Intratympanic steroid treatment in idiopathic sudden sensorineural hearing loss: A control study

Otolaryngology–Head and Neck Surgery (2006) 134, 940-945

ORIGINAL RESEARCH

Intratympanic steroid treatment in idiopathic sudden sensorineural hearing loss: A control study John Xenellis, MD, Nikolaos Papadimitriou, MD, Thomas Nikolopoulos, MD, Paulos Maragoudakis, MD, John Segas, MD, Antonios Tzagaroulakis, MD, and Eleutherios Ferekidis, MD, Athens, Greece BACKGROUND AND OBJECTIVE: Although systemic steroids in sudden sensorineural hearing loss (SSHL) appears to be the most effective and the most widely accepted treatment today, a significant number of patients do not respond to steroid treatment or they cannot receive steroids for medical reasons. Intratympanic (IT) administration of steroids appears to be an alternative or additional method of management without the side effects of intravenous steroids. The aim of this study is to investigate the effectiveness and safeness of IT administration of steroids in patients who had not responded to IV treatment and to compare treatment efficacy with controls. STUDY DESIGN AND SETTING: Our study consisted of 37 patients with SSHL who, at the end of 10 days of therapy with intravenous steroids as a 1st line treatment, had pure-tone 4-frequency (0.5, 1, 2, and 4 kHz) average (PTA) of worse than 30 dB or worse than 10 dB from the contralateral ear (defined as failed intravenous treatment). They were randomized into 2 groups, treatment and control. The 19 patients of the treatment group received approximately 0.5 mL sterile aqueous suspension of methylprednisolone acetate in a concentration of 80 mg/2 mL by direct injection. The procedure was carried out 4 times within a 15-day period. An audiogram was performed before each injection and approximately 1.5 months after the last session. RESULTS: All patients tolerated the procedure well. No perforation or infection was noticed in any of the patients at their last visit. With regard to the 19 patients who received intratympanic treatment, in 9 patients, the PTA threshold improved more than 10 db, in 10 patients there was no change greater than 10 db, and no patients deteriorated more than 10 db. In the control group, none of the patients showed any change greater From the Department of Otolaryngology, School of Medicine, University of Athens, “Hippokration” Hospital, Athens, Greece. Reprint requests. John Xenellis, MD, Department of Otolaryngology, 54 Vas Sophias Ave, GR-115 28 Athens, Greece.

than 10 db. The difference was statistically significant (P ⫽ 0.002). The treatment group showed an improvement in mean PTA of 14.9 dB, whereas the control group showed a deterioration of 0.8 dB, and this difference also was statistically significant (P ⫽ 0.0005). IT treatment (P ⫽ 0.0001), better post-IV PTA (P ⫽ 0.0008), and absence of vertigo (P ⫽ 0.02) were good predictors of the outcome. In contrast, sex, age, affected ear, days to admission, and pattern of the initial audiogram showed no significant influence on the outcome. CONCLUSION AND SIGNIFICANCE: IT steroid administration after failed intravenous steroids is a safe and effective treatment in sudden sensorineural hearing loss. © 2006 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.

N

early 60 years after the first report of sudden sensorineural hearing loss (SSHL) by De Kleyn,1 the scientific community still is searching for answers with regard to the disorder; etiology, pathophysiology, and management. In the vast majority of patients with SSHL, no specific cause can be identified; therefore, the disease is called idiopathic, an exclusion diagnosis.2 Treatments with almost 51 regimens or methods of management varying from surgery to cytotoxic agents, Ginko biloba, and magnesium have been tried,3 alone or in combinations; some empirically and others with doubtful clinical efficiency. Administration of steroids systematically (IV or per mouth) is considered to be the SSHL treatment of choice worldwide, although their specific action remains unknown. E-mail address: [email protected].

0194-5998/$32.00 © 2006 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2005.03.081

Xenellis et al

Intratympatic steroid treatment in . . .

