The Laryngoscope

C 2015 The American Laryngological,

V
Rhinological and Otological Society, Inc.

Pulse Steroid Therapy in Idiopathic Sudden Sensorineural Hearing

Loss: A Randomized Controlled Clinical Trial

Ali Eftekharian, MD; Maryam Amizadeh, MD

Objectives/Hypothesis: To evaluate in patients with idiopathic sensorineural hearing loss whether pulse therapy with
methylprednisolone leads to better recovery of hearing than traditional oral prednisolone therapy.
Study Design: Randomized controlled trial.
Methods: Sixty-seven patients diagnosed with idiopathic sensorineural hearing loss were randomly divided into two
groups based on therapy. The study group received 500-mg daily intravenous methylprednisolone for 3 consecutive days, fol-
lowed by 1 mg/kg (maximum 60 mg) oral prednisolone for 11 days (total treatment: 14 days). The control group received
1 mg/kg (maximum 60 mg) oral prednisolone for 14 days. Hearing change was evaluated by comparing initial hearing tests
and the third-month hearing tests in three ways: 1) pure tone improvement in each individual tone (0.5, 1, 2, 3, and 4 kHz);
2) word-recognition score improvement; and 3) complete, partial, and no recovery of hearing calculated (as defined by Amer-
ican Academy of Otolaryngology—Head and Neck Surgery Clinical Practice Guidelines).
Results: Sixty of 67 patients, 29 of 34 patients in the study group and 31 of 33 patients in the control group, completed
the study. Frequency-specific hearing improvement did not differ significantly among the groups. Word-recognition score
improvement was 20.34% 6 27.35% for the study group and 13.41% 6 23.48% for the control group, which had no statisti-
cally significant difference. There was also no significant difference in hearing recovery rates for the two groups.
Conclusion: Pulse therapy with methylprednisolone and traditional oral prednisolone therapy resulted in similar hear-
ing improvement.
Key Words: Sudden sensorineural hearing loss, pulse therapy, randomized controlled trial, steroid, methylprednisolone.
Level of Evidence: 1b.
Laryngoscope, 00:000–000, 2015

INTRODUCTION cally. The therapeutic dose is very wide and depends on

Sudden sensorineural hearing loss has been defined
as a sensorineural hearing loss of 30 dB or more cover-
ing at least three contiguous audiometric frequencies,
which occur within 3 days or fewer.1
Most of the cases are idiopathic, with a reported
incidence of 5 to 20 per 100,000 population per year.2
Idiopathic sudden sensorineural hearing loss (ISSNHL)
is defined as sudden sensorineural hearing loss with no
identifiable cause, despite adequate investigation.3
Many treatment regimens have been proposed for
this disease. However, the comparative efficacy of these
treatments is not known, considering that the definitive
etiology is also commonly not known. Systemic cortico-
steroid treatment is one of the few treatment options
that has data showing efficacy, although even those data
are somewhat equivocal.3
Glucocorticoids have profound antiinflammatory
and immunosuppressive actions when used therapeuti-
the indication for treatment but can vary more than
200-fold. Steroid pulse therapy is a specific therapeutic
entity that refers to the administration of 250 mg or
more prednisolone equivalent a day (usually intrave-
nously) for 1 or a few (usually  5) days.4
Since its first use for the treatment of acute rejec-
tion after kidney transplantation in 1973,5 steroid pulse
therapy has come to be used in a variety of conditions
such as nephrotic syndrome, crescentic glomerulonephri-
tis, systemic lupus erythematous (SLE), optic neuritis,
pemphigus vulgaris, dermatomyositis, leukocytoclastic
vasculitis, and rheumatoid arthritis.6,7
Searching the literature, there is a lack of sufficient
studies available regarding steroid pulse therapy in
ISSNHL.
This prospective randomized study is conducted to
evaluate whether in ISSNHL patients pulse therapy
with methylprednisolone leads to better recovery of
hearing than traditional oral prednisolone therapy.

