- Email: [email protected]
Oral steroid regimens for idiopathic sudden sensorineural hearing loss
ORIGINAL ARTICLES Oral steroid regimens for idiopathic sudden sensorineural hearing loss WILLIAM H. SLATTERY,
MD,
LAUREL M. FISHER,
PHD,
ZARINA IQBAL,
OBJECTIVE: To determine hearing recovery in patients with idiopathic sudden hearing loss treated with varying amounts of oral steroids. STUDY DESIGN AND SETTING: A retrospective chart review (n ⴝ 75) in a tertiary care clinic examined sudden hearing loss patients treated with 1 60-mg prednisone taper, 1 course of steroid less than a 60-mg taper, or any 2 courses of oral steroid. RESULTS: Overall, 35% of the patients recovered a clinically significant amount of hearing. Recovery was associated with immediate treatment (within 2 weeks from onset), better hearing at the onset of treatment, and treatment with the higher dose of prednisone in patients with just 1 additional symptom (dizziness or tinnitus). Patients tended to continue to experience some recovery in hearing up to 4 months after treatment. CONCLUSION: Immediate treatment of patients with unilateral idiopathic sudden hearing loss and additional symptoms (dizziness or tinnitus) with a 14-day course of 60 mg prednisone (with taper) is recommended. EBM rating: B-3. (Otolaryngol Head Neck Surg 2005;132:5-10.)
I
diopathic sudden sensorineural hearing loss affects between 5 to 20 persons per 100,000 annually1 and was first described in 1944.2 Two of the primary hypotheses for idiopathic sudden loss are damage to the auditory nerve from inflammation due to a viral infection or due to a vascular incident. Wilson et al3 reported the only randomized controlled trial of oral steroid compared From the House Ear Institute, Los Angeles, CA. In addition to the first author, the physicians of the House Ear Clinic; John House, MD, Derald Brackmann, MD, William Luxford, MD, Antonio De La Cruz, MD, M. Jennifer Derebery, MD, Rick Friedman, MD, PhD, and Jose Fayad, MD, contributed patients to the study. A portion of this work was originally presented at the Annual Meeting of the American Academy of Otolaryngology, September 2001. Reprint requests: William H. Slattery, MD, House Ear Institute/House Clinic, 2100 West Third Street, Los Angeles, CA 90057; e-mail, [email protected]. 0194-5998/$30.00 Copyright © 2005 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. doi:10.1016/j.otohns.2004.09.072
MPH,
and NANCY LIU,
MD,
Los Angeles, California
with placebo treatment, ushering in oral steroids as the standard of care for sudden loss. Generally, patients with sudden loss present to primary care or emergency room physicians. Ninety-eight percent of these physicians prescribe steroids,4 usually the Medrol Dose Pack (first day 24-mg methylprednisolone, tapered over 5 days). A range of steroid doses have been reviewed in the literature, from very small amounts to intravenous administration.5,6 Some studies do not report the amount of oral steroid given, apparently putting all patients who received any dose of steroid together in a “treated” group.7 The optimal dose of oral steroid associated with hearing recovery is not clear. In the 1 randomized clinical trial of oral steroid for sudden hearing loss, Wilson et al3 included 2 investigational sites that delivered 2 different doses of oral steroid (16-mg taper of dexamethasone, 48-mg taper of methylprednisolone). The sample sizes of the 2 treatment groups were too small to detect any differences in response (power ⬍.4, nQuery Advisor 5.0). Therefore, the 2 treatment groups were combined for the overall analysis, demonstrating the efficacy of oral steroids relative to placebo, but not the amount. Our current practice is to prescribe a 60-mg dose of prednisone, tapered over 14 days. In addition to the amount of steroid associated with recovery, the length of time the medication should be given has not been well established. Some physicians have begun to prescribe a second course of oral steroid in the absence of recovery from the first course. It is unknown whether a second course would promote hearing recovery in the absence of a response to the first course. Further, the time course of recovery is not well documented. It appears that patients may experience some hearing recovery after drug treatment has ended, in some cases up to 1 month after treatment.8 Whether patients continue to recover hearing beyond 1 month after treatment is unknown. Many of the previous studies of sudden hearing loss lament the lack of comparability across studies. There are no standard inclusion criteria, thus, there has been great variability in the amount of hearing loss, including patients with bilateral loss or a nonnormal contralat5
6
Otolaryngology– Head and Neck Surgery January 2005
SLATTERY et al
Table 1. Inclusion/exclusion criteria Inclusion Criteria: ● Hearing loss of at least 30 dB across 3 contiguous frequencies within 72 hours. ● Presented to any physician within 10 days of hearing loss onset. ● Received oral steroid treatment. ● An audiogram at the time of presentation to the physician and at least 1 follow-up audiogram. ● No evidence of retrocochlear disease on MRI. Exclusion Criteria: ● A cause for the sudden loss was determined, such as an acoustic neuroma. ● Medication history for treatment of sudden loss could not be determined. ● Nonaffected ear had poor hearing (PTA ⬎50 dB).
eral ear,7,9-12 the age at onset (some studies include children), and how additional symptoms of dizziness and tinnitus are reported. Most investigators agree that idiopathic sudden hearing loss is a multifaceted disease entity, with a number of suggested causes.9,13 The route to understanding a multifaceted disease is to carefully restrict the characteristics of patients included in a treatment study, then sound conclusions can be drawn. The present study aims to address these issues. This is a retrospective chart review designed to assess the effect of differences in amount of oral steroid on hearing recovery in sudden hearing loss patients. We hypothesized that a 60-mg taper of prednisone is the optimal treatment for sudden hearing loss. Strict inclusion criteria were applied to the selection of patients in order to create a homogenous sample for comparison of treatment effects. We examine both statistically significant improvement and clinically significant improvement in a sample of 75 patients. METHODS Subjects All charts for patients receiving a diagnosis of sudden hearing loss who presented to the House Ear Clinic between October 1999 and September 2002 were retrospectively examined for the inclusion and exclusion criteria shown in Table 1. A total of 75 patients met the inclusion/exclusion criteria, 34 females (45%) and 41 males (55%). The left ear was the affected ear in 41 (55%) cases. The patients were grouped by type of treatment received for sudden hearing loss: group 1 received a course of 60-mg prednisone tapered over 14 days (see Table 2). Group 2 received a lesser dose of prednisone, frequently a Medrol Dose pack prior to presentation. Group 3 received any 2 courses of oral steroid, usually a Medrol Dose Pack, followed by a course of 60-mg prednisone tapered over 14 days.
