The Combination Effects of Early Intratympanic Dexamethasone Injection for the Patients with Sudden Sensorineural Hearing Loss

Abstract

Introduction Spontaneous recovery rate of sudden sensorineural hearing loss (SSNHL) is up to 38-65%, including partial response.1,2,3) Systemic steroid therapy and peripheral vasodilator might be helpful to recover the hearing.3) How steroids affect the inner ear still remains unclear. Steroids may increase labyrinthine circulation or influence the cochlear fluid homeostasis, possibly by attenuating an inflammatory progress.4,5) Most recovery occurs within 2 weeks after onset, so early treatment is important for prognosis.2)Animal studies demonstrate that the intratympanic route of administration results in significantly higher inner ear levels of steroids as compared with systemic administration.6,7) Intratympanic dexamethasone (ITD) offers the potential for directed delivery of high concentrations of therapeutic agents to the inner ear while avoiding systemic side effects of steroids. So recently, intratympanic dexamethasone injection (ITDI) is applied as salvage treatment for SSNHL patients who failed initial systemic treatment or for patients who concerned to have hazard risk on systemic steroids.8,9,10) And some reports show early intervention with ITD resulted in effective hearing recovery in patients with SSNHL.11,12) However, clinicians often follow cases in which hearing improves after a long period of time after discharge. Therefore the result of combination therapy is ambiguous between delayed effects of traditional systemic therapy and additional effects of ITDI. In this study, all patients including the control group were limited to Siegel's criteria IV right after initial systemic treatment. And then we investigated the effectiveness of combination therapy, early ITDI accompanied with systemic therapy on SSNHL by comparing the recovery rate of patients who only received traditional treatment. Materials and Methods We retrospectively reviewed the medical records and audiograms of the patients with SSNHL diagnosed from January 2005 to October 2010. SSNHL is defined as a hearing loss of 30 dB or more, affecting at least 3 consecutive audiometric frequencies, developing within 72 hours or less, and not attributable to any commonly identifiable cause of sudden hearing loss. In this study, we included subjects who hospitalized for 5 days within 1 week after symptoms developed and who showed no improvement of hearing (Siegel's criteria IV) at pure tone audiometry performed after 5 days of traditional systemic treatment, namely at discharge day. All patients were treated with traditional systemic treatment in the following manner; 12-day course of oral steroids (1 mg/kg prednisolone for 5 days, followed by tapering for 7 days) as well as agents that decrease blood viscosity (intravenous low molecular Dextran, 1,000 mL/day for 5 days) and vitamins. And then patients randomized to the ITDI group (n=47) were administered first ITDI at discharge day or first visiting day at outpatient clinic within 2 weeks after initiation of traditional treatment, whereas patients randomized to the control group (n=104) were administered traditional treatment only. All patients were followed up for at least 2 months. ITDI therapy The ITDI procedure was performed under a microscope. With the patient supine and the head turned to the opposite site, Xylocaine® 10% pump spray (lidocaine 10 mg/dose, Astrazeneca) was used to induce local anesthesia. The Dexamethasone (Dexamethasone®, 5 mg/mL) was loaded into a 1-mL tuberculin-type syringe with a long 25 gauge needle attached on it. One needle hole was made in the anesthetized area for air to escape during the middle ear injection. A second hole was made for the injection at anterosuperior portion of tympanic membrane and the drug solution was infused into the middle ear space in a quantity sufficient to fill the space or at least cover the round-window niche. After the injection, the head was placed slightly lower than the body, and the subject was instructed to lie in the supine position with the head turned 45 degrees toward the contralateral side, keeping the treated ear up for 20 minutes. During this procedure, patient were instructed to avoid swallowing. ITDI was performed at least 4 times at intervals of 4-7 days. Outcome assessment The therapeutic effects were evaluated 2 months after treatment, using pure tone average (PTA, average hearing threshold at 500, 1,000, 2,000 and 3,000 Hz). The Siegel's criteria for hearing improvement is used in this study and shown in Table 1. We compared last concreted hearing level and recovery rate according to initial hearing level (mild, moderate, moderately-severe, severe, and profound hearing loss). A significant differences between the ITDI and control groups were tested using the χ2 test, Fisher's exact test and t-test, with p<0.05 defined as the cut-off for statistical significance. Results Age, sex, degree of initial hearing loss, and the time delay between onset of hearing loss and treatment were not statistically significant different between ITDI and control group (Table 2). Results of final hearing improvement on the basis of Siegel's criteria were showed in Fig. 1. For statistical analysis, improvement was defined as hearing results categorized as I, II and III of Siegel's criteria and no improvement was defined as hearing results categorized as IV of Siegel's criteria. On the basis of Siegel's criteria, 7 of 47 (14.9%) ITDI patients were recovered in Siegel's criteria 1 and 10 of 47 (21.3%), 13 of 47 (27.7%) ITDI were respectively recovered in Siegel's criteria 2 and 3. In control group, 15.4%, 8.7% and 21.2% patients were recovered in the Siegel's criteria 1, 2 and 3, respectively (Fig. 1). So, the overall hearing improvement rate was 63.8% in ITDI group, which was significantly higher than 45.2% in control group (p=0.034)(Table 3). When we subdivided the patients according to the initial degree of hearing loss, the patients who treated with ITDI showed significant higher recovery rate than control group (83.8% vs. 50.0%, p=0.049) on subjects with initially severe hearing loss (Table 3). When we analyzed hearing improvements according to the frequency, we observed a clinically significant hearing improvement at lower and