From the Department of Otorhinolaryngology, Shahid-Beheshti

University of Medical Sciences (A.E., M.A.), Tehran, Iran
Editor’s Note: This Manuscript was accepted for publication
February 10, 2015.
The authors have no funding, financial relationships, or conflicts
of interest to disclose.
Send correspondence to Ali Eftekharian, Department of Otorhino-
laryngology, Loghman Hospital, Kamali Ave. Kargar, 13336–31151
Tehran, Iran. E-mail: alishko@gmail.com
DOI: 10.1002/lary.25244
MATERIALS AND METHODS
Setting
A prospective randomized controlled trial on the effect of
pulse therapy with methylprednisolone on ISSNHL was per-
formed between January 2009 and October 2013 in a
university-based tertiary care hospital. Institutional review
board approval was obtained before proceeding with the study.

Laryngoscope 00: Month 2015 Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
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 TABLE I.
Inclusion and Exclusion Criteria.
Inclusion Criteria
1. Sensorineural hearing loss of 30 dB or more covering at
least three contiguous audiometric frequencies, which
occur within three days or fewer
2. No identifiable cause despite adequate investigation
3. Normal or near normal hearing in the contralateral ear
4. Age between 18–60 years
5. No more than 10 days from the onset of disease
6. No history of previous treatment
7. No contraindication for proposed therapy
Exclusion Criteria
1. Any identified etiology during therapy
2. Previous disease or surgery in the affected ear
3. Pregnant or lactating women
Participants
Eighty-one patients diagnosed with ISSNHL offered
enrollment into this study. Patients were the ones with idio-
pathic sensorineural hearing loss of 30 dB or more covering at
least three contiguous audiometric frequencies, which occur
within 3 days or fewer. To exclude known causes of hearing
loss, a complete history and physical examination, audiological
and vestibular tests, contrast-enhanced magnetic resonance
imaging of the temporal bone and cerebellopontine angle, and
laboratory workup were undertaken. Inclusion and exclusion
criteria are shown in Table I. Eleven patients did not meet
inclusion and exclusion criteria, and three declined to
participate.
After informed written consent, 67 patients were random-
ized into two groups; 34 patients in the study group and 33
patients in the control group (S 5 study group; C 5 control
group).
Randomization
Randomization sequence was created using Stata 10.0
(StataCorp., College Station, TX) statistical software and was
stratified with a 1:1 allocation using random block sizes of 2, 4,
and 6 in the research department of the center, independent of
the participating researchers.
Treatment Groups
Group S received 500-mg daily intravenous methylpredni-
solone for 3 consecutive days, followed by 1 mg/kg (maximum
60 mg) oral prednisolone for 11 days (total treatment: 14 days).
Group C received 1mg/kg (maximum 60 mg) oral prednisolone
for 14 days. Fourteen days of prednisolone was traditional ther-
apy at our center, which is consistent with the recently recom-
mended clinical practice guideline of the American Academy of
Otolaryngology–Head and Neck Surgery (AAOHNS)
Foundation.3
Outcomes
Pure-tone audiogram and word recognition score (WRS)
were performed before the treatment and with follow-up at sec-
ond week and third month (final outcome) afterward. Pure-tone
average (PTA) was calculated as the average of the thresholds
at 0.5, 1, 2, and 3 kHz. Severity of the disease was based on
Laryngoscope 00: Month 2015 Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
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PTA. Up to 40 dB loss was defined as mild, 41 to 70 dB as mod-
erate, 71 to 90 dB as severe, and 91 dB loss and more was
defined as profound hearing loss.
The primary outcome was hearing improvement, which
was compared between the two groups in three ways:
1. Pure tone improvement in each individual tone (0.5, 1, 2, 3
and 4 kHz)
2. WRS improvement
3. Complete, partial, and no recovery of hearing based on initial
hearing tests and third-month tests compared between the
two groups. These were calculated (Table II) as defined in
the recent clinical practice guideline of the AAOHNS.3 Nei-
ther the audiologist nor the author who analyzed the results
of treatment was aware of the treatment modality or of the
patient’s group allocation.
Statistics
In order to be significantly different at the 0.05 confidence
level with 80% power, the sample size for the two groups were
estimated to be 48 patients per group. Allowing for a 10% drop-
out rate, this would require 53 patients per group, or 106 in
total. We anticipated 3 years of recruitment time.
The intention to include 106 patients between 2009 and