Table 2. Course of 60 mg prednisone for idiopathic sudden sensorineural hearing loss Dosage schedule
Prednisone 10-mg tablets
Day 1-9 Day 10 Day 11 Day 12 Day 13 Day 14 Total prednisone over 14 days
6 tablets (60 mg) 4 tablets (40 mg) 3 tablets (30 mg) 2 tablets (20 mg) 1 tablet (10 mg) 1/2 tablet in AM (5 mg) 645 mg
Average age at onset of hearing loss, amount of hearing loss, and time to treatment are shown in Table 3. There were no significant differences between the groups at presentation (P ⬎ 0.05). Forty-six (61%) patients experienced the additional symptom of dizziness and 68 (91%) experienced tinnitus in addition to hearing loss. Two (3%) patients did not experience either tinnitus or dizziness at onset and 55% (n ⫽ 41) experienced both symptoms. There were no differences in frequency of these additional symptoms by group at presentation. Outcome Analysis The outcome variables were 4 frequency pure-tone average (PTA) and speech discrimination score (SDS). Repeated measures analysis compared pre- and posttreatment hearing by group. Hearing was also categorized by amount of hearing recovered after treatment. The posttreatment assessment occurred an average of 44 days after hearing loss. The time from hearing loss to posttreatment assessment did not differ by treatment groups (P ⬎ 0.05). A clinical success was considered to be recovery of hearing to within 50% of the difference between affected and unaffected ear at the baseline audiogram.12,14,15 Group success rates were compared by 2. Parametric and nonparametric correlations were used to examine for relationships among patient demographics and hearing improvement. Posttreatment hearing (PTA and SDS) was analyzed using an analysis of covariance controlling for differences in time to treatment and pretreatment hearing levels. Significance levels for all analyses were set at P ⬎ 0.05. RESULTS There were no adverse events as a result of steroid treatment in the 75 patients included in the study. Hearing outcome was assessed in a repeated measures analysis of variance. Treatment with oral steroids significantly improved hearing, as assessed by both PTA and speech discrimination (Ps ⬍ 0.001). There was no effect of treatment group; patients from each group
Otolaryngology– Head and Neck Surgery Volume 132 Number 1
SLATTERY et al 7
Table 3. Average demographics by treatment group (standard deviation)
Age at onset of hearing loss (y) Time to first treatment (d) Unaffected ear: Pretreatment PTA (dB) Pretreatment speech discrimination score (% correct) Affected ear: Pretreatment PTA (dB) Pretreatment speech discrimination score (% correct)
60-mg Taper (n ⴝ 37)
Less than 60 mg (n ⴝ 25)
Any 2 courses (n ⴝ 13)
51.3 (11.2) 11.1 (14.4)
54.3 (9.2) 6 (7.2)
48.2 (12.0) 14.7 (14.4)
10.7 (6.8) 96.9 (9.3)
13.0 (8.8) 98.4 (3.1)
12.1 (9.8) 97.9 (3.1)
80.1 (30.0) 24.1 (34.8)
83.0 (31.9) 24.0 (33.2)
69.8 (31.4) 29.9 (42.5)
No significant differences by group on any variable.
Table 4. Average hearing outcome (pure-tone average, speech discrimination) by treatment group (standard deviation)
Posttreatment PTA (dB) Posttreatment speech discrimination score (%) Improvement from pre- to posttreatment PTA (dB) Improvement from pre- to posttreatment SDS (%) Success rate* Number recovering to normal hearing (PTA ⬍25 dB)
60-mg Taper (n ⴝ 37)
Less than 60 mg (n ⴝ 25)
Any 2 courses (n ⴝ 13)
61.0 (34.7) 38.9 (39.9) 19.1 (22.5) 12.1 (21.3) 14/37 (38%) 5/37 (13.5%)
64.0 (31.2) 45.3 (42.7) 19.0 (21.9) 18.3 (23.8) 9/25 (36%) 1/25 (4.0%)
50.8 (23.2) 46.8 (40.4) 19.0 (19.2) 19.1 (26.6) 3/13 (23%) 2/13 (15.4%)
*Success is defined as an improvement in pure-tone average equaling or exceeding 50% of the difference between pretreatment unaffected and affected ear.
experienced similar changes in hearing from initial treatment to posttreatment (see Table 4). Across the 3 treatment groups, 35% experienced a clinically successful outcome, defined as a recovery of at least 50% of the difference between the ears. A 2 analysis revealed no significant differences in the percentage of clinical successes by treatment group. There were no group differences in the percentage of ears recovering to normal or to a PTA less than or equal to 25 dB (see Table 4). Differences in posttreatment PTA were further examined with an analysis of covariance with time to treatment and pretreatment PTA as covariates, with treatment group and presence of additional symptoms (1 or 2 symptoms) as fixed factors. The model resulted in an R2 of 66%, indicating that the factors and covariates were associated with a large portion of the variance in posttreatment PTA. Both time to treatment and pretreatment PTA were significant covariates (Ps ⬍ 0.003), confirming the use of these variables as covariates. The majority of those experiencing a clinically successful outcome were treated within 2 weeks of onset of hearing loss. Better pretreatment hearing was associated with better posttreatment hearing. There were no significant main effects of either treatment group or presence of additional symptoms. A significant interaction of treatment group and additional symptoms was found (P ⬍ 0.02). An exami-
nation of the means revealed that less than a 60-mg taper dose was associated with no differences in posttreatment PTA between patients with an additional symptom (PTA, 68 dB) and patients with both dizziness and tinnitus (PTA, 62 dB). A 60-mg taper dose was associated with significantly better posttreatment PTA (48 dB) for patients with 1 additional symptom. Patients with both symptoms and who received a 60-mg taper dose of steroid did not show much posttreatment benefit (PTA, 68 dB). Put another way, the 60-mg prednisone taper resulted in greater improvement for the patients with 1 additional otologic symptom, whereas the smaller amount of prednisone did not result in a better result for patients with 1 additional symptom. Patients with 2 additional symptoms were at the greatest disadvantage, no amount of prednisone in this study produced increased benefit. The correlations among the patient characteristics and hearing variables were examined. Patients with better hearing before treatment or who were not experiencing symptoms of dizziness or tinnitus tended to delay seeking treatment. Conversely, patients with poorer hearing or experiencing dizziness and tinnitus sought treatment within the first week of symptom onset. Younger patients tended to have less hearing loss than older patients and tended to not experience dizziness and tinnitus with the hearing loss. (See Table 5 for correlation coefficients.)