Table 1 Standard SSHL evaluation protocol 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

941 Table 2 Idiopathic SSHL* treatment protocol

Standard ENT examination. Basic audiometry. Auditory brain stem response. Electronystagmography when vestibular symptomatology exists. Magnetic resonance imaging with contrast. Complete blood count. Erythrocyte sedimentation rate Blood chemistries. T3, T4, TSH. Syphilis serology (VDRL* or PTA†). Toxoplasma antibody testing. Antigen-nonspecific serologic tests (ANA‡, AMA§, ASMA**). Rheumatoid factor. Acute and convalescent titers for EBV, CMV, and HSV. Total circulating immunoglobulins. Total serum complement.

1. Prednisolone IV†, 1 mg/kg per day for 10 days, divided in 3 doses, gradually tapered for 5 days. 2. Acyclovir, 4 g/day for 5 days, divided in 5 doses. 3. Buflomedil hydrochloride, 300 mg, divided in 3 doses, for 10 days. 4. Ranitidine during steroid treatment. *SSHL: Sudden sensorineural hearing loss. †IV: Intravenous.

ficial effect of systemic steroids without their side effects. Although a controlled method of delivering IT steroids appears yet unfeasible, there is evidence to suggest that IT administration results in significantly higher concentrations of steroids in perilymph and endolymph compared with the case of systemic administration in animal models.4,5 The aim of the present study is to assess the effectiveness and safety of the IT administration of steroids, in terms of hearing recovery and possible complications.

*VDRL: venereal disease research laboratory. †FTA: fluorescent treponemal antibody. ‡ANA: antinuclear antobody. §AMA: antimitochondrial antibody. **ASMA: anti-smooth-muscle antibody.

MATERIAL AND METHODS

Setting aside the controversy concerning dosage and duration of treatment, the efficacy of steroids remains the subject of many clinical trials. However, systemic administration of steroids may have serious side effects, and such treatment may be contraindicated in patients with peptic ulcer, glaucoma, diabetes, hypertension, osteoporosis, and other diseases, as well as those with pregnancy. Therefore, intratympanic (IT) administration of steroids appears to be an attractive method of management that may have the bene-

Because it is well documented6,7 that IV steroids are effective in the management of SSHL, it was considered unethical to replace 1st line IV with IT treatment. Therefore, the present study included patients who had not responded to IV treatment and who after this treatment were randomized 1:1 into IT treatment or control group. Inclusion criteria in this study were as follows: (1) SSHL, defined as a sensorineural hearing loss of at least 30 dB in 3 contiguous frequencies over a period of 3 days or less, (2) time period from onset of hearing loss to treatment

Table 3 Baseline characteristics of the sample Intratympanic treatment Characteristic Sex Male Female Ear Left Right Vertigo No Yes Audiogram shape Ascending Flat Descending Deaf

Control

Frequency

%

Frequency

%

P value

9 10

52.9 50.0

8 10

47.1 50.0

0.999

13 6

68.4 31.6

11 7

61.1 38.9

0.904

15 4

78.9 21.1

14 4

77.8 22.2

0.999

2 4 9 4

10.5 21.1 47.4 21.1

5 4 5 4

27.8 22.2 27.8 22.2

0.483

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Otolaryngology–Head and Neck Surgery, Vol 134, No 6, June 2006

Table 4 Final hearing outcome in patients treated with intratympanic steroids and controls Group

PTA* improvement ⬎ 10 dB

No change

PTA deterioration ⬎ 10 dB

Intratympanic treatment Controls

9 patients 0 patients

10 patients 18 patients

0 patients 0 patients

*PTA: Pure tone average.