2012 was not fulfilled. We experienced a much slower pace of
patient recruitment and more dropout rate than expected. The
study continued until October 2013 with only 81 patients
enrolled, so the authors decided to suspend the study and ana-
lyze the results for the enrolled patients to see if any meaning-
ful data were present.
Statistical analyses were done using SPSS 18.0 (SPSS Inc,
Chicago, IL). Significance was determined at the confidence
level of P < 0.05, indicating standard deviations when needed.
RESULTS
Sixty-seven patients were randomized into two
groups: 34 patients in the study group and 33 patients
in the control group.
In the study group, two patients were lost to follow-
up, and we missed their final audiograms and one
TABLE II.
Hearing Recovery Classification.
1. Complete recovery: Return to within 10 dB HL of the unaffected
ear and recovery of word recognition scores to within 5% to 10%
of the unaffected ear.
2. Partial recovery: Should be defined in 2 ways based on whether
or not the degree of initial hearing loss after the event of SSNHL
rendered the ear nonserviceable (based on the AAO–HNSF
definition).
a: For ears that were rendered nonserviceable by the episode
of SSNHL, return to serviceable hearing should be considered a
significant improvement (partial recovery) and recovery to less
than serviceable levels as “no recovery.”
b: For ears with SSNHL to hearing levels that are still in the
serviceable range, a 10-dB HL improvement in pure-tone
thresholds or an improvement in WRS of  10% should be con-
sidered partial recovery.
3. No recovery: Anything less than a 10-dB HL improvement
should be classified as no recovery.
Nonserviceable hearing:  50% Speech discrimination score and  50
dB on pure tone average.
AAO-HNSF 5 American Academy of Otolaryngology—Head and
Neck Surgery Foundation; HL 5 hearing loss; SSNHL 5 sudden sensorineu-
ral hearing loss; WRS 5 word recognition scores.
Fig. 1. Study flow diagram.
ISSNHL 5 idiopathic sudden sensor-
ineural hearing loss. [Color figure
can be viewed in the online issue,
which is available at www.laryngo-
scope.com.]
patient due to personal conflict and discontinued inter-
vention. For the same reasons, two patients were lost to
follow-up in the control group. The final number of
patients who met the inclusion and exclusion criteria,
followed up for at least 3 months after treatment and
enrolled in statistical analysis, was 29 in the study
group and 31 in the control group (Fig. 1).
The demographics and baseline audiologic data of
the patients are summarized in Table III, which shows
that there was no significant difference between the two
groups and they were well-matched.
Table IV shows comparison of hearing improvement
3 months after treatment in the two groups. The hearing
threshold improvement at 500; 1,000; 2,000; 3,000; and
4,000 Hz was similar between the two groups. PTA and
WRS improvements also had no statistically significant
difference between the two groups.
Table V shows comparison of hearing recovery rates
3 months after treatment in the two groups. There were
no significant differences among the hearing recovery
rates between the study and control groups. The
patients of each group were also divided into the
patients with initial profound hearing loss and patients
with initial hearing better than profound. Comparison of
hearing recovery rates 3 months after treatment (Table
VI) in these individualized groups also showed statisti-
cally insignificant difference.
No complications or adverse effects were observed
in either group.
DISCUSSION
This prospective, randomized, controlled clinical
trial of comparing pulse methylprednisolone and pred-
nisolone in the treatment of ISSNHL showed that this
Laryngoscope 00: Month 2015 Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
therapy had no clear advantage over traditional oral
prednisolone therapy.
Because the success of treatment of any disorder
depends on a full understanding of the underlying path-
ophysiological characteristics, the treatment of ISSNHL
still remains a matter of controversy. Systemic steroid
treatment is one of the few treatment options that has
data showing efficacy, although even those data are
somewhat equivocal.3 Glucocorticoids exert a variety of
immunosuppressive, antiinflammatory, and antiallergic
effects on primary and secondary immune cells and tis-
sues. Their therapeutic effects are considered to be medi-
ated by four different mechanisms of action: the classical
genomic mechanism of action caused by the cytosolic
glucocorticoid receptor (cGCR); secondary nongenomic
effects, which are also initiated by the cGCR;
membrane-bound glucocorticoid receptor-mediated non-
genomic effects; and nonspecific, nongenomic effects
caused by interactions with cellular membranes.8 Gluco-