8
Otolaryngology– Head and Neck Surgery January 2005
SLATTERY et al
Table 5. Correlation coefficients (significance level) among patient characteristics and hearing in the affected ear (n ⫽ 75) Variable
Age at hearing loss
Time from loss to treatment
Experiencing dizziness/tinnitus
Time from loss to treatment Experiencing dizziness/tinnitus Pretreatment PTA Pretreatment SDS*
⫺.16 (NS) .18 (.06) .35 (.002) ⫺.39 (.001)
— .02 (NS) ⫺.21 (.07) .21 (.09)
— — .17 (.07) ⫺.25 (.02)
NS, Not significant; PTA, 4-frequency pure tone average; SDS, speech discrimination. *n ⫽ 66.
Change after Finishing Treatment For a subset of 34 patients, additional follow-up audiograms were available at an average of 4 months after the onset of hearing loss. Change in PTA was examined across the pretreatment to the second posttreatment evaluation without regard to treatment group. There was a statistically significant improvement in PTA from the evaluation at the end of treatment to the second posttreatment evaluation (P ⬍ 0.001). One additional patient improved at least 50% of the baseline difference in PTA between the unaffected and affected ears with no further treatment. DISCUSSION Patients with idiopathic sudden hearing loss were grouped on the basis of treatment received for a retrospective analysis of hearing outcome. Patients receiving a 14-day 60-mg course of prednisone with taper, those receiving less than 60 mg with taper, and those receiving any 2 doses of oral steroids were compared pre- and posttreatment. There were no treatment group differences in posttreatment PTA or SDS. Posttreatment outcome differed significantly by the amount of hearing present at the time of receiving the first treatment and by the presence or absence of additional otologic symptoms (dizziness and/or tinnitus). Receiving prompt treatment (within 14 days from onset of loss) or mild to moderate hearing loss was associated with better hearing outcome, regardless of the amount of oral steroid given as treatment. These results are consistent with the previous literature on treatment of sudden hearing loss.1,9 We did not find an overall treatment group difference in the percentage of patients who improved a clinically significant amount or to within normal hearing. Just 35% of the sample in this study could be defined as experiencing a clinical improvement, regardless of the amount of oral steroid received. This does not exceed the previously reported rates of spontaneous recovery of 45% to 65%.3,9,11 However, a treatment group difference emerged when controlling for time to treatment and
amount of hearing loss. Receiving the 60-mg taper was associated with better outcome for patients with a single additional symptom relative to those with 2 additional symptoms. Receiving the smaller dose of oral steroid did not give this advantage to those with only a single additional symptom. This suggests that the higher dose of prednisone is the treatment to which patients with somewhat less otologic damage may best respond. Those with 2 additional symptoms may have the poorest prognosis, regardless of the amount of steroid treatment. Sudden hearing loss has received much attention without commensurate answers to major clinical questions. Several reasons for the lack of consistent findings are inconsistent patient inclusion criteria, small sample sizes with enormous variability, and the need for a better disease marker than simply an audiologic profile. Clinical descriptions and study inclusion criteria vary widely. For example, some studies do not report the hearing in the unaffected ear,15 others report that some patients had poorer hearing in the unaffected ear relative to what was defined as the affected ear.7,16 It is generally assumed that the status of the unaffected ear does not indicate different patient populations or causes. However, it is not clear that the same disease mechanism is involved in patients with a pre-existing hearing loss in one ear. Examining outcomes on the basis of contralateral ear status in addition to the affected ear is an important step in controlling for this unknown factor. Here we excluded patients with poor hearing in the unaffected ear. Conclusions based on small samples sizes are particularly vulnerable when there is significant variability in the data. The data in the present study, as in most of the sudden hearing loss literature, were quite variable, with affected ear presentation PTA ranging from 10 dB to complete loss. The present study used multivariate statistical techniques to exploit the variability in the data by examining relationships among the variables. Sample sizes much smaller than 70 patients are not appropriate for this approach and alternative techniques should be used.