administration of 30 days or less, (3) no history of ear disease, (4) no specific cause for the SSHL after proper investigation (Table 1), (5) the patient had received fullcourse standard treatment for 10 days (Table 2), and (6) pure-tone 4-frequency (0.5, 1, 2, and 4 KHz) average (PTA) worse than 30 dB or worse than 10 dB from the contralateral ear at the end of IV steroid treatment. The treatment group consisted of 19 patients. The control group consisted of 18 patients. The patients were informed about the new treatment, the procedure, and the possible benefits and risks. They all agreed to take part in the study. Treatment took place on an outpatient basis. The IT treatment consisted of 1.5-2 mL sterile aqueous suspension of methylprednisolone acetate in a concentration of 80 mg/2 mL (DepoMedrol, 80 MG/2 ML; Pharmacia Corporation, USA) instilled slowly with a fineneedle syringe (21 G) through the posterior–inferior quadrant of the tympanic membrane of the affected ear. The procedure was considered successful when the whitish fluid could be seen through the tympanic membrane in the middle-ear cavity. Methylprednisolone was allowed to perfuse the middle ear for 30 minutes with the patient’s head tilted 45° away. Patients were instructed to swallow as little as possible and stay still. The procedure was performed 4 times within a 15-day period. Some of the patients complained of a burning discomfort. We overcame this problem by adding approximately 0.1 mL of Lidocaine hydrochloride 2% (Xylocaine 2%, AstraZen-

eca Pharmaceuticals, USA) in the solution for the remaining sessions. Hearing assessment was performed with pure-tone audiometry beginning the day of admittance and with follow-up every other day. In the IT treatment group, puretone audiometry was performed before each injection as well as 1.5 months after intratympanic treatment had been completed (2 months after IV treatment had been completed). The final assessment of the patients in the control group was performed 2 months after IV treatment had been completed. Quantitative variables are described by mean ⫾ SEM, whereas frequency distribution tables are used for all categorical variables. The statistical associations between treatment group and controls were based either on the ␹2 statistic with continuity correction or 2-samples t test. All tests are 2-sided, and level of statistical significance was set at 5%. Patients’ baseline characteristics according to sex, site of affected ear, presence of vertigo, and shape of initial audiogram are described in Table 3. The mean age of the patients was 50.9 years and 50.3 years, and the mean interval from hearing loss onset to IV treatment administration was 11.8 days and 8.1 days, for the treatment and control groups, respectively. There was no statistically significant difference between the 2 groups with regard to age and time to admission (t ⫽ ⫺0.125, degrees of freedom [df] ⫽ 35, P ⫽ 0.901 and t ⫽ 1.390, df ⫽ 35, P ⫽ 0.173, respectively).

Table 5 PTA distribution in the 2 groups during the study Group Treatment N§ Mean SEM** Control N Mean SEM

Baseline PTA*

Post-IV† PTA

Baseline–Post-IV PTA difference

Post-IT‡ PTA (2 mo later)

Post-IV–post-IT PTA difference

19 75.6 4.6

19 70.1 4.8

19 ⫺5.5 2.5

19 55.1 4.2

19 ⫺14.9 3.9

18 75.6 4.5

18 68.9 4.0

18 ⫺6.7 3.5

18 69.7 3.9

18 0.8 0.7

*PTA: Pure tone average. †IV: Intravenous. ‡IT: Intratympanic. §N: Number of patients. **SEM: Standard error of the mean.

Xenellis et al

Figure 1

Intratympatic steroid treatment in . . .

943 Table 5 shows the PTA distribution throughout the 3 stages of the study. All patients had severe to profound hearing loss, with a mean PTA of 75.6 dB in both groups at admission. Baseline mean PTA, mean PTA after completion of IV treatment, and their difference did not differ significantly in the 2 groups (P ⬎ 0.05). This confirms that the 2 groups were comparable before IT treatment. After IT treatment, the patients in the treatment group showed a significant improvement in PTA (mean PTA, 55.1) compared with the control group (mean PTA, 69.7) at the end of the follow-up (t ⫽ ⫺2.539, df ⫽ 35, P ⫽ 0.0157. Fig 1). The treatment group showed an improvement in mean PTA of 14.9 dB, whereas the control group showed a deterioration of 0.8 dB. This difference also was statistically significant (t ⫽ 3.859, df ⫽ 35, P ⫽ 0.0005). Raw PTA values for the 2 groups are given in Tables 6 and 7. With regard to potential predictors of the final PTA outcome, we found that IT treatment (P ⫽ 0.0001), better post-IV PTA (P ⫽ 0.0008), and absence of vertigo (P ⫽ 0.0295) were good predictors of the outcome. In contrast, sex (P ⫽ 0.237), age (P ⫽ 0.085), affected ear (P ⫽ 0.493), days to admission (P ⫽ 0.259), and shape of the initial audiogram (P ⫽ 0.213) did not show any significant influence on the outcome.