corticoids (GCs) mediate their function through binding
to glucocorticoid receptors present in the cell cytoplasm,
which are then translocated to the nucleus and bind to
specific DNA regulatory sequences known as glucocorti-
coid response elements. This interaction results in the
up- or down-regulation of specific genes affecting the
expression of several cytokines and/or adhesion mole-
cules. Genomic effects of GCs can be seen as early as 30
minutes after exposure to the drug, as opposed to nonge-
nomic effects that are detected in seconds to minutes
after exposure.7
Pulse therapy is the administration of supraphar-
macologic doses of drugs in an intermittent manner to
enhance the therapeutic effect and reduce the side
effects.6 Steroid pulse therapy has come to be used in a
variety of diseases such as nephrotic syndrome,
3
 TABLE III. cells and proinflammatory cytokine production, leading
Demographics and Baseline Audiologic Features of Patients in the to reduced expression of adhesion molecules and reduced
Two Groups. movement of neutrophils into sites of inflammation.6
Study Group Control Group Steroids have many effects in the inner ear, but it
(n 5 29) (n 5 31) P Value is unclear whether the suppression of an immune
response, changes in microvascular circulation, minera-
Mean age (years) 42.2 6 12.6 40.1 6 11.9 0.816
locorticoid effects, or a decrease in endolymphatic pres-
Sex–Male:Female, n 17:12 15:16 0.427 sure are beneficial in ISSNHL.11–13 Considering that the
Vertigo 18 20 0.844 antiinflammatory effect of corticosteroids is viewed to
Tinnitus 21 24 0.655 play an important part in the recovery from ISSNHL, a
Days from onset to treatment 6.7 6 2.2 7.3 6 2.3 0.396 more powerful suppression of the immune system with
Severity of hearing loss, n high-dose corticosteroid therapy (pulse therapy) might
Mild 1 3 0.625 enhance or quicken recovery.11
Moderate 3 6 There are few reports of pulse therapy in ISSNHL.
Severe 12 12
Narozny et al.14 seems to be the first to study the effect
of this treatment in ISSNHL. Their study group
Profound 13 10
received 1,000 mg of methylprednisolone intravenously
Hearing level in each frequency (dB)
for 3 days, prednisolone 60 mg per day in decreasing
0.5 KHz 65.51 6 34.26 62.5 6 29.77 0.724
doses, plus hyperbaric oxygen therapy. Their control
1 KHz 72.24 6 32.83 63.87 6 30.73 0.312 group received 30 mg prednisolone per day in decreas-
2 KHz 80.34 6 25.14 66.12 6 28.71 0.066 ing dose for up to 14 days. They showed that the study
3 KHz 86.20 6 23.66 74.83 6 25.28 0.078 group had significantly better recovery of hearing lev-
4 KHz 87.24 6 23.91 77.74 6 24.62 0.092 els. Three points that should be emphasized in this
PTA (dB) 76.07 6 25.60 66.85 6 26.54 0.177 study are: 1) The two groups were treated in two dis-
WRS (%) 32.24 6 38.13 49.64 6 36.79 0.243 tinct periods; 2) the study group received hyperbaric
oxygen therapy in addition to steroid, which can have
PTA 5 pure-tone average: average of the thresholds at 0.5, 1, 2, and an influence on the results; and 3) the control group
3 kHz; WRS 5 word recognition score.
had not been given a sufficient dose of prednisolone, as
it is should have been. Westerlaken and et al.,11 in a
crescentic glomerulonephritis, SLE, optic neuritis, pem- randomized, prospective, double-blind clinical trial,
phigus vulgaris, dermatomyositis, leukocytoclastic vas- allocated their patients to pulse therapy or control
culitis, rheumatoid arthritis, Kawasaki disease, Henoch treatment. Pulse therapy consisted of 300 mg dexa-
Schonlein purpura, and Graves’ disease.6,7,9,10 Intrave- methasone for 3 consecutive days, followed by 4 days of
nous pulses of methylprednisolone in doses of 1,000 mg placebo. Control treatment consisted of 70 mg predni-
daily for 3 to 5 days are commonly used to treat severe sone per day, tapered in steps of 10 mg per day to 0 mg.
manifestations of SLE or systemic vasculitis, but it has Their treatment lasted 7 days for both groups. The
been suggested that 100 mg of methylprednisolone is authors stated that overall improvement in pure-tone
enough to saturate most of the glucocorticoid receptors thresholds and speech discrimination scores was not
and that higher doses mediate nongenomic effects.7 significantly better in patients who were given dexa-
Despite more than 3 decades of steroid pulse-therapy methasone than in those who were given standard
use, there is little clarity on the mechanism of action, prednisone. Although it was a good multicenter study
magnitude of benefits, and adverse effects; however, it with 71 cases, it again seems that patients of the con-
seems that the effects of corticosteroid pulses appear to trol group had not received enough dose of
include down-regulation of the activation of immune prednisolone.

