Intratympanic Steroid Therapy for Sudden Sensorineural Hearing Loss

Abstract

Introduction Sudden sensorineural hearing loss (SSHL) is defined as a hearing loss of 30 dB or more, affecting at least 3 consecutive frequencies, occurring within 3 days without any identifiable cause. It is relatively common disease, affecting 5 to 20 per 100,000 persons per year. The cause, pathophysiology, and management of SSHL are still not known. Spontaneous recovery in untreated patients has been reported as ranging from 38% to 65%.1,2,3,4)At this time, systemic administration of steroid is most commonly accepted treatment for SSHL. The use of systemic steroid for SSHL is originally based on the study by Wilson, et al.4) In their prospective, double-blind, clinical trial, they showed that patients with idiopathic sudden SNHL treated with systemic steroid had a statistically better recovery (78%) than patients receiving placebo or no treatment (38%). Moskowitz, et al.5) in 1984 showed similar response rate: 89% of steroid group showed recovery, while 44% of untreated patients showing recovery. On the contrary, Cinamon, et al.6) reported no significant differences between steroid and placebo in their prospective, placebo-controlled study, questioning the efficacy of steroid in SSHL. Systemic steroid has many side effects: immune suppression, weight gain, osteoporosis, avascular necrosis of the hip, mood swings, and skin and endocrine changes. The use of systemic steroid is contraindicated in patients with peptic ulcer, glaucoma, diabetes, tuberculosis, and those are pregnant. Intratympanic administration delivers medication into the inner ear through round window membrane. In 1996, Silverstein, et al.7) reported on the use of intratympanic steroid therapy for a refractory cases of SSHL and demonstrated a modest improvement in small number of patients. Since there had been no treatment option for the cases that are refractory to systemic steroid, the idea of topical administration of steroid via transtympanic route ignites numerous clinical trials for refractory cases and animal studies regarding the pharmacokinetics of steroid in the inner ear. An online search for the PubMed databases using the following terms "sudden hearing loss, intratympanic steroid" resulted in 81 listings. After excluding animal studies and review articles, we found 47 publications concerning clinical evaluation of the efficacy of intratympanic steroid injection (ITS) in SSHL patients since 1996 (Table 1). Among these, 15 articles have been published in 2011, showing an otologist's high interest on this subject in recent period. Many advantages of this procedure explains the enthusiasm for ITS. It can be done under local anesthesia at the office setting with relatively low cost, exerts its effect only at the affected ear, and bypasses systemic side effects of steroid. The technique is minimally invasive, easily to perform, and well tolerated by patients. Furthermore, through the animal study, it was proven that the perilymphatic concentration of corticosteroid is much higher when the medications were administered through a transtympanic route compared with systemic administration.8,9)Although many clinical studies have been performed enthusiastically, well-designed, prospective randomized controlled studies on this subject are relatively few. Thus, the optimum protocols including the time to start ITS, types and doses of steroid, and administration method are still in controversial. Here, we conducted a literature review regarding published researches on ITS to date to provide update information of this valuable treatment tool for SSHL. Mechanism of Action Intratympanically injected steroid enters the scala tympani through the round window membrane, while most of them is lost through the eustachian tube to the pharynx. Round window membrane is a semi-permeable membrane with outer squamous epithelial layer faces middle ear cavity and inner mesothelial layer continuous with the lining of the scala tympani.10) The lack of a continuous basement membrane suggests that substances may transit to or from the inner ear. Molecules as large as 1 μm can pass through this layer into the inner ear. Thus, the round window membrane provides little barrier to the movement of most drugs or other molecules into the inner ear. Although the human round window membrane (60-70 μm) is thicker than experimental animals (10-15 μm), the morphological structure of the round window membrane (RWM)(and probably therefore its permeability) is much the same. In humans, mucosal membranous veils often cover the RWM and may inhibit diffusion by adding an extra barrier. Steroids injected into the middle ear reach the scala tympani through round window membrane within minutes11) and quickly reach scala vestibuli and scala media through the spiral ligament laterally and/or Rosenthal's canal medially.12,13) Actual measurement and modeling of drug entry and dispersion suggests a concentration gradient exists from base to apex, but sufficient amounts can reach the apical regions.12,14)The two main effects of steroid in the inner ear are thought as immune suppression and ion homeostasis. Numerous cochlear insults induces cochlear inflammatory processes via pro-inflammatory cytokines and chemokines and production of reactive oxygen species (nitric oxide, etc.), which are responsive to steroid treatment. Glucocorticoids also have a significant binding affinity for the mineralocorticoid receptor and affect ion homeostasis in the inner ear. Methods of Administration Most authors favor simple intratympanic injection under local or topical anesthesia at office setting. The patients were positioned supine position with the head turned to the healthy side. The ear canal was anesthetized using 2% lidocaine injection or a 10% lidocaine pump spray. All the procedure is performed under the microscopic view. An air vent is made before the injection at anterosuperior portion of