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, followed 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 American 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 statistically 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 hearing improvement. Key Words: Sudden sensorineural hearing loss, pulse therapy, randomized controlled trial, steroid, methylprednisolone. Level of Evidence: 1b. Laryngoscope, 00:000–000, 2015
INTRODUCTION Sudden sensorineural hearing loss has been defined as a sensorineural hearing loss of 30 dB or more covering 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 corticosteroid 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 therapeutiFrom 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 Otorhinolaryngology, Loghman Hospital, Kamali Ave. Kargar, 13336–31151 Tehran, Iran. E-mail: [email protected] DOI: 10.1002/lary.25244
Laryngoscope 00: Month 2015
cally. The therapeutic dose is very wide and depends on 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 intravenously) for 1 or a few (usually 5) days.4 Since its first use for the treatment of acute rejection after kidney transplantation in 1973,5 steroid pulse therapy has come to be used in a variety of conditions such as nephrotic syndrome, crescentic glomerulonephritis, 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.
MATERIALS AND METHODS Setting A prospective randomized controlled trial on the effect of pulse therapy with methylprednisolone on ISSNHL was performed between January 2009 and October 2013 in a university-based tertiary care hospital. Institutional review board approval was obtained before proceeding with the study.
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
1
PTA. Up to 40 dB loss was defined as mild, 41 to 70 dB as moderate, 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:
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
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 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.
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
Statistics
3. Pregnant or lactating women
Participants Eighty-one patients diagnosed with ISSNHL offered enrollment into this study. Patients were the ones with idiopathic 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 randomized 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 methylprednisolone 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 therapy at our center, which is consistent with the recently recommended 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 second 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
2
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% dropout 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 analyze the results for the enrolled patients to see if any meaningful 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 followup, 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 considered 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 sensorineural hearing loss; WRS 5 word recognition scores.
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
Fig. 1. Study flow diagram. ISSNHL 5 idiopathic sudden sensorineural hearing loss. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
patient due to personal conflict and discontinued intervention. 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 statistically insignificant difference. No complications or adverse effects were observed in either group.
DISCUSSION This prospective, randomized, controlled clinical trial of comparing pulse methylprednisolone and prednisolone in the treatment of ISSNHL showed that this Laryngoscope 00: Month 2015
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 pathophysiological 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 tissues. Their therapeutic effects are considered to be mediated 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 nongenomic effects; and nonspecific, nongenomic effects caused by interactions with cellular membranes.8 Glucocorticoids (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 glucocorticoid response elements. This interaction results in the up- or down-regulation of specific genes affecting the expression of several cytokines and/or adhesion molecules. Genomic effects of GCs can be seen as early as 30 minutes after exposure to the drug, as opposed to nongenomic effects that are detected in seconds to minutes after exposure.7 Pulse therapy is the administration of suprapharmacologic 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,
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
3
TABLE III. Demographics and Baseline Audiologic Features of Patients in the Two Groups. Study Group (n 5 29)
Mean age (years)
42.2 6 12.6
40.1 6 11.9
0.816
17:12
15:16
0.427
18 21
20 24
0.844 0.655
6.7 6 2.2
7.3 6 2.3
0.396 0.625
Sex–Male:Female, n Vertigo Tinnitus Days from onset to treatment
Control Group (n 5 31) P Value
Severity of hearing loss, n Mild
1
3
Moderate
3
6
Severe Profound
12 13
12 10
Hearing level in each frequency (dB) 0.5 KHz 1 KHz
65.51 6 34.26 62.5 6 29.77 0.724 72.24 6 32.83 63.87 6 30.73 0.312
2 KHz
80.34 6 25.14 66.12 6 28.71 0.066
3 KHz 4 KHz
86.20 6 23.66 74.83 6 25.28 0.078 87.24 6 23.91 77.74 6 24.62 0.092
PTA (dB)
76.07 6 25.60 66.85 6 26.54 0.177
WRS (%)
32.24 6 38.13 49.64 6 36.79 0.243
PTA 5 pure-tone average: average of the thresholds at 0.5, 1, 2, and 3 kHz; WRS 5 word recognition score.
