Address for correspondence : Dong-Kee Kim, MD, PhD, Department of Otolaryngology-Head and Neck Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 64 Daeheung-ro, Jung-gu, Daejeon 34943, Korea
Tel : +82-42-220-9273, Fax : +82-42-221-9580, E-mail : cider12@catholic.ac.kr

Introduction

Sudden sensorineural hearing loss (SSNHL) is a frightening disease that often prompts an urgent or emergent visit to a physician. SSNHL is defined as sensorineural hearing loss of 30 dB or more over at least three contiguous audiometric frequencies and an onset of less than 3 days.1) Its incidence has been estimated at 8 to 15 per 100000 persons per year.2) The etiology of idiopathic SSNHL remains obscure. Different theories attempt to explain this problem including disturbance of cochlear blood flow, viral infections, autoimmune disease and Reissner's membrane rupture.3,4,5)
The recovery rates of SSNHL are still low in spite of laborious efforts of many physicians. A maximum of 32% to 65% of cases of SSNHL may recover spontaneously.1,6) The various treatment options on SSNHL including steroids, antiviral agents, and vasodilators are failed to show definite efficacies over this spontaneous recovery rate.7,8,9,10) Prognostic factors include patient age, presence of vertigo at onset, degree of hearing loss, audiometric configuration, and time between onset of hearing loss and treatment.6,11) Among these factors, initial degree of hearing loss is one of important prognostic factors, and patients with profound SSNHL patients rarely recover normal hearing even when treated.12)
When we encounter patients with profound SSNHL, who have medical problems which are contraindicated for systemic steroids, we feel a dilemma in systemic steroid use, because the prognosis is expected as poor and side effects of steroid could harm the patients. In the clinical practice guideline of American Academy of Otolaryngology-Head and Neck Surgery, initial corticosteroids are stated as an option according to medical conditions of the patients.1) In this dilemma, intra-tympanic steroid injection (ITS) could be an alternative, and a recent systematic review concluded that ITS can be a valuable solution for patients with SSNHL who either cannot tolerate systemic steroid therapy or are refractory to it.13,14)
In this study, we investigated whether ITS treatment alone as an initial treatment for the patients with severe or profound SSNHL, who have medical problems in systemic steroid use, have equivalent efficacies compared to systemic steroid use.

Subjects and Method

This study was conducted by a retrospective chart review, and approved by the institutional review board of Daejeon St. Mary's Hospital (DC14RISI0059). 43 patients, who visited our hospital as severe or profound degree SSNHL from March 2012 to March 2014, were included in this study. Patients were included in this study if they met diagnostic criteria of SSNHL, and also presented initial hearing levels of pure tone audiometry, which were averaged at 500, 1000, 2000, and 4000 Hz, were equal to or greater than 70 dB HL. The patients, who had Ménière's disease, cerebellopontine angle tumors, or other causes of sensorineural hearing loss were excluded, and the patients who had delay of treatment more than 15 days, were also excluded.
Systemic steroid was used initially, in 32 patients who did not have any medical problem in steroid use. 11 patients with medical problems were treated by ITS alone. The regimen of systemic steroid was 48 mg of methylprednisolone for 5 days, and then tapered for consecutively during 5 days. ITS injections were performed by anesthetizing the tympanic membrane with 5 percent lidocaine ointment. We then injected 0.3 to 0.4 cc of dexamethasone (5 mg/mL) into the middle ear with a 26-gauge needle over the anterior superior region of the membrane. During this procedure, patients were instructed to avoid swallowing or moving for 20 minutes. ITS was performed four times during two weeks. After initial treatment, we checked a pure tone audiometry again. When a patients showed complete recovery by Siegel's criteria,15) we ended the treatment and followed up the hearing 1 month later, and if the patients showed partial to no improvement, we conducted salvage ITS in both groups, and also followed up the hearing 1 month after final treatment (Fig. 1).
We compared clinical and audiologic data of two groups and also compared hearing outcomes in the two patient groups. Statistical tests were performed using the Mann-Whitney U test and chi-square test (SPSS version 18.0; SPSS Inc., Chicago, IL, USA) to compare the difference between the ITS and systemic steroid groups.