tympanic membrane with myringotomy knife.15,16,17,18,19) Air vent is not obligatory procedure, but it is very helpful for injecting adequate amount of drug into the confined middle ear space by allowing the escape of excessive air (Fig. 1). Steroid solution is injected at the uppermost portion of tympanic membrane in supine position using 1 mL tuberculin syringe with fine needle (21-27) gauge spinal needle. In general, 0.3-0.5 mL of medicine is enough to fill the tympanic cavity. Patients remains with the treated ear upwards for 15-60 min, and were instructed to refrain from swallowing. A recent study20) showed that absolute and relative drug levels in the perilymph were highly dependent on how long the drug remained in the middle ear. Therefore, it is reasonable that the physician should insure that there is enough medicine in the middle ear. The protocol of steroid injection into middle ear differed in many aspects, including the technique of delivery, the duration of remaining in supine position after injection, the number and amount of injections, and the type of steroid used. Until now, there is no general consensus on these aspects. Treatment Protocol The duration of treatment, frequency, and total number of injection is variable among the studies. Reviewing clinical studies on ITS, we found total of 47 articles since 1996 (Table 1) were found. Thirty-six studies used simple intratympanic injection as a route of steroid administration, 3 studies injected steroid through ventilation tube, and 1 study injected steroid through laser assisted myringotomy. Seven studies infused steroid continuously to the round window membrane using microwick (n=2) or microcatheter (n=5). Considering the studies using simple intratympanic injection, total number of injection ranges from single shot up to 15 times of injections, while total of 4 times is most commonly used by authors (14 of 36 simple intratympanic injection studies). Schedule of the injection differed also, ranging from daily injection (n=6), 3 times a week (n=8), twice a week (n=16), and weekly injection (n=4). The duration of treatment varies from a single day (n=4), 3-7 days (n=5), 8-14 days (n=23), 15-21 days (n=8) and more than 3 weeks (n=5). The total number of injection ranges from single injection (n=5), 3 injections (n=7), 4 injections (n=12), 5 injections (n=4), 6 injections (n=3), and 8 injections (n=3). To summarize, most authors favor injection schedule of ‘twice a week for 2 weeks of duration with total of 4 injections' as a simple intratympanic injection protocol. The Type of Steroid Used: Dexamethasone vs. Methylprednisolone Parnes, et al.8) evaluated intratympanic dexamethasone, hydrocortisone and methylprednisolone in guinea pigs. Of the tested drugs, methylprednisolone achieved the highest concentration for the longest duration in both endolymph and perilymph. But on clinical application some patients complain a burning sensation after injecting methylprednisolone into middle ear due to its acidic property. This might hinder vigorous use of methylprednisolone in clinical practice in spite of the promising result from the animal study, because we found that the most common type of steroid used in ITS has been dexamethasone (n=25) relative to methylprednisolone (n=10) from this literature review. To relieve these complaints, some authors give methylprednisone together with lidocaine, or buffered it with sodium bicarbonate to lessen acidity. Recent meta-analysis report showed there was no apparent difference in the efficacy of dexamethasone relative to methylprednisolone. A direct comparison of these medications has not been done.21)Steroid concentration ranged considerably from 4 mg/mL to 24 mg/mL (dexamethasone) or from 20 mg/mL to 62.5 mg/mL (methylprednisolone). Unfortunately, dexamethasone 24 mg/mL was removed from the market in the late 2,000 and can now only be produced as a compound. Hyaluronic Acid Dissolving steroids in hyaluronic acid, was done in the clinical trials, to prolongs the presence of the drug in the tympanic cavity and facilitate transport across the round window membrane.15,22,23) In animal experiments, the perilymph dexamethasone concentrations at 24 hours after treatment were significantly higher in the ears treated with intratympanic dexamethasone with hyaluronic acid gel than in those treated with intratympanic dexamethasone alone.24) Additionally, improvement in hearing at low frequencies (0.5, 0.75, and 1 kHz) has been reported in patients with profound SSHL who received intratympanic dexamethasone/hyaluronic acid.25) Ventilation Tube Some inserted a ventilation tube in the tympanic membrane through which steroid is injected to allow air escape and prevent bubble formation.26,27,28,29) The use of ventilation tube has several disadvantages. It is difficult to insert the needle through the tube without touching the tube, hence the patient feels pain without prior anesthesia. It is also difficult to confirm whether the tip was inside the mesotympanum because of the height of the tube blocks surgeon's view. Healing of perforation after tube removal is reported to be prolonged with an average of 15 weeks, and it may be due to effect of steroid on the wound healing.26) Laser-Assisted Myringotomy Topical steroids can be administered through a laser-assisted myringotomy, made with a CO2 laser unit.26,30) This technique permits easy insertion of the needle through the perforation and confirmation of the filling of the mesotympanum with the solution. The wide diameter of the perforation also allows the air to escape. Moreover, less discomfort is caused. However, the duration until closure is prolonged. Absorbing Material in the Round Window Niche Some injected the steroids onto absorbing material in the round window niche.7,15,17,19) Endoscopic Assistance The round window niche can be obstructed by fibrous tissue, fat plug, or pseudo membrane that may impede the diffusion of the steroid into the