crescentic glomerulonephritis, SLE, optic neuritis, pemphigus vulgaris, dermatomyositis, leukocytoclastic vasculitis, rheumatoid arthritis, Kawasaki disease, Henoch Schonlein purpura, and Graves’ disease.6,7,9,10 Intravenous pulses of methylprednisolone in doses of 1,000 mg daily for 3 to 5 days are commonly used to treat severe manifestations of SLE or systemic vasculitis, but it has been suggested that 100 mg of methylprednisolone is enough to saturate most of the glucocorticoid receptors and that higher doses mediate nongenomic effects.7 Despite more than 3 decades of steroid pulse-therapy use, there is little clarity on the mechanism of action, magnitude of benefits, and adverse effects; however, it seems that the effects of corticosteroid pulses appear to include down-regulation of the activation of immune
cells and proinflammatory cytokine production, leading to reduced expression of adhesion molecules and reduced movement of neutrophils into sites of inflammation.6 Steroids have many effects in the inner ear, but it is unclear whether the suppression of an immune response, changes in microvascular circulation, mineralocorticoid effects, or a decrease in endolymphatic pressure are beneficial in ISSNHL.11–13 Considering that the antiinflammatory effect of corticosteroids is viewed to play an important part in the recovery from ISSNHL, a more powerful suppression of the immune system with high-dose corticosteroid therapy (pulse therapy) might enhance or quicken recovery.11 There are few reports of pulse therapy in ISSNHL. Narozny et al.14 seems to be the first to study the effect of this treatment in ISSNHL. Their study group received 1,000 mg of methylprednisolone intravenously for 3 days, prednisolone 60 mg per day in decreasing doses, plus hyperbaric oxygen therapy. Their control group received 30 mg prednisolone per day in decreasing dose for up to 14 days. They showed that the study group had significantly better recovery of hearing levels. Three points that should be emphasized in this study are: 1) The two groups were treated in two distinct periods; 2) the study group received hyperbaric oxygen therapy in addition to steroid, which can have an influence on the results; and 3) the control group had not been given a sufficient dose of prednisolone, as it is should have been. Westerlaken and et al.,11 in a randomized, prospective, double-blind clinical trial, allocated their patients to pulse therapy or control treatment. Pulse therapy consisted of 300 mg dexamethasone for 3 consecutive days, followed by 4 days of placebo. Control treatment consisted of 70 mg prednisone per day, tapered in steps of 10 mg per day to 0 mg. Their treatment lasted 7 days for both groups. The authors stated that overall improvement in pure-tone thresholds and speech discrimination scores was not significantly better in patients who were given dexamethasone than in those who were given standard prednisone. Although it was a good multicenter study with 71 cases, it again seems that patients of the control group had not received enough dose of prednisolone.
TABLE IV. Hearing Improvement 3 Months After Treatment in the Two Groups. Hearing Improvement
Hearing improvement at each frequency (dB)
Study Group (n 5 29)
Control Group (n 5 31)
P Value
Mean
SD
Mean
SD
0.5 KHz
52.06
41.41
50.00
33.26
0.833
1 KHz 2 KHz
55.68 65.51
41.93 38.57
51.93 55.48
34.58 35.10
0.706 0.296
3 KHz
66.72
35.96
60.96
32.28
0.516
4 KHz PTA improvement (dB)
72.58 60.00
34.86 37.84
66.12 54.59
30.40 31.80
0.447 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.
Laryngoscope 00: Month 2015
4
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
TABLE V. Recovery Results of Patients in the Two Groups. Recovery*
Study Group (n 5 29)
Control Group (n 5 31)
P Value
Complete recovery, n
7
6
0.48
Partial recovery, n No recovery, n
10 12
11 14
0.48 0.99
*Defined in Table II.
The present controlled study was intended to confirm/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 2week, 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 recovery. In our study, five patients in group S (38.46%) and five patients in group C (50%) with initial profound 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 treating 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 incidence 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 (n 5 13)
Group C (n 5 10)
Group S (n 5 16)
Group C (n 5 21)
Complete recovery, n
1
3
6
3
Partial recovery, n No recovery, n
4 8
2 5
6 4
9 9
Initial Hearing Level
P Value
0.36
group C 5 control group; group S 5 study group.
Laryngoscope 00: Month 2015
0.23
exclusion criteria are strictly applied. Multicenteric studies may better overcome this problem. Alternatively, in a recently updated guideline for reporting parallel group randomized trials, Moher et al. stated that socalled underpowered trials may be acceptable because they ultimately could be combined in a systematic review and meta-analysis.22 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 similar hearing improvement in ISSNHL.