Otolaryngology– Head and Neck Surgery Volume 132 Number 1
Characterization of sudden hearing loss currently depends on pure-tone threshold measurements, and, to a lesser extent, speech discrimination scores. Measures of hearing are noninvasive, clinically useful methods to assess damage to the auditory system, but are nonspecific as to underlying mechanism. There is a long history of attempts to develop a more biologically informative marker of sudden loss1,11,13,17 centering on assessment of inflammatory responses. For example, erythrocyte sedimentation rate (ESR) is a nonspecific indicator of inflammation and can show elevated values in a number of conditions.18 ESR values can reflect changes with corticosteroid treatment for diseases with a known inflammatory component, such as polymyalgia rheumatica.19 ESR values in sudden hearing loss patients have been reported.9,20,21 However, these studies have not consistently related laboratory values to treatment outcome or to amount of hearing loss. Byl9 noted that elevated ESR was associated with poorer recovery, while Fetterman et al20 reported the percentage of patients with an elevated ESR, but no association with treatment outcome. Wilson et al3collected ESR information on their subjects but did not report levels or relationship of those levels to outcome. Another potential biomarker for sudden hearing loss is antiendothelial cell antibodies expression (AECAs), which have been linked to autoimmune diseases, such as systemic vasculitis.17 Cadoni et al1 investigated AECA positivity in patients with sudden hearing loss and a control group. A statistically significant proportion of patients with sudden hearing loss exhibited AECA positivity (54%) relative to the controls (14%). Treatment of the sudden hearing loss was based on the AECA results. Those with increased levels of AECAs were given a 1-month course of methylprednisolone and those who were AECA negative were given a 15-day course. A significant difference in hearing recovery between the treatment groups was found. Of the patients who were AECA negative, 93% showed recovery relative to 53% recovery of the AECA positive patients, despite the extra 2 weeks they took methylprednisolone. The association between pretreatment hearing loss, AECA positivity, and recovery was not analyzed. Thus, it is not known whether the patients who did not recover had worse pretreatment hearing relative to those who recovered in each patient group. However, it appears that AECA assessment in patients with sudden hearing loss may have some clinical utility. Further work to develop biomarkers of sudden loss is necessary before either AECA expression or ESR can be recommended for management of sudden hearing loss.
SLATTERY et al 9
The main hypotheses for sudden hearing loss causes are viral or vascular mechanisms. These hypotheses currently have what Chen et al7 have described as “circumstantial evidence” for support. For example, the rapid onset of loss appears much like responses to strokes or patients report the hearing loss in conjunction with or soon after an upper respiratory infection. These observations are hints at cause but are not evidence for an hypothesis. Studies such as Cardoni et al1 examining a biological marker for sudden hearing loss will also provide support for hypotheses regarding cause and differentiating groups of patients based on specific causes. CONCLUSION Oral steroid remains the standard of care for patients with sudden hearing loss. Patients should seek treatment immediately and receive a high dose of prednisone (60-mg taper) for at least 14 days for the best chance of recovery, particularly if they have only 1 additional symptom, such as dizziness or tinnitus. Time to treatment, amount of hearing loss, and presence of additional symptoms (dizziness or tinnitus) are associated with amount of recovery. Finally, patients tend to continue to recover hearing as late as 4 months posttreatment, although type of treatment does not appear to affect amount of continued recovery. We thank Karen Berliner, PhD, for her helpful editorial comments on an earlier draft of this manuscript. REFERENCES 1. Cadoni G, Agostino S, Manna R, et al. Clinical associations of serum antiendothelial cell antibodies in patients with sudden sensorineural hearing loss. Laryngoscope 2003;113(5):797-801. 2. DeKleyn A. Sudden complete or partial loss of function of the octavus-system in apparently normal person. Acta Otolaryngol 1944;32:407-25. 3. Wilson WR, Byl FM, Laird N. The efficacy of steroids in the treatment of Idiopathic sudden hearing loss: a double-blind clinical study. Arch Otolaryngol 1980;106(12):772-6. 4. Loughran S. Management of sudden sensorineural hearing loss: a consultant survey. J Laryngol Otol 2000;114(11):837-9. 5. Lalaki P, Markou K, Tsalighopoulos MG, et al. Transiently evoked otoacoustic emissions as a prognostic indicator in idiopathic sudden hearing loss. Scand Audiol Suppl 2001;52:141-5. 6. Lefebvre PP, Staecker H. Steroid perfusion of the inner ear for sudden sensorineural hearing loss after failure of conventional therapy: a pilot study. Acta Otolaryngol 2002;122(7):698-702. 7. Chen CY, Halpin C, Rauch SD. Oral steroid treatment of sudden sensorineural hearing loss: a ten year retrospective analysis. Otol Neurotol 2003;24(5):728-33. 8. Cinamon U, Bendet E, Kronenberg J. Steroids, carbogen or placebo for sudden hearing loss: a prospective double-blind study. Eur Arch Otorhinolaryngol 2001;258(9):477-80. 9. Byl FM, Jr. Sudden hearing loss: eight years’ experience and suggested prognostic table. Laryngoscope 1984;94(5 Pt 1):647-61. 10. Grandis JR, Hirsch BE, Wagener MM. Treatment of idiopathic sudden sensorineural hearing loss. Am J Otol 1993;14(2):183-5.
Otolaryngology– Head and Neck Surgery January 2005
10 SLATTERY et al
11. Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86(4 Pt 1):463-80. 12. Wilkins SA, Jr, Mattox DE, Lyles A. Evaluation of a “shotgun” regimen for sudden hearing loss. Otolaryngol Head Neck Surg 1987;97(5):474-80. 13. Berrocal JR, Ramirez-Camacho R. Sudden sensorineural hearing loss: supporting the immunologic theory. Ann Otol Rhinol Laryngol 2002;111(11):989-97. 14. Moskowitz D, Lee KJ, Smith HW. Steroid use in idiopathic sudden sensorineural hearing loss. Laryngoscope 1984;94(5 Pt 1):664-6. 15. Zadeh MH, Storper IS, Spitzer JB. Diagnosis and treatment of sudden-onset sensorineural hearing loss: a study of 51 patients. Otolaryngol Head Neck Surg 2003;128(1):92-8. 16. Minoda R, Masuyama K, Habu K, et al. Initial steroid hormone
17. 18. 19.
20. 21.
dose in the treatment of idiopathic sudden deafness. Am J Otol 2000;21(6):819-25. Ottaviani F, Cadoni G, Marinelli L, et al. Anti-endothelial autoantibodies in patients with sudden hearing loss. Laryngoscope 1999;109(7 Pt 1):1084-7. Brigden ML. Clinical utility of the erythrocyte sedimentation rate. Am Fam Physician 1999;60(5):1443-50. Leeb BF, Bird HA, Nesher G, et al. EULAR response criteria for polymyalgia rheumatica: results of an initiative of the European Collaborating Polymyalgia Rheumatica Group (subcommittee of ESCISIT). Ann Rheum Dis 2003;62(12):1189-94. Fetterman BL, Saunders JE, Luxford WM. Prognosis and treatment of sudden sensorineural hearing loss. Am J Otol 1996;17(4):529-36. Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86(4 Pt 1):463-80.
