abnormalities in patients with no brainstem findings.
Robinson and Rudge reported a 79% rate of BERA abnormality in clinically brainstem-involved patients and a
51% rate of BERA abnormality in clinically brainstem-noninvolved patients.11

Japaridze et al observed BERA changes in 26 of 40 MS patients.12 BERA abnormalities were unilateral in 17

(42.5%) of 40 patients and bilateral in 9 (22.5%) patients. Loss at waves III and V was reported in 15% of the
patients. Santos et al performed BERA with click stimuli on MS patients.13 They reported no significant
difference between the control and MS groups in absolute latency value of wave I obtained at different stimulus
repetition rates. Similar results were also reported by other studies.11,14 Santos et al detected a distinctive
latency delay in wave III and V of MS patients at 51 clicks/sec, and 61 clicks/sec repetition rates when compared
with the control group. They reported a significant increase in the I-III interval of MS patients at a stimulus
repetition rate of 61 clicks/sec.13

Don et al and Robinson and Rudge reported an increase in delay value of the wave V in tandem with the
increase in the stimulus repetition rate.11,15 Jacobson and Jacobson observed an increase in brainstem
conduction time in MS patients compared with a normal group.16 Accordingly, at 51 and 61 clicks/sec stimulus
repetition rates, the absolute delay value of wave V should increase, and at 61 clicks/sec stimulus, the I-III
interpeak interval should increase in MS patients. As for wave III of the ears in our study, 5 MS patients (25%)
had more prolonged wave III compared to participants in the control group. One of these patients also had
prolongation in wave I.

Keith et al found no difference in wave peak latencies of patients and healthy people in BERA.17 However, in MS
patients, they detected prolongation in waves III and V peak latencies and a decline in their amplitudes, as well
as prolongation in I-III, III-V, and I-V interpeak latencies. General prolongation in interpeak intervals was found to
be 27.5%. Findings of Sand et al18 supported the findings of Keith et al. Protti-Patterson and Young reported no
change in BERA in MS patients.19 Many researchers indicate that interpeak interval abnormalities in MS

5especially
de 8 occur in the III-V interval.20,21 29-10-17 22:21
Regarding the ears included in our study, no significant difference was found in patients in the MS group when
 examined in
Evaluation of terms of III-Vevoked
transiently interpeak intervals.emis...
otoacoustic Among the earshttps://www.entjournal.com/print/article/evaluatio...
that were included in our study, 9 ears (22.5%)
had prolonged wave V peak latency, 3 (7.5%) had unilaterally prolonged wave I peak latency, and 1 (2.5%) had
bilaterally prolonged wave I peak latency. The I-V interpeak interval in 8 ears (20%) and the I-III interpeak
interval in 3 ears (7.5%) were more prolonged than those of participants in the control group.

Pure-tone audiograms, tympanograms, and OAE tests did not generate any abnormal findings. Therefore, the
results of these tests showed that there was not additional peripheral ear pathology in any of our cases.

Prolonged wave III peak latency and I-III interval were seen in one of our patients who was 1 of the 3 patients
who had prolonged wave I peak latency. Changes in wave I on BERA tests of MS patients in our study was found
to be 12.5%.

One frequently observed change in BERA in MS is a possible difference between the two ears in terms of wave
peak latencies and interpeak intervals. This is called an interaural difference. When the ears in this study were
examined in terms of the interaural difference between wave peak latencies and interpeak intervals, 2 ears (5%)
in the MS group had only a prolonged wave V; no significant interaural difference was found regarding I-III, III-V,
and I-V interpeak intervals.

There are many BERA studies regarding MS cases in the literature.6-22 According to these studies, abnormal
BERA findings vary between 34 and 73% in MS patients, while 23% of patients do not exhibit any changes. In our
study, we found abnormal BERA findings at a rate of 72.5% in MS patients.

Cutler et al claim that MRI is more sensitive than BERA in possible MS patients while MRI and BERA have equal
importance in diagnosed MS patients.22 Giesser et al found plaque on MRI in 65.4% of 26 MS cases and BERA
abnormality in 80.8%.23 They suggested that BERA is a more sensitive way of confirming brainstem lesions.
Baum et al reported BERA abnormality rate as 44.2% and plaque prevalence rate in MRI as 39.5%.24 Capra et al
stated that BERA was less sensitive than MRI in determining anterior plaques in the brainstem; however, BERA
had a more effective diagnosis capacity in active and silent brainstem lesions.1

Hendler et al reported that unilateral abnormalities at wave I, II, and III that occur with the MRI abnormalities
were seen at lower parts of the brainstem, and the pathology was on the same side as the stimulated ear.25 On
the other hand, they also reported that abnormalities on wave IV and V were generally associated with the MRI
abnormalities at the upper part of the auditory pons, the lower mesencephalon, and at the level of capsula
interna and corona radiata. Hendler et al also reported that the pathology may be located either on the same
side as the stimulated ear or on the opposite side.

O'Riordan et al presented 81 patients who experienced a single acute clinical episode, called a clinically isolated
syndrome, with features highly suggestive of MS on 10-year follow-up by T2-weighted brain MRI.26 The initial
brain MRI was abnormal in 54 patients (67%). Follow-up of patients with an abnormal MRI revealed progression
to clinically definite MS in 45 of 54 patients (83%). For those with a normal brain MRI, progression to clinically
definite MS occurred in 3 of 27 (11%). Some of the patients who experienced a single acute clinical episode
might not present MRI findings of a lesion as mentioned in the O'Riordan study. On the other hand,
demonstration of T2-hyperintense brain lesions with features highly suggestive of MS, called radiologically
isolated syndrome, in asymptomatic individuals is possible, and is mentioned in the literature.26,27

Okuda et al acquired MR imaging data from 41 subjects with a radiologically isolated syndrome, but only 10
(24.4%) patients progressed to either clinically isolated syndrome or clinically definite MS after a median follow-
up period of 5.4 years.27

In conclusion, we demonstrate that electrophysiologic changes can be detected in patients with MS via BERA as
a noninvasive, reproducible, and inexpensive method. These findings, in addition to the other imaging methods,
laboratory tests, and clinical follow-up may assist physicians to make a definite diagnosis of MS.

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From the Department of Otorhinolaryngology, Istanbul Medeniyet University, Goztepe Training and Research
Hospital, Istanbul, Turkey.
Corresponding author: Gul Ozbilen Acar, MD, Ata 3/4 Daire: 249 Kat: 20 Sedef Cad. 38. Ada 34750
Atasehir/Kadky stanbul, Turkey. Email: gulozbilenacar@gmail.com (mailto:gulozbilenacar@gmail.com)
Ear Nose Throat J. 2016 October-November;95(10-11):E12

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