mid-frequencies (250, 500 and 1,000 Hz) in the ITDI group than in the control group (p=0.010 at 250 Hz, p=0.007 at 500 Hz, and p=0.011 at 1,000 Hz)(Fig. 2). Discussion Clinically SSNHL has possibility of high spontaneous recovery.1,2,3) If hearing impro-vement starts during traditional systemic treatment, progress of the disease tends to improve within a few days. But some of patients show hearing improvement even after 1 month. In the article by Yeo, et al.13) delayed recovery occurred later than one month after discharge in 9.9% of 121 patients whose final hearing was improved over a period of three months. They emphasized that we should not overlook the possibility of delayed recovery and the overestimated efficacy of the intratympanic steroid administration as a salvage modality.13)ITDI in SSNHL is used in cases of 1) alternative initial treatment substituted the systemic steroid therapy for patients who concerned to have hazard risk on systemic steroids, 2) salvage treatment after failure of initial systemic steroid therapy, and 3) combination therapy with ITDI and systemic steroid therapy. Recent studies recommend that ITDI for salvage treatment should be started within 1 month after initial treatment failure.8,9) However usefulness and effects of initial combination therapy are still controversial.11,12,14,15,16) Interestingly, many studies which concluded no efficacy of combination therapy were used the treatment protocol of simultaneous or initial ITDI with systemic steroid therapy.14,15,16) In these cases, patients with probable recovery when treated only high dose pulse therapy of systemic steroids could even included, therethrough confused the results of ITDI. On the other hand, a few studies reported sequential ITDI modality right after systemic steroids produced a significant benefit of hearing.17,18) Even though there is unclear, Park, et al.15) guessed that simultaneous additional effect of ITDI was too small to be significant compared with systemic steroids alone. Our study did not designed for patients started simultaneous ITDI with beginning of systemic therapy, but for patients who refractory to systemic pulse therapy (Siegel's criteria IV) during hospitalization and started ITDI after 5 to 14 days of systemic treatment. Control group was also determined as Siegel's criteria IV patients during hospitalization. So that we tried to avoid unnecessary ITDI and to exclude delay effect of systemic steroids as possible. The overall hearing improvement was observed in 30 of 47 ITDI patients (63.8%), which was significantly higher than 45.2% of 104 patients in control group (p=0.034). It means that additional effects of ITDI are greater than delayed effects of only traditional systemic therapy. Higher recovery rate showed at especially severe hearing loss. It corresponds with steroid effective zone (40-90 dB). It is known that the less severe the hearing loss, the better the prognosis for recovery. But in our study, patients who showed a slight hearing improvement during the traditional treatment were excluded, so patient groups with less severe hearing loss didn't show better prognosis. Administration of dexamethasone through the round window may distribute from base to the apex of the cochlea. According to Hargunani's study, dexamethasone were seen in the inner ear within 15 minutes, reaching their highest staining intensity at 1 hour.19) The drug was not seen after 24 hours. The drug distribution followed that of the glucocorticoid receptor.19) Although dexamethasone effect on the damaged hair cell from base to apex has not yet been determined, we observed a clinically significant hearing improvement at lower and mid-frequencies (250, 500 and 1,000 Hz) in the ITDI group than in the control group. This results is similar to other reports.8,9,14) Choung, et al.8) explained this phenomenon is by the difference in the damage threshold or the reversibility for recovery of hair cells according to the location. According to Heydt's experiment on mice about round window gentamicin-induced hair cell toxicity, damage proceeds from base to apex and the transition from damaged to undamaged sensory epithelium occurs at the apical end of the damaged region.20) when the concentration of steroid reaches to a even distribution in cochlea, the recovery may easily occur at low frequencies than at high frequencies. Further studies will be needed to clarify the pharmacologic actions of ITD on individual hair cells and different response to steroid from the base to the apex within the cochlea. The purposes to perform ITDI within 5 to 14 days of systemic steroid therapy in our clinics are following; 1) to avoid unnecessary ITDI for recoverable patients during systemic pulse 5 days-therapy, 2) to diminish the waiting stress of patients, 3) this technique is office-based minimally invasive procedure with relatively low cost, and well tolerated by patients and 4) to get the benefit for hearing improvement as soon as possible. People with acute profound hearing loss was severely distressed and handicapped.21) And abnormal cellular stress responses within the cochlea may be responsible for SSNHL.22) Because no aggravation of hearing loss owing to ITDI, early intervention is less stressful rather than waiting delayed recovery for patients with refractory SSNHL and is more effective for hearing improvement. So we recommend the sequential ITDI should be performed at last hospital-day or first office-visiting day for patients with Siegel's IV criteria on SSNHL patients. Conclusion Early combination therapy of intratympanic dexamethasone injection within 2 weeks accompanied with initial systemic treatment shows better hearing recovery for sudden sensorineural hearing loss patients without early response to systemic treatment. Our results indicate that early combination therapy is recommendable in refractory and severe hearing loss patients instead of waiting the expected failure of initial systemic therapy. REFERENCES: 1.Hughes GB, Freedman MA, Haberkamp TJ, Guay ME. Sudden sensorineural hearing loss. Otolaryngol Clin North Am 1996;29:393-405. 2.Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86:463-80. 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;106:772-6. 4.Shirwany NA, Seidman MD, Tang W. 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