Hearing results in treatment and control groups.

RESULTS All patients tolerated the procedure well. A mild ear pain occurring the 1st postinjection hour was easily controlled with common analgesics. No perforation or infection was noticed in any of the patients at their last visit. With regard to the 19 patients who received IT treatment, in 9, the PTA threshold improved more than 10 db; in 10 patients, there was no change greater than 10 db; and no patients deteriorated more than 10 db. In the control group, all patients did not show any change greater than 10 db (Table 4). The difference was statistically significant (P ⫽ 0.002).

DISCUSSION SSHL represents a symptom or clinical sign, rather than a disease. By all means, the affected site is the inner ear and

Table 6 Raw values of treatment group Patient number*

Gender

Age (y)

Days to admission

Baseline PTA†

Post-IV‡ or Pre-IT§ PTA

Post-IT PTA (2 mo later)

Contralateral ear PTA

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

F M M M F F M F F M F M F M F F M F M

63 62 52 41 58 68 55 79 49 41 57 52 30 54 28 38 55 38 48

8 15 13 3 16 16 15 4 1 4 4 7 15 20 20 20 20 3 5

100 100 63 84 100 58 74 74 83 65 100 90 70 71 97 41 54 34 78

100 86 55 62 100 46 65 39 83 61 100 71 67 71 97 41 54 44 89

62 78 38 54 100 61 61 34 48 53 81 56 61 54 32 33 35 38 68

32 30 26 24 31 34 23 27 20 17 23 25 13 27 12 24 21 20 22

*N: Patient number. †PTA: Pure tone average. ‡IV: Intravenous. §IT: Intratympanic.

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Table 7 Raw values of control group Patient number*

Gender

Age (y)

Days to admission

Baseline PTA†

Post-IV‡ PTA

Post-IV PTA (2 mo later)

Contralateral ear PTA

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

F F M F F F M M F M M F M M M F F F

27 48 53 54 58 30 66 65 15 48 70 60 59 53 58 72 20 52

10 7 4 7 7 1 3 8 1 2 20 1 5 20 7 10 8 15

48 87 76 39 68 93 100 73 100 95 58 64 82 51 86 88 96 57

68 63 82 48 60 96 86 57 92 59 59 59 72 65 74 64 100 36

68 66 82 51 60 96 88 60 90 62 59 62 75 55 76 66 100 38

18 23 33 24 21 15 27 25 14 23 25 27 24 30 25 27 12 23

*N: Patient number. †PTA: Pure tone average. ‡IV: Intravenous.

sensorineural deafness can be a manifestation of many different diseases. It occurs in 5-20 per 100,000 population.2,8 However, only in approximately 10% of cases can a specific cause be identified.2 The prevalent etiopathogenic theories in the literature include viral infection, membrane rupture, vascular alterations, and immune response.9 More often, an inference of cause is made of associated findings, but these could be incidental rather than causal. Stokroos et al10 reported a beneficial synergistic effect of steroids and antiviral drugs in guinea pigs with experimentally induced herpetic labyrinthitis but failed to replicate the results in humans with SSHL.11 However, part of the literature supports the idea of viral etiology as seroconversion of viral antibody titers, and evidence of viral labyrinthitis among patients with SSHL has been documented.9,12 Although various methods of management have been used in the literature, the high spontaneous recovery rate of idiopathic SSHL makes any comparison of these treatment methods difficult. It varies from 32% to 65% among untreated cases and is expected to occur during the first 2 weeks after onset;2,7 variables like severity of hearing loss, shape of audiogram curve, and presence of vertigo may influence spontaneous recovery rate.8 Wilkins et al13 treated 132 patients with SSHL by using a combination of regimens, targeting any potential cause of SSHL. They found that the overall outcome was no better than that expected from spontaneous recovery. The only area in which the bulk of the literature appears to reach a consensus is in the systemic administration of corticosteroids,6,7 which is considered to be the treatment of choice. Their efficacy has been attributed to anti-inflam-