Results

The mean age of the patients who received ITS only was 65.2±11.5, and it was significantly higher than that of systemic steroid group (Table 1). As expected, the patients in ITS only group had significantly more comorbidities than systemic steroid group, and they had diabetes mellitus in 81.8%, and hypertension in 72.7% of the patients, and as minor comorbities, they had angina, asthma, stomach cancer, adrenal insufficiency, active hepatitis B (Table 1).
Before the treatment, the mean initial hearing level of affected ear and unaffected ear of the patients of two groups were not significantly different, but the mean interval between onset and initial treatment was significantly longer in ITS group (Table 1). After initial treatment, any patients of ITS only group did not recovered completely by Siegel's criteria, and 8 of 11 patients received additional salvage ITS, and 3 patients refused. 5 patients of systemic steroid group recovered completely after initial treatment, 26 patients underwent salvage ITS, and 1 patients who recovered partially after initial treatment, refused salvage ITS.
The mean follow up periods of two groups were not different as 6.5±1.4 weeks in ITS only, and 6.5±2.6 weeks in systemic steroid group (Table 2). In final pure tone audiometry, the mean hearing level of affected ear of two groups were not different, the mean gain of two groups also were not different, and the mean differences with unaffected ear also showed no differences (Table 2). Multiple linear regression analysis was performed to assess the association between the final hearing level with clinical and audiological factors. The interval between onset and initial treatment, and the initial hearing level were significantly related to the final hearing level. Any other factors than these factors, have showed no statistical significance to the final hearing level and, especially, the therapeutic method (ITS vs systemic steroid) did not showed significant relation to the final hearing level (Table 3). When the patients were classified by Siegel's criteria, the distributions of two groups were not different significantly, but 16% (n=5) patients of systemic steroid group recovered completely (Fig. 2). During and after the treatment, all the patients in present study did ant have any medical problems with steroid use.

Discussion

In 1986, Sakata, et al.16) applied inner ear anesthetic therapy and middle ear infusion therapy with a steroid solution to patients with severe Meniere disease not responding to other treatments including drug therapy, and compared the results of treatment. This was the first introduction of ITS as a treatment method. Since it was introduced, there have been many studies on ITS including how steroid moves in the inner ear, where it works, what effects it has, the time for starting ITS, method, and dose. At present, ITS is spotlighted and used more as an effective therapy for SSNHL than for Meniere's disease, and for this reason, ITS in sudden hearing loss is a much more frequent theme than Meniere's disease among ITS research papers found through PubMed search.
With regard to ITS in sudden hearing loss, Hamid and Trune17) said through MEDLINE search that the most common type of steroid used has been methylprednisolone based on an animal study and the most commonly used method worldwide is direct perfusion into the middle ear. Steroid, after injected, reaches the inner ear scala tympani through the round window membrane in a few minutes, and quickly reaches scala vestibuli through the spiral ligament laterally and/or Rosenthal's canal medially. According to the findings of Plontke, et al.,18) dexamethasone-21-dihydrogen phosphate (Dex-p) content in the perilymph from apical regions was substantially lower than Dex-p from the basal turn after an intra-tympanic (IT) injection of the drug in guinea pigs. If the variability in peak concentration and gradient is also present under clinical conditions this may contribute to the heterogeneity of outcome that is observed after IT application of glucocorticoids for various inner ear disease.
Currently ITS is applied as salvage treatment for SSNHL when oral steroid therapy does not work or it is used as additional treatment to oral steroid therapy. However, the role of ITS as an early therapy for SSNHL is drawing attention. Hong, et al.19) compared curative effects between a group treated with IT dexamethasone once a day for eight days (n=32) and another with oral prednisolone for eight days (n=31) and reported that the two groups were not different in the pure-tone averages or the hearing recovery rate. Han, et al.20) divided the subjects into the peroral steroid group (n=48), the intravenous steroid group (n=32), and the ITS group (n=34), and compared the curative effects among the groups, but found no significant difference in hearing gain and the recovery rate among the groups (p>0.05). Therefore, they say that we consider ITS to be a more reasonable alternative as an initial treatment for SSNHL. Other grounds for their suggestion of ITS as an early therapy for SSNHL are that ITS is less likely than systemic steroids to have peripheral vascular complications, poor glycemic control, systemic side effects (e.g., gastrointestinal trouble, mood changes, weight gain, and electrolyte abnormalities), etc., that in many animal experimental studies, ITS has been proven to result in significantly higher perilymph concentrations of steroids than intravenous or oral administration, etc.18)
In this study, ITS only therapy showed a curative effect similar to that of systemic steroid therapy in severe or profound SSNHL patients for whom systemic steroid therapy was inadequate. Accordingly, ITS only therapy is considered a great alternative in case the patient's condition does not allow systemic steroid therapy or the patient rejects systemic steroid therapy. When systemic steroid therapy is applicable, however, it should be considered first as an early treatment because the therapy is more likely to bring about complete recovery.
This study has limitations such as irregularity in the conditions of patients assigned to each group due to ethical issues, the small sample size of patients with severe or profound sudden sensorineural hearing loss, failure to compensate for age and treatment start time, and confusion in outcome analysis resulting from the application of salvage ITS also to the systemic steroid group. So, these problems need to be resolved through additional research. However, the authors' point is supported by the absence of significant difference in the curative effect between two groups, although the ITS group included more poor prognostic factors including older age, delay in start of treatment, and more concomitant diseases.