BIBLIOGRAPHY 1. Whitaker S. Idiopathic sudden hearing loss. Am J Otol 1980;1:180–183. 2. Battaglia A, Burchette R, Cueva R. Combination therapy (intratympanic dexamethasone 1 high-dose prednisone taper) for the treatment of idiopathic sudden sensorineural hearing loss. Otol Neurotol 2008;29:453– 460. 3. Stachler RJ, Chandrasekhar SS, Archer SM, et al. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg 2012;146:S1– S35. 4. Buttgereit F, da Silva JA, Boers M, Burmester GR, Cutolo M, Jacobs J, et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002;61:718–722. 5. Woods JE, Anderson CF, DeWeerd JH, et al. High-dosage intravenously administered methylprednisolone in renal transplantation. A preliminary report. JAMA 1973;223:896–899. 6. Sinha A, Bagga A. Pulse steroid therapy. Indian J Pediatr 2008;75:1057– 1066. 7. Franchin G, Diamond B. Pulse steroids: how much is enough? Autoimmun Rev 2006;5:111–113. 8. Stahn C, Lowenberg M, Hommes DW, Buttgereit F. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol 2007;275:71–78. 9. Kubota S, Ohye H, Nishihara E, et al. Effect of high dose methylprednisolone pulse therapy followed by oral prednisolone administration on the production of anti-TSH receptor antibodies and clinical outcome in Graves’ disease. Endocr J 2005;52:735–741. 10. Kamata Y, Nara H, Sato H, Masuyama JI, Minota S, Yoshio T. Effect of steroid pulse therapy on mixed connective tissue disease with pulmonary arterial hypertension. Ann Rheum Dis 2005;64:1236– 1237. 11. Westerlaken BO, de Kleine E, van der Laan B, Albers F. The treatment of idiopathic sudden sensorineural hearing loss using pulse therapy: a prospective, randomized, double-blind clinical trial. Laryngoscope 2007;117: 684–690. 12. Garcia Berrocal JR, Ramirez-Camacho R. Immune response and immunopathology of the inner ear: an update. J Laryngol Otol 2000;114:101– 107. 13. Schreiber BE, Agrup C, Haskard DO, Luxon LM. Sudden sensorineural hearing loss. Lancet 2010;375:1203–1211. 14. Narozny W, Sicko Z, Przewozny T, Stankiewicz C, Kot J, Kuczkowski J. Usefulness of high doses of glucocorticoids and hyperbaric oxygen therapy in sudden sensorineural hearing loss treatment. Otol Neurotol 2004; 25:916–923. 15. Wen YH, Chen PR, Wu HP. Prognostic factors of profound idiopathic sudden sensorineural hearing loss. Eur Arch Otorhinolaryngol 2014;271: 1423–1429. 16. Stokroos RJ, Albers FW, Tenvergert EM. Antiviral treatment of idiopathic sudden sensorineural hearing loss: a prospective, randomized, doubleblind clinical trial. Acta Otolaryngol 1998;118:488–495.
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
5
17. Nosrati-Zarenoe R, Hultcrantz E. Corticosteroid treatment of idiopathic sudden sensorineural hearing loss: randomized triple-blind placebo-controlled trial. Otol Neurotol 2012;33:523–531. 18. Hong SM, Park CH, Lee JH. Hearing outcomes of daily intratympanic dexamethasone alone as a primary treatment modality for ISSHL. Otolaryngol Head Neck Surg 2009;141:579–583. 19. Joachims HZ, Segal J, Golz A, Netzer A, Goldenberg D. Antioxidants in treatment of idiopathic sudden hearing loss. Otol Neurotol 2003;24:572– 575.
Laryngoscope 00: Month 2015
6
20. Lim HJ, Kim YT, Choi SJ, et al. Efficacy of 3 different steroid treatments for sudden sensorineural hearing loss: a prospective, randomized trial. Otolaryngol Head Neck Surg 2013;148:121–127. 21. Kang HS, Park JJ, Ahn SK, Hur DG, Kim HY. Effect of high dose intravenous vitamin C on idiopathic sudden sensorineural hearing loss: a prospective single-blind randomized controlled trial. Eur Arch Otorhinolaryngol 2013;270:2631–2636. 22. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg 2012;10:28–55.