TABLE IV.
Hearing Improvement 3 Months After Treatment in the Two Groups.
Hearing Improvement Study Group (n 5 29) Control Group (n 5 31) P Value

Hearing improvement at each frequency (dB) Mean SD Mean SD

0.5 KHz 52.06 41.41 50.00 33.26 0.833
1 KHz 55.68 41.93 51.93 34.58 0.706
2 KHz 65.51 38.57 55.48 35.10 0.296
3 KHz 66.72 35.96 60.96 32.28 0.516
4 KHz 72.58 34.86 66.12 30.40 0.447
PTA improvement (dB) 60.00 37.84 54.59 31.80 0.551
WRS improvement (%) 58.58 42.44 63.06 41.14 0.680

PTA 5 pure-tone average: average of the thresholds at 0.5, 1, 2, and 3 kHz; SD 5 standard deviation; WRS 5 word recognition score.

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 TABLE V.
Recovery Results of Patients in the Two Groups.
Study Group Control Group
Recovery* (n 5 29) (n 5 31)
Complete recovery, n 7 6
Partial recovery, n 10 11
No recovery, n 12 14
*Defined in Table II.
The present controlled study was intended to con-
firm/reject earlier findings from the database in which
the effect of pulse steroid had been observed. According
to the Table III, there was no significant difference
between the two groups before treatment, and they
were well-matched. According to the Tables IV and V, it
seems that pulse therapy—at least with our studied
protocol—has no superior therapeutic effect than a 2-
week, 60-mg oral prednisolone protocol. In the other
hand, because no complications or adverse effects were
seen in either group, this point does not demonstrate
the superiority of one treatment regimen over the
other.
Wen et al.,15 in a recent retrospective analysis
of medical records of 2,185 patients with ISSHL,
showed that a higher degree of hearing loss at the
initial presentation indicated a poorer prognosis; and
they found that at 2-month follow-up, only 29.8 % of
these patients showed some degree of hearing recov-
ery. In our study, five patients in group S (38.46%)
and five patients in group C (50%) with initial pro-
found hearing loss had either complete or partial
hearing recovery. Because it also showed statistically
insignificant difference, it can be concluded that our
pulse therapy was neither better nor worse in treat-
ing ISSNHL.
There are some limitations in this study. The small
sample sizes presented in this study limit the certainty
of its conclusions. Many studies—or, as Stokroos et al.16
stated—almost every study concerning ISSNHL therapy
suffers from this limitation2,11,17–21 due to the low inci-
dence of the condition, especially when inclusion and
TABLE VI.
Recovery Results of Patients With and Without Initial Profound
Hearing Loss.
Profound Hearing
Loss Not Profound Loss
Group S Group C Group S
Initial Hearing Level (n 5 13) (n 5 10) (n 5 16)
Complete recovery, n 1 3
Partial recovery, n 4 2
No recovery, n 8 5
P Value 0.36
group C 5 control group; group S 5 study group.
exclusion criteria are strictly applied. Multicenteric
studies may better overcome this problem. Alternatively,
in a recently updated guideline for reporting parallel
P Value group randomized trials, Moher et al. stated that so-
called underpowered trials may be acceptable because
0.48 they ultimately could be combined in a systematic
0.48 review and meta-analysis.22
0.99 Our study was not double-blinded, but neither the
audiologist nor the author who analyzed the results of
treatment was aware of the treatment modality or of the
patient’s group allocation.
We agree with Westerlaken et al.11 that ISSNHL is
probably multifactorial in origin, and the failure as a
group to benefit from pulse therapy does not exclude the
possibility that a subgroup is highly responsive to this
treatment. We feel that a multicenter study with more
patients is needed to provide better evaluation and be
able to assess subgroups.
CONCLUSION
Within the paradigm used in this investigation,
pulse therapy with 500-mg daily methylprednisolone
and standard-dose prednisolone therapy resulted in sim-
ilar hearing improvement in ISSNHL.
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