MD,
LAUREL M. FISHER,
PHD,
ZARINA IQBAL,
OBJECTIVE: To determine hearing recovery in patients with idiopathic sudden hearing loss treated with varying amounts of oral steroids. STUDY DESIGN AND SETTING: A retrospective chart review (n ⴝ 75) in a tertiary care clinic examined sudden hearing loss patients treated with 1 60-mg prednisone taper, 1 course of steroid less than a 60-mg taper, or any 2 courses of oral steroid. RESULTS: Overall, 35% of the patients recovered a clinically significant amount of hearing. Recovery was associated with immediate treatment (within 2 weeks from onset), better hearing at the onset of treatment, and treatment with the higher dose of prednisone in patients with just 1 additional symptom (dizziness or tinnitus). Patients tended to continue to experience some recovery in hearing up to 4 months after treatment. CONCLUSION: Immediate treatment of patients with unilateral idiopathic sudden hearing loss and additional symptoms (dizziness or tinnitus) with a 14-day course of 60 mg prednisone (with taper) is recommended. EBM rating: B-3. (Otolaryngol Head Neck Surg 2005;132:5-10.)
I
diopathic sudden sensorineural hearing loss affects between 5 to 20 persons per 100,000 annually1 and was first described in 1944.2 Two of the primary hypotheses for idiopathic sudden loss are damage to the auditory nerve from inflammation due to a viral infection or due to a vascular incident. Wilson et al3 reported the only randomized controlled trial of oral steroid compared From the House Ear Institute, Los Angeles, CA. In addition to the first author, the physicians of the House Ear Clinic; John House, MD, Derald Brackmann, MD, William Luxford, MD, Antonio De La Cruz, MD, M. Jennifer Derebery, MD, Rick Friedman, MD, PhD, and Jose Fayad, MD, contributed patients to the study. A portion of this work was originally presented at the Annual Meeting of the American Academy of Otolaryngology, September 2001. Reprint requests: William H. Slattery, MD, House Ear Institute/House Clinic, 2100 West Third Street, Los Angeles, CA 90057; e-mail, [email protected]. 0194-5998/$30.00 Copyright © 2005 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. doi:10.1016/j.otohns.2004.09.072
MPH,
and NANCY LIU,
MD,
Los Angeles, California
with placebo treatment, ushering in oral steroids as the standard of care for sudden loss. Generally, patients with sudden loss present to primary care or emergency room physicians. Ninety-eight percent of these physicians prescribe steroids,4 usually the Medrol Dose Pack (first day 24-mg methylprednisolone, tapered over 5 days). A range of steroid doses have been reviewed in the literature, from very small amounts to intravenous administration.5,6 Some studies do not report the amount of oral steroid given, apparently putting all patients who received any dose of steroid together in a “treated” group.7 The optimal dose of oral steroid associated with hearing recovery is not clear. In the 1 randomized clinical trial of oral steroid for sudden hearing loss, Wilson et al3 included 2 investigational sites that delivered 2 different doses of oral steroid (16-mg taper of dexamethasone, 48-mg taper of methylprednisolone). The sample sizes of the 2 treatment groups were too small to detect any differences in response (power ⬍.4, nQuery Advisor 5.0). Therefore, the 2 treatment groups were combined for the overall analysis, demonstrating the efficacy of oral steroids relative to placebo, but not the amount. Our current practice is to prescribe a 60-mg dose of prednisone, tapered over 14 days. In addition to the amount of steroid associated with recovery, the length of time the medication should be given has not been well established. Some physicians have begun to prescribe a second course of oral steroid in the absence of recovery from the first course. It is unknown whether a second course would promote hearing recovery in the absence of a response to the first course. Further, the time course of recovery is not well documented. It appears that patients may experience some hearing recovery after drug treatment has ended, in some cases up to 1 month after treatment.8 Whether patients continue to recover hearing beyond 1 month after treatment is unknown. Many of the previous studies of sudden hearing loss lament the lack of comparability across studies. There are no standard inclusion criteria, thus, there has been great variability in the amount of hearing loss, including patients with bilateral loss or a nonnormal contralat5
6
Otolaryngology– Head and Neck Surgery January 2005
SLATTERY et al
Table 1. Inclusion/exclusion criteria Inclusion Criteria: ● Hearing loss of at least 30 dB across 3 contiguous frequencies within 72 hours. ● Presented to any physician within 10 days of hearing loss onset. ● Received oral steroid treatment. ● An audiogram at the time of presentation to the physician and at least 1 follow-up audiogram. ● No evidence of retrocochlear disease on MRI. Exclusion Criteria: ● A cause for the sudden loss was determined, such as an acoustic neuroma. ● Medication history for treatment of sudden loss could not be determined. ● Nonaffected ear had poor hearing (PTA ⬎50 dB).
eral ear,7,9-12 the age at onset (some studies include children), and how additional symptoms of dizziness and tinnitus are reported. Most investigators agree that idiopathic sudden hearing loss is a multifaceted disease entity, with a number of suggested causes.9,13 The route to understanding a multifaceted disease is to carefully restrict the characteristics of patients included in a treatment study, then sound conclusions can be drawn. The present study aims to address these issues. This is a retrospective chart review designed to assess the effect of differences in amount of oral steroid on hearing recovery in sudden hearing loss patients. We hypothesized that a 60-mg taper of prednisone is the optimal treatment for sudden hearing loss. Strict inclusion criteria were applied to the selection of patients in order to create a homogenous sample for comparison of treatment effects. We examine both statistically significant improvement and clinically significant improvement in a sample of 75 patients. METHODS Subjects All charts for patients receiving a diagnosis of sudden hearing loss who presented to the House Ear Clinic between October 1999 and September 2002 were retrospectively examined for the inclusion and exclusion criteria shown in Table 1. A total of 75 patients met the inclusion/exclusion criteria, 34 females (45%) and 41 males (55%). The left ear was the affected ear in 41 (55%) cases. The patients were grouped by type of treatment received for sudden hearing loss: group 1 received a course of 60-mg prednisone tapered over 14 days (see Table 2). Group 2 received a lesser dose of prednisone, frequently a Medrol Dose pack prior to presentation. Group 3 received any 2 courses of oral steroid, usually a Medrol Dose Pack, followed by a course of 60-mg prednisone tapered over 14 days.