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
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, followed 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 American 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 statistically 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 hearing improvement. Key Words: Sudden sensorineural hearing loss, pulse therapy, randomized controlled trial, steroid, methylprednisolone. Level of Evidence: 1b. Laryngoscope, 00:000–000, 2015
INTRODUCTION Sudden sensorineural hearing loss has been defined as a sensorineural hearing loss of 30 dB or more covering 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 corticosteroid 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 therapeutiFrom 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 Otorhinolaryngology, Loghman Hospital, Kamali Ave. Kargar, 13336–31151 Tehran, Iran. E-mail: [email protected] DOI: 10.1002/lary.25244
Laryngoscope 00: Month 2015
cally. The therapeutic dose is very wide and depends on 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 intravenously) for 1 or a few (usually 5) days.4 Since its first use for the treatment of acute rejection after kidney transplantation in 1973,5 steroid pulse therapy has come to be used in a variety of conditions such as nephrotic syndrome, crescentic glomerulonephritis, 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.
MATERIALS AND METHODS Setting A prospective randomized controlled trial on the effect of pulse therapy with methylprednisolone on ISSNHL was performed between January 2009 and October 2013 in a university-based tertiary care hospital. Institutional review board approval was obtained before proceeding with the study.
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
1
PTA. Up to 40 dB loss was defined as mild, 41 to 70 dB as moderate, 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:
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
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 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.
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
Statistics
3. Pregnant or lactating women
Participants Eighty-one patients diagnosed with ISSNHL offered enrollment into this study. Patients were the ones with idiopathic 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 randomized 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 methylprednisolone 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 therapy at our center, which is consistent with the recently recommended 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 second 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
2
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% dropout 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 analyze the results for the enrolled patients to see if any meaningful 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 followup, 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 considered 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 sensorineural hearing loss; WRS 5 word recognition scores.
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
Fig. 1. Study flow diagram. ISSNHL 5 idiopathic sudden sensorineural hearing loss. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
patient due to personal conflict and discontinued intervention. 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 statistically insignificant difference. No complications or adverse effects were observed in either group.
DISCUSSION This prospective, randomized, controlled clinical trial of comparing pulse methylprednisolone and prednisolone in the treatment of ISSNHL showed that this Laryngoscope 00: Month 2015
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 pathophysiological 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 tissues. Their therapeutic effects are considered to be mediated 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 nongenomic effects; and nonspecific, nongenomic effects caused by interactions with cellular membranes.8 Glucocorticoids (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 glucocorticoid response elements. This interaction results in the up- or down-regulation of specific genes affecting the expression of several cytokines and/or adhesion molecules. Genomic effects of GCs can be seen as early as 30 minutes after exposure to the drug, as opposed to nongenomic effects that are detected in seconds to minutes after exposure.7 Pulse therapy is the administration of suprapharmacologic 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,
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
3
TABLE III. Demographics and Baseline Audiologic Features of Patients in the Two Groups. Study Group (n 5 29)
Mean age (years)
42.2 6 12.6
40.1 6 11.9
0.816
17:12
15:16
0.427
18 21
20 24
0.844 0.655
6.7 6 2.2
7.3 6 2.3
0.396 0.625
Sex–Male:Female, n Vertigo Tinnitus Days from onset to treatment
Control Group (n 5 31) P Value
Severity of hearing loss, n Mild
1
3
Moderate
3
6
Severe Profound
12 13
12 10
Hearing level in each frequency (dB) 0.5 KHz 1 KHz
65.51 6 34.26 62.5 6 29.77 0.724 72.24 6 32.83 63.87 6 30.73 0.312
2 KHz
80.34 6 25.14 66.12 6 28.71 0.066
3 KHz 4 KHz
86.20 6 23.66 74.83 6 25.28 0.078 87.24 6 23.91 77.74 6 24.62 0.092
PTA (dB)
76.07 6 25.60 66.85 6 26.54 0.177
WRS (%)
32.24 6 38.13 49.64 6 36.79 0.243
PTA 5 pure-tone average: average of the thresholds at 0.5, 1, 2, and 3 kHz; WRS 5 word recognition score.