matory and immunosuppressive action. Another possible mechanism of steroids’ efficacy recently has been proposed after the detection of glucocorticoid and mineralocorticoid receptors in the cochlear labyrinth in humans and animals, mainly in the spiral ligament and stria vascularis.14 Gross et al15 suggested that corticosteroids affect the Na, K-ATPase system and influence local microhomeostasis by regulation of cochlear fluid and electrolyte balance. The same investigators doubted the anti-inflammatory or immunosuppressive role of corticosteroids because spironolactone, a mineralocorticoid receptor antagonist, effectively blocked prednisolone from improving hearing in autoimmune strain mice. IT delivery of medication was introduced 50 years ago by Schuknecht for the treatment of Meniere’s disease, as cited by Jackson and Silverstein.16 Perfusion of the middle ear with aminoglycosides has become during the last decade the most frequently used 1st-choice treatment in vertigo associated with Meniere’s disease.17 IT administration of corticosteroids as an alternative treatment modality for SSHL appears attractive because it avoids the side effects of systemic steroids and obtains higher inner-ear concentrations. Parnes et al,4 in a well-designed animal study, compared the concentration of hydrocortisone, methylprednisolone, and dexamethasone in cochlea fluids after intravenous and topical administration. IT administration resulted in higher endolymph and perilymph levels. Moreover, methylprednisolone displayed the best pharmacokinetic profile. Those investigators concluded that IT methylprednisolone appears to have the greatest potential for clinical application. Additionally, the procedure is supposed

Xenellis et al

Intratympatic steroid treatment in . . .

to be safe, inexpensive, and easy to perform. The results of the present study revealed that nearly half of the patients in the treatment group (47.4%) showed significant hearing improvement with IT administration of methylprednisolone after unsuccessful IV steroid administration, whereas none in the control group had similar improvement. To our knowledge, there are no other control studies assessing the effectiveness of IT steroid administration in SSHL in the English literature. Gianoli and Li18 reported a 44% hearing recovery rate with IT administration of steroids in 23 patients with SSHL. Silverstein et al19 and Parnes et al4 found partial response in 38% and 54% of their cases, respectively. The patients who were treated with IT steroids in these studies either had failed to improve after systemic steroids or could not receive systemic steroids for medical reasons. None of these studies had a control group. The present study suggests that IT steroid administration is effective in patients with SSHL. Although it may also be effective as 1st-line treatment, we can only recommend it for the patients who have failed traditional systemic steroid administration because of the design of the present study. Our encouraging results supported by other noncontrolled studies in the literature indicate the need for standardized techniques for the application of medications through the round window membrane (RWM). Various techniques already have been proposed by several investigators: sustained-release devices (microwick or microcatheter),17 gelatin sponge,20 and use of facilitating agents.5 However, the efficiency of these needs to be explored. Moreover, surgical exploration of the inner ear and RWM niche and assessment with endoscopes has been advocated by other investigators, because as partial or total RWM obstruction has been found in 29% to 33% of the ears.21 Although animal data suggest potential ototoxicity of direct steroid application to the RWM,22 this has not been documented in human studies. Persistent tympanic perforations also have been reported after high concentrations of dexamethasone perfusion.16 We did not have such complications among our patients. In conclusion, the results of the present study suggest that IT steroid administration after failed intravenous steroids is a safe and effective treatment in SSHL.20

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