Table 2. Course of 60 mg prednisone for idiopathic sudden sensorineural hearing loss Dosage schedule
Prednisone 10-mg tablets
Day 1-9 Day 10 Day 11 Day 12 Day 13 Day 14 Total prednisone over 14 days
6 tablets (60 mg) 4 tablets (40 mg) 3 tablets (30 mg) 2 tablets (20 mg) 1 tablet (10 mg) 1/2 tablet in AM (5 mg) 645 mg
Average age at onset of hearing loss, amount of hearing loss, and time to treatment are shown in Table 3. There were no significant differences between the groups at presentation (P ⬎ 0.05). Forty-six (61%) patients experienced the additional symptom of dizziness and 68 (91%) experienced tinnitus in addition to hearing loss. Two (3%) patients did not experience either tinnitus or dizziness at onset and 55% (n ⫽ 41) experienced both symptoms. There were no differences in frequency of these additional symptoms by group at presentation. Outcome Analysis The outcome variables were 4 frequency pure-tone average (PTA) and speech discrimination score (SDS). Repeated measures analysis compared pre- and posttreatment hearing by group. Hearing was also categorized by amount of hearing recovered after treatment. The posttreatment assessment occurred an average of 44 days after hearing loss. The time from hearing loss to posttreatment assessment did not differ by treatment groups (P ⬎ 0.05). A clinical success was considered to be recovery of hearing to within 50% of the difference between affected and unaffected ear at the baseline audiogram.12,14,15 Group success rates were compared by 2. Parametric and nonparametric correlations were used to examine for relationships among patient demographics and hearing improvement. Posttreatment hearing (PTA and SDS) was analyzed using an analysis of covariance controlling for differences in time to treatment and pretreatment hearing levels. Significance levels for all analyses were set at P ⬎ 0.05. RESULTS There were no adverse events as a result of steroid treatment in the 75 patients included in the study. Hearing outcome was assessed in a repeated measures analysis of variance. Treatment with oral steroids significantly improved hearing, as assessed by both PTA and speech discrimination (Ps ⬍ 0.001). There was no effect of treatment group; patients from each group
Otolaryngology– Head and Neck Surgery Volume 132 Number 1
SLATTERY et al 7
Table 3. Average demographics by treatment group (standard deviation)
Age at onset of hearing loss (y) Time to first treatment (d) Unaffected ear: Pretreatment PTA (dB) Pretreatment speech discrimination score (% correct) Affected ear: Pretreatment PTA (dB) Pretreatment speech discrimination score (% correct)
60-mg Taper (n ⴝ 37)
Less than 60 mg (n ⴝ 25)
Any 2 courses (n ⴝ 13)
51.3 (11.2) 11.1 (14.4)
54.3 (9.2) 6 (7.2)
48.2 (12.0) 14.7 (14.4)
10.7 (6.8) 96.9 (9.3)
13.0 (8.8) 98.4 (3.1)
12.1 (9.8) 97.9 (3.1)
80.1 (30.0) 24.1 (34.8)
83.0 (31.9) 24.0 (33.2)
69.8 (31.4) 29.9 (42.5)
No significant differences by group on any variable.
Table 4. Average hearing outcome (pure-tone average, speech discrimination) by treatment group (standard deviation)
Posttreatment PTA (dB) Posttreatment speech discrimination score (%) Improvement from pre- to posttreatment PTA (dB) Improvement from pre- to posttreatment SDS (%) Success rate* Number recovering to normal hearing (PTA ⬍25 dB)
60-mg Taper (n ⴝ 37)
Less than 60 mg (n ⴝ 25)
Any 2 courses (n ⴝ 13)
61.0 (34.7) 38.9 (39.9) 19.1 (22.5) 12.1 (21.3) 14/37 (38%) 5/37 (13.5%)
64.0 (31.2) 45.3 (42.7) 19.0 (21.9) 18.3 (23.8) 9/25 (36%) 1/25 (4.0%)
50.8 (23.2) 46.8 (40.4) 19.0 (19.2) 19.1 (26.6) 3/13 (23%) 2/13 (15.4%)
*Success is defined as an improvement in pure-tone average equaling or exceeding 50% of the difference between pretreatment unaffected and affected ear.
experienced similar changes in hearing from initial treatment to posttreatment (see Table 4). Across the 3 treatment groups, 35% experienced a clinically successful outcome, defined as a recovery of at least 50% of the difference between the ears. A 2 analysis revealed no significant differences in the percentage of clinical successes by treatment group. There were no group differences in the percentage of ears recovering to normal or to a PTA less than or equal to 25 dB (see Table 4). Differences in posttreatment PTA were further examined with an analysis of covariance with time to treatment and pretreatment PTA as covariates, with treatment group and presence of additional symptoms (1 or 2 symptoms) as fixed factors. The model resulted in an R2 of 66%, indicating that the factors and covariates were associated with a large portion of the variance in posttreatment PTA. Both time to treatment and pretreatment PTA were significant covariates (Ps ⬍ 0.003), confirming the use of these variables as covariates. The majority of those experiencing a clinically successful outcome were treated within 2 weeks of onset of hearing loss. Better pretreatment hearing was associated with better posttreatment hearing. There were no significant main effects of either treatment group or presence of additional symptoms. A significant interaction of treatment group and additional symptoms was found (P ⬍ 0.02). An exami-
nation of the means revealed that less than a 60-mg taper dose was associated with no differences in posttreatment PTA between patients with an additional symptom (PTA, 68 dB) and patients with both dizziness and tinnitus (PTA, 62 dB). A 60-mg taper dose was associated with significantly better posttreatment PTA (48 dB) for patients with 1 additional symptom. Patients with both symptoms and who received a 60-mg taper dose of steroid did not show much posttreatment benefit (PTA, 68 dB). Put another way, the 60-mg prednisone taper resulted in greater improvement for the patients with 1 additional otologic symptom, whereas the smaller amount of prednisone did not result in a better result for patients with 1 additional symptom. Patients with 2 additional symptoms were at the greatest disadvantage, no amount of prednisone in this study produced increased benefit. The correlations among the patient characteristics and hearing variables were examined. Patients with better hearing before treatment or who were not experiencing symptoms of dizziness or tinnitus tended to delay seeking treatment. Conversely, patients with poorer hearing or experiencing dizziness and tinnitus sought treatment within the first week of symptom onset. Younger patients tended to have less hearing loss than older patients and tended to not experience dizziness and tinnitus with the hearing loss. (See Table 5 for correlation coefficients.)