crescentic glomerulonephritis, SLE, optic neuritis, pemphigus vulgaris, dermatomyositis, leukocytoclastic vasculitis, rheumatoid arthritis, Kawasaki disease, Henoch Schonlein purpura, and Graves’ disease.6,7,9,10 Intravenous pulses of methylprednisolone in doses of 1,000 mg daily for 3 to 5 days are commonly used to treat severe manifestations of SLE or systemic vasculitis, but it has been suggested that 100 mg of methylprednisolone is enough to saturate most of the glucocorticoid receptors and that higher doses mediate nongenomic effects.7 Despite more than 3 decades of steroid pulse-therapy use, there is little clarity on the mechanism of action, magnitude of benefits, and adverse effects; however, it seems that the effects of corticosteroid pulses appear to include down-regulation of the activation of immune
cells and proinflammatory cytokine production, leading to reduced expression of adhesion molecules and reduced movement of neutrophils into sites of inflammation.6 Steroids have many effects in the inner ear, but it is unclear whether the suppression of an immune response, changes in microvascular circulation, mineralocorticoid effects, or a decrease in endolymphatic pressure are beneficial in ISSNHL.11–13 Considering that the antiinflammatory effect of corticosteroids is viewed to play an important part in the recovery from ISSNHL, a more powerful suppression of the immune system with high-dose corticosteroid therapy (pulse therapy) might enhance or quicken recovery.11 There are few reports of pulse therapy in ISSNHL. Narozny et al.14 seems to be the first to study the effect of this treatment in ISSNHL. Their study group received 1,000 mg of methylprednisolone intravenously for 3 days, prednisolone 60 mg per day in decreasing doses, plus hyperbaric oxygen therapy. Their control group received 30 mg prednisolone per day in decreasing dose for up to 14 days. They showed that the study group had significantly better recovery of hearing levels. Three points that should be emphasized in this study are: 1) The two groups were treated in two distinct periods; 2) the study group received hyperbaric oxygen therapy in addition to steroid, which can have an influence on the results; and 3) the control group had not been given a sufficient dose of prednisolone, as it is should have been. Westerlaken and et al.,11 in a randomized, prospective, double-blind clinical trial, allocated their patients to pulse therapy or control treatment. Pulse therapy consisted of 300 mg dexamethasone for 3 consecutive days, followed by 4 days of placebo. Control treatment consisted of 70 mg prednisone per day, tapered in steps of 10 mg per day to 0 mg. Their treatment lasted 7 days for both groups. The authors stated that overall improvement in pure-tone thresholds and speech discrimination scores was not significantly better in patients who were given dexamethasone than in those who were given standard prednisone. Although it was a good multicenter study with 71 cases, it again seems that patients of the control group had not received enough dose of prednisolone.
TABLE IV. Hearing Improvement 3 Months After Treatment in the Two Groups. Hearing Improvement
Hearing improvement at each frequency (dB)
Study Group (n 5 29)
Control Group (n 5 31)
P Value
Mean
SD
Mean
SD
0.5 KHz
52.06
41.41
50.00
33.26
0.833
1 KHz 2 KHz
55.68 65.51
41.93 38.57
51.93 55.48
34.58 35.10
0.706 0.296
3 KHz
66.72
35.96
60.96
32.28
0.516
4 KHz PTA improvement (dB)
72.58 60.00
34.86 37.84
66.12 54.59
30.40 31.80
0.447 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.
Laryngoscope 00: Month 2015
4
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
TABLE V. Recovery Results of Patients in the Two Groups. Recovery*
Study Group (n 5 29)
Control Group (n 5 31)
P Value
Complete recovery, n
7
6
0.48
Partial recovery, n No recovery, n
10 12
11 14
0.48 0.99
*Defined in Table II.
The present controlled study was intended to confirm/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 2week, 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 recovery. In our study, five patients in group S (38.46%) and five patients in group C (50%) with initial profound 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 treating 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 incidence 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 (n 5 13)
Group C (n 5 10)
Group S (n 5 16)
Group C (n 5 21)
Complete recovery, n
1
3
6
3
Partial recovery, n No recovery, n
4 8
2 5
6 4
9 9
Initial Hearing Level
P Value
0.36
group C 5 control group; group S 5 study group.
Laryngoscope 00: Month 2015
0.23
exclusion criteria are strictly applied. Multicenteric studies may better overcome this problem. Alternatively, in a recently updated guideline for reporting parallel group randomized trials, Moher et al. stated that socalled underpowered trials may be acceptable because they ultimately could be combined in a systematic review and meta-analysis.22 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 similar hearing improvement in ISSNHL.