inner ear. A temporal bone study31) demonstrated this is in 32% of the examined ears. These anatomic variations of the round window niche may explain the wide variations in the treatment outcomes found in the clinical setting. Several authors examined the round window niche endoscopically and performed lysis of any adhesions blocking access to the round window membrane.7,28,32,33) Sustained Release Vehicles Sustained release vehicles will provide a more continuous perfusion and achieve a constant level of drug in the inner ear. In 1999, Silverstein developed a proprietary device called the MicroWick (Micromedics Inc., Eagan, MN, USA)(Fig. 2A), a small polyvinyl acetate sponge that is inserted through the tympanic membrane into the round window niche, which can be done under local anesthesia. Patient can self-instill medication through external auditory canal, which is absorbed via the MicroWick into the inner ear. When ITS is performed as salvage therapy with this device, 9-14 dB of mean pure tone threshold improvement and 31-53% of subjects showed at least some improvement.34,35,36)Another sustained-release vehicle is a round window microcatheter (Fig. 2B). This is a small vinyl catheter connected to a microinfusion pump that is inserted into the round window niche via a posterior tympanotomy under general anesthesia. Hearing improvement had been reported after using microcatheter in 35-100% of the patients who had been refractory to systemic steroid.37,38,39,40)Disadvantages of the sustained release vehicles therapy is potential tympanic membrane perforation, greater expenditure of time and financial resources. Microcatheter is no longer available because the FDA removed it from the market. Purpose of Treatment Intratympanic steroids can be used as 3 ways for treatment of SNHL: as a salvage therapy after failure of systemic steroids, adjunctive treatment given concomitantly with systemic steroids, and initial treatment without use of systemic steroids. Salvage therapy Most of the studies used intratympanic steroids as a salvage therapy for SSHL patients who failed the initial systemic therapy. Among the 47 articles that we have reviewed, 29 studies evaluated intratympanic steroid treatment of SSHL as a salvage therapy, and most of the studies showed at least some benefit from ITS treatment: 25-100% of subjects showed improvement (control: 39-87%) of 2-33 dB of mean pure tone threshold (control: -1-16 dB). Initial therapy Until now, 14 studies have tried ITS as a sole initial therapy (2 studies for patients with diabetes mellitus), and most studies presented at least some benefit suggesting ITS as initial therapy was equivalent to standard systemic steroid therapy: 12-100% of subjects showed improvement (control: 52-87%) of 17-41 dB of mean pure tone threshold (control: 13-29 dB). The only exception is Alimoglu, et al.'s41) study which reported the proportion of patients responding to therapy was lower in ITS group (47%) than that of the oral steroid+hyperbaric oxygen group (87%). Combination therapy It is still unclear if combination therapy is superior to monotherapy. There have been 7 studies which examined the efficacy of ITS combined with systemic steroid therapy. In the 5 studies, the efficacy of combination therapy was not significantly higher than that of systemic steroid therapy. The other studies demonstrated higher hearing response rate in combination group compared to systemic steroid therapy. Interval between First Treatment and ITS The interval between the sudden hearing loss and start of treatment, which is a known variable to affect recovery, varied from days to months among the studies. Many studies reported better results when initial or salvage treatment was started within 2 weeks from the onset. Frequency-Related Hearing Improvement In some studies, hearing improvement was analyzed according to frequency. Because the locally administered steroid penetrates through the round window membrane and spread from the basal turn to the apex. Thus, it is reasonable to expect that more hearing improvement might occur in higher frequencies than in lower frequencies. However, some authors reported that ITS in the treatment of SSHL patients are more effective at low frequencies.42,43) A possible explanation for this phenomenon would be the differential vulnerability of basal and apical hair cells. The base of the cochlea is more vulnerable to trauma and free radicals than the apex. We can find some evidence of this hypothesis on the fact that hearing loss from noise, ototoxic drugs, or trauma easily occurs in the hightone, basal area of the cochlea. Moreover, outer and inner hair cells in the base of the cochlea develop ultra structural abnormalities more rapidly than those in the apical turns following severe, total cochlear ischemia. Disadvantages of ITS There are some potential disadvantages to ITS. The loss of drug solution through eustachian tube is uncontrollable with a simple intratympanic injection technique. Some patients complain pain even after anesthesia and transient vertigo associated with the injections. There are also very low risks of persistent tympanic membrane perforation, otitis media, otomycosis, mastoiditis, and potential for further hearing loss. Conclusion Although prosperous studies have been reported in regard of ITS for the treatment of SSHL, it is difficult to draw conclusions from those studies because each studies use different steroid types and doses, treatment protocols, previous treatments, route of administration, and duration from onset of symptoms to treatment and improvement criteria. Few studies have well designed format. Due to the ethical reasons, it is not possible to use a placebo control group. Since it is known that the spontaneous recovery rate in un-treated patients ranging from 32% to 65%, we cannot assure the efficacy of separated from the natural history of the disease. 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