8
Otolaryngology– Head and Neck Surgery January 2005
SLATTERY et al
Table 5. Correlation coefficients (significance level) among patient characteristics and hearing in the affected ear (n ⫽ 75) Variable
Age at hearing loss
Time from loss to treatment
Experiencing dizziness/tinnitus
Time from loss to treatment Experiencing dizziness/tinnitus Pretreatment PTA Pretreatment SDS*
⫺.16 (NS) .18 (.06) .35 (.002) ⫺.39 (.001)
— .02 (NS) ⫺.21 (.07) .21 (.09)
— — .17 (.07) ⫺.25 (.02)
NS, Not significant; PTA, 4-frequency pure tone average; SDS, speech discrimination. *n ⫽ 66.
Change after Finishing Treatment For a subset of 34 patients, additional follow-up audiograms were available at an average of 4 months after the onset of hearing loss. Change in PTA was examined across the pretreatment to the second posttreatment evaluation without regard to treatment group. There was a statistically significant improvement in PTA from the evaluation at the end of treatment to the second posttreatment evaluation (P ⬍ 0.001). One additional patient improved at least 50% of the baseline difference in PTA between the unaffected and affected ears with no further treatment. DISCUSSION Patients with idiopathic sudden hearing loss were grouped on the basis of treatment received for a retrospective analysis of hearing outcome. Patients receiving a 14-day 60-mg course of prednisone with taper, those receiving less than 60 mg with taper, and those receiving any 2 doses of oral steroids were compared pre- and posttreatment. There were no treatment group differences in posttreatment PTA or SDS. Posttreatment outcome differed significantly by the amount of hearing present at the time of receiving the first treatment and by the presence or absence of additional otologic symptoms (dizziness and/or tinnitus). Receiving prompt treatment (within 14 days from onset of loss) or mild to moderate hearing loss was associated with better hearing outcome, regardless of the amount of oral steroid given as treatment. These results are consistent with the previous literature on treatment of sudden hearing loss.1,9 We did not find an overall treatment group difference in the percentage of patients who improved a clinically significant amount or to within normal hearing. Just 35% of the sample in this study could be defined as experiencing a clinical improvement, regardless of the amount of oral steroid received. This does not exceed the previously reported rates of spontaneous recovery of 45% to 65%.3,9,11 However, a treatment group difference emerged when controlling for time to treatment and
amount of hearing loss. Receiving the 60-mg taper was associated with better outcome for patients with a single additional symptom relative to those with 2 additional symptoms. Receiving the smaller dose of oral steroid did not give this advantage to those with only a single additional symptom. This suggests that the higher dose of prednisone is the treatment to which patients with somewhat less otologic damage may best respond. Those with 2 additional symptoms may have the poorest prognosis, regardless of the amount of steroid treatment. Sudden hearing loss has received much attention without commensurate answers to major clinical questions. Several reasons for the lack of consistent findings are inconsistent patient inclusion criteria, small sample sizes with enormous variability, and the need for a better disease marker than simply an audiologic profile. Clinical descriptions and study inclusion criteria vary widely. For example, some studies do not report the hearing in the unaffected ear,15 others report that some patients had poorer hearing in the unaffected ear relative to what was defined as the affected ear.7,16 It is generally assumed that the status of the unaffected ear does not indicate different patient populations or causes. However, it is not clear that the same disease mechanism is involved in patients with a pre-existing hearing loss in one ear. Examining outcomes on the basis of contralateral ear status in addition to the affected ear is an important step in controlling for this unknown factor. Here we excluded patients with poor hearing in the unaffected ear. Conclusions based on small samples sizes are particularly vulnerable when there is significant variability in the data. The data in the present study, as in most of the sudden hearing loss literature, were quite variable, with affected ear presentation PTA ranging from 10 dB to complete loss. The present study used multivariate statistical techniques to exploit the variability in the data by examining relationships among the variables. Sample sizes much smaller than 70 patients are not appropriate for this approach and alternative techniques should be used.
Otolaryngology– Head and Neck Surgery Volume 132 Number 1
Characterization of sudden hearing loss currently depends on pure-tone threshold measurements, and, to a lesser extent, speech discrimination scores. Measures of hearing are noninvasive, clinically useful methods to assess damage to the auditory system, but are nonspecific as to underlying mechanism. There is a long history of attempts to develop a more biologically informative marker of sudden loss1,11,13,17 centering on assessment of inflammatory responses. For example, erythrocyte sedimentation rate (ESR) is a nonspecific indicator of inflammation and can show elevated values in a number of conditions.18 ESR values can reflect changes with corticosteroid treatment for diseases with a known inflammatory component, such as polymyalgia rheumatica.19 ESR values in sudden hearing loss patients have been reported.9,20,21 However, these studies have not consistently related laboratory values to treatment outcome or to amount of hearing loss. Byl9 noted that elevated ESR was associated with poorer recovery, while Fetterman et al20 reported the percentage of patients with an elevated ESR, but no association with treatment outcome. Wilson et al3collected ESR information on their subjects but did not report levels or relationship of those levels to outcome. Another potential biomarker for sudden hearing loss is antiendothelial cell antibodies expression (AECAs), which have been linked to autoimmune diseases, such as systemic vasculitis.17 Cadoni et al1 investigated AECA positivity in patients with sudden hearing loss and a control group. A statistically significant proportion of patients with sudden hearing loss exhibited AECA positivity (54%) relative to the controls (14%). Treatment of the sudden hearing loss was based on the AECA results. Those with increased levels of AECAs were given a 1-month course of methylprednisolone and those who were AECA negative were given a 15-day course. A significant difference in hearing recovery between the treatment groups was found. Of the patients who were AECA negative, 93% showed recovery relative to 53% recovery of the AECA positive patients, despite the extra 2 weeks they took methylprednisolone. The association between pretreatment hearing loss, AECA positivity, and recovery was not analyzed. Thus, it is not known whether the patients who did not recover had worse pretreatment hearing relative to those who recovered in each patient group. However, it appears that AECA assessment in patients with sudden hearing loss may have some clinical utility. Further work to develop biomarkers of sudden loss is necessary before either AECA expression or ESR can be recommended for management of sudden hearing loss.