BIBLIOGRAPHY 1. Whitaker S. Idiopathic sudden hearing loss. Am J Otol 1980;1:180–183. 2. Battaglia A, Burchette R, Cueva R. Combination therapy (intratympanic dexamethasone 1 high-dose prednisone taper) for the treatment of idiopathic sudden sensorineural hearing loss. Otol Neurotol 2008;29:453– 460. 3. Stachler RJ, Chandrasekhar SS, Archer SM, et al. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg 2012;146:S1– S35. 4. Buttgereit F, da Silva JA, Boers M, Burmester GR, Cutolo M, Jacobs J, et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002;61:718–722. 5. Woods JE, Anderson CF, DeWeerd JH, et al. High-dosage intravenously administered methylprednisolone in renal transplantation. A preliminary report. JAMA 1973;223:896–899. 6. Sinha A, Bagga A. Pulse steroid therapy. Indian J Pediatr 2008;75:1057– 1066. 7. Franchin G, Diamond B. Pulse steroids: how much is enough? Autoimmun Rev 2006;5:111–113. 8. Stahn C, Lowenberg M, Hommes DW, Buttgereit F. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol 2007;275:71–78. 9. Kubota S, Ohye H, Nishihara E, et al. Effect of high dose methylprednisolone pulse therapy followed by oral prednisolone administration on the production of anti-TSH receptor antibodies and clinical outcome in Graves’ disease. Endocr J 2005;52:735–741. 10. Kamata Y, Nara H, Sato H, Masuyama JI, Minota S, Yoshio T. Effect of steroid pulse therapy on mixed connective tissue disease with pulmonary arterial hypertension. Ann Rheum Dis 2005;64:1236– 1237. 11. Westerlaken BO, de Kleine E, van der Laan B, Albers F. The treatment of idiopathic sudden sensorineural hearing loss using pulse therapy: a prospective, randomized, double-blind clinical trial. Laryngoscope 2007;117: 684–690. 12. Garcia Berrocal JR, Ramirez-Camacho R. Immune response and immunopathology of the inner ear: an update. J Laryngol Otol 2000;114:101– 107. 13. Schreiber BE, Agrup C, Haskard DO, Luxon LM. Sudden sensorineural hearing loss. Lancet 2010;375:1203–1211. 14. Narozny W, Sicko Z, Przewozny T, Stankiewicz C, Kot J, Kuczkowski J. Usefulness of high doses of glucocorticoids and hyperbaric oxygen therapy in sudden sensorineural hearing loss treatment. Otol Neurotol 2004; 25:916–923. 15. Wen YH, Chen PR, Wu HP. Prognostic factors of profound idiopathic sudden sensorineural hearing loss. Eur Arch Otorhinolaryngol 2014;271: 1423–1429. 16. Stokroos RJ, Albers FW, Tenvergert EM. Antiviral treatment of idiopathic sudden sensorineural hearing loss: a prospective, randomized, doubleblind clinical trial. Acta Otolaryngol 1998;118:488–495.
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
5
17. Nosrati-Zarenoe R, Hultcrantz E. Corticosteroid treatment of idiopathic sudden sensorineural hearing loss: randomized triple-blind placebo-controlled trial. Otol Neurotol 2012;33:523–531. 18. Hong SM, Park CH, Lee JH. Hearing outcomes of daily intratympanic dexamethasone alone as a primary treatment modality for ISSHL. Otolaryngol Head Neck Surg 2009;141:579–583. 19. Joachims HZ, Segal J, Golz A, Netzer A, Goldenberg D. Antioxidants in treatment of idiopathic sudden hearing loss. Otol Neurotol 2003;24:572– 575.
Laryngoscope 00: Month 2015
6
20. Lim HJ, Kim YT, Choi SJ, et al. Efficacy of 3 different steroid treatments for sudden sensorineural hearing loss: a prospective, randomized trial. Otolaryngol Head Neck Surg 2013;148:121–127. 21. Kang HS, Park JJ, Ahn SK, Hur DG, Kim HY. Effect of high dose intravenous vitamin C on idiopathic sudden sensorineural hearing loss: a prospective single-blind randomized controlled trial. Eur Arch Otorhinolaryngol 2013;270:2631–2636. 22. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg 2012;10:28–55.
Eftekharian et al.: Pulse Steroid in Sudden Sensorineural Hearing Loss