1. Stachler RJ, Chandrasekhar SS, Archer SM, Rosenfeld RM, Schwartz SR, Barrs DM, et al. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg 2012;146(3 Suppl):S1-35.

2. Hughes GB, Freedman MA, Haberkamp TJ, Guay ME. Sudden sensorineural hearing loss. Otolaryngol Clin North Am 1996;29(3):393-405.

3. Cole RR, Jahrsdoerfer RA. Sudden hearing loss: an update. Am J Otol 1988;9(3):211-5.

4. Shikowitz MJ. Sudden sensorineural hearing loss. Med Clin North Am 1991;75(6):1239-50.

5. Thurmond M, Amedee RG. Sudden sensorineural hearing loss: etiologies and treatments. J La State Med Soc 1998;150(5):200-3.

6. Conlin AE, Parnes LS. Treatment of sudden sensorineural hearing loss: II. A Meta-analysis. Arch Otolaryngol Head Neck Surg 2007;133(6):582-6.

7. Agarwal L, Pothier DD. Vasodilators and vasoactive substances for idiopathic sudden sensorineural hearing loss. Cochrane Database Syst Rev 2009;(4):CD003422.

8. Bennett MH, Kertesz T, Perleth M, Yeung P, Lehm JP. Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus. Cochrane Database Syst Rev 2012;10:CD004739.

9. Awad Z, Huins C, Pothier DD. Antivirals for idiopathic sudden sensorineural hearing loss. Cochrane Database Syst Rev 2012;8:CD006987.

10. Wei BP, Stathopoulos D, O'Leary S. Steroids for idiopathic sudden sensorineural hearing loss. Cochrane Database Syst Rev 2013;7:CD003998.

11. Fetterman BL, Saunders JE, Luxford WM. Prognosis and treatment of sudden sensorineural hearing loss. Am J Otol 1996;17(4):529-36.

12. Wen YH, Chen PR, Wu HP. Prognostic factors of profound idiopathic sudden sensorineural hearing loss. Eur Arch Otorhinolaryngol 2014;271(6):1423-9.

13. Seggas I, Koltsidopoulos P, Bibas A, Tzonou A, Sismanis A. Intratympanic steroid therapy for sudden hearing loss: a review of the literature. Otol Neurotol 2011;32(1):29-35.

14. Kakehata S, Sasaki A, Oji K, Futai K, Ota S, Makinae K, et al. Comparison of intratympanic and intravenous dexamethasone treatment on sudden sensorineural hearing loss with diabetes. Otol Neurotol 2006;27(5):604-8.

15. Siegel LG. The treatment of idiopathic sudden sensorineural hearing loss. Otolaryngol Clin North Am 1975;8(2):467-73.

16. Sakata E, Kitago Y, Murata Y, Teramoto K. [Treatment of Ménière's disease. Middle ear infusion with lidocaine and steroid solution]. Auris Nasus Larynx 1986;13(2):79-89.

17. Hamid M, Trune D. Issues, indications, and controversies regarding intratympanic steroid perfusion. Curr Opin Otolaryngol Head Neck Surg 2008;16(5):434-40.

18. Plontke SK, Biegner T, Kammerer B, Delabar U, Salt AN. Dexamethasone concentration gradients along scala tympani after application to the round window membrane. Otol Neurotol 2008;29(3):401-6.

19. 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(5):579-83.

20. Han CS, Park JR, Boo SH, Jo JM, Park KW, Lee WY, et al. Clinical efficacy of initial intratympanic steroid treatment on sudden sensorineural hearing loss with diabetes. Otolaryngol Head Neck Surg 2009;141(5):572-8.