SLATTERY et al 9
The main hypotheses for sudden hearing loss causes are viral or vascular mechanisms. These hypotheses currently have what Chen et al7 have described as “circumstantial evidence” for support. For example, the rapid onset of loss appears much like responses to strokes or patients report the hearing loss in conjunction with or soon after an upper respiratory infection. These observations are hints at cause but are not evidence for an hypothesis. Studies such as Cardoni et al1 examining a biological marker for sudden hearing loss will also provide support for hypotheses regarding cause and differentiating groups of patients based on specific causes. CONCLUSION Oral steroid remains the standard of care for patients with sudden hearing loss. Patients should seek treatment immediately and receive a high dose of prednisone (60-mg taper) for at least 14 days for the best chance of recovery, particularly if they have only 1 additional symptom, such as dizziness or tinnitus. Time to treatment, amount of hearing loss, and presence of additional symptoms (dizziness or tinnitus) are associated with amount of recovery. Finally, patients tend to continue to recover hearing as late as 4 months posttreatment, although type of treatment does not appear to affect amount of continued recovery. We thank Karen Berliner, PhD, for her helpful editorial comments on an earlier draft of this manuscript. REFERENCES 1. Cadoni G, Agostino S, Manna R, et al. Clinical associations of serum antiendothelial cell antibodies in patients with sudden sensorineural hearing loss. Laryngoscope 2003;113(5):797-801. 2. DeKleyn A. Sudden complete or partial loss of function of the octavus-system in apparently normal person. Acta Otolaryngol 1944;32:407-25. 3. Wilson WR, Byl FM, Laird N. The efficacy of steroids in the treatment of Idiopathic sudden hearing loss: a double-blind clinical study. Arch Otolaryngol 1980;106(12):772-6. 4. Loughran S. Management of sudden sensorineural hearing loss: a consultant survey. J Laryngol Otol 2000;114(11):837-9. 5. Lalaki P, Markou K, Tsalighopoulos MG, et al. Transiently evoked otoacoustic emissions as a prognostic indicator in idiopathic sudden hearing loss. Scand Audiol Suppl 2001;52:141-5. 6. Lefebvre PP, Staecker H. Steroid perfusion of the inner ear for sudden sensorineural hearing loss after failure of conventional therapy: a pilot study. Acta Otolaryngol 2002;122(7):698-702. 7. Chen CY, Halpin C, Rauch SD. Oral steroid treatment of sudden sensorineural hearing loss: a ten year retrospective analysis. Otol Neurotol 2003;24(5):728-33. 8. Cinamon U, Bendet E, Kronenberg J. Steroids, carbogen or placebo for sudden hearing loss: a prospective double-blind study. Eur Arch Otorhinolaryngol 2001;258(9):477-80. 9. Byl FM, Jr. Sudden hearing loss: eight years’ experience and suggested prognostic table. Laryngoscope 1984;94(5 Pt 1):647-61. 10. Grandis JR, Hirsch BE, Wagener MM. Treatment of idiopathic sudden sensorineural hearing loss. Am J Otol 1993;14(2):183-5.
Otolaryngology– Head and Neck Surgery January 2005
10 SLATTERY et al
11. Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86(4 Pt 1):463-80. 12. Wilkins SA, Jr, Mattox DE, Lyles A. Evaluation of a “shotgun” regimen for sudden hearing loss. Otolaryngol Head Neck Surg 1987;97(5):474-80. 13. Berrocal JR, Ramirez-Camacho R. Sudden sensorineural hearing loss: supporting the immunologic theory. Ann Otol Rhinol Laryngol 2002;111(11):989-97. 14. Moskowitz D, Lee KJ, Smith HW. Steroid use in idiopathic sudden sensorineural hearing loss. Laryngoscope 1984;94(5 Pt 1):664-6. 15. Zadeh MH, Storper IS, Spitzer JB. Diagnosis and treatment of sudden-onset sensorineural hearing loss: a study of 51 patients. Otolaryngol Head Neck Surg 2003;128(1):92-8. 16. Minoda R, Masuyama K, Habu K, et al. Initial steroid hormone
17. 18. 19.
20. 21.
dose in the treatment of idiopathic sudden deafness. Am J Otol 2000;21(6):819-25. Ottaviani F, Cadoni G, Marinelli L, et al. Anti-endothelial autoantibodies in patients with sudden hearing loss. Laryngoscope 1999;109(7 Pt 1):1084-7. Brigden ML. Clinical utility of the erythrocyte sedimentation rate. Am Fam Physician 1999;60(5):1443-50. Leeb BF, Bird HA, Nesher G, et al. EULAR response criteria for polymyalgia rheumatica: results of an initiative of the European Collaborating Polymyalgia Rheumatica Group (subcommittee of ESCISIT). Ann Rheum Dis 2003;62(12):1189-94. Fetterman BL, Saunders JE, Luxford WM. Prognosis and treatment of sudden sensorineural hearing loss. Am J Otol 1996;17(4):529-36. Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86(4 Pt 1):463-80.