Early Intratympanic Methylprednisolone in Sudden SNHL: A Frequency-wise Analysis

Abstract

Sudden sensorineural hearing loss is a dire medical emergency which must be treated at the earliest to get better long term hearing results. Our study aims to determine the efficacy of intratympanic steroid (Methylprednisolone) on auditory outcomes in patients of sudden sensorineural hearing loss and study the relation between time of onset of hearing loss to start of therapy and frequency-wise recovery of hearing loss. A prospective cohort clinical study with 33 patients with sudden hearing loss of 30 dB or more were treated with the intratympanic injection of methylprednisolone and the effect of the drug was observed. In this study, 33 patients with sudden onset (unilateral or bilateral) of hearing loss were treated with intratympanic methylprednisolone. The duration at which the drug was administered and the age of the participants was taken into consideration. Main outcome measures included audiometry results at low, medium and high hearing loss frequencies. The specific frequency at which the hearing improvement took place was tabulated. It was observed that hearing improved significantly if the steroid is injected within the first 4 days of onset (p < 0.05) at all the frequencies. A gain of 15 dB or more was achieved in more than 78% patients after injecting methylprednisolone intratympanically. A statistically significant association was found between recovery rate and frequency of hearing loss with patients showing greater improvement at low hearing loss frequency in comparison to mid and high frequencies (p < 0.05). The drug efficacy does not change with the age of the patient.

Introduction

Sudden sensorineural hearing loss (SNHL) is a medical emergency which needs to be tackled at the earliest. It is defined as 30 dB or greater shift in bone conduction thresholds in three consecutive frequencies within 72 h or less [1]. Hearing loss, which occurs over more than 3 days is defined as a rapidly progressive hearing loss. In the US alone, 4000 new cases of SNHL occur annually and the incidence is 1 person in 10,000/year [2]. Various treatment modalities have been used in the treatment of SNHL like oral, intravenous and intratympanic steroids, hyperbaric oxygen and vasodilators. In this study, we propose to analyze the efficacy of intratympanic methylprednisolone at different hearing loss frequencies in the treatment of sudden SNHL.

Plausible Theories in Causing Idiopathic Sudden SNHL

Infections

Most evidence in the recent literature support the inflammatory processes of the inner ear as the reason for hearing loss with viral diseases likely to be the commonest cause. Changes of the inner ear revealed atrophy of the organ of Corti, the tectorial membrane and stria\vascularis with intact neural elements. This has been confirmed with histological studies researchers. In a study of 122 patients by Wilson et al. [3] with SNHL, there was an increase in the concentration of the viral titer as compared to control groups. It was found that Herpes simplex infections occurred as a part of multiple viral infections in 70% of the cases.

Vascular

The inner ear has long been known to be intolerant to hypoxia. Pearlman et al. [4] illustrated that with the disruption of blood flow to the cochlea for 30 min, cochlear potentials were permanently damaged. However, histological evidence of vascular compromise has shown conflicting reports; partial occlusion results in loss of spiral ganglion and total occlusion results in labyrinthine ossificans due to fibrous in-growth. Fisch [5] has shown that peri-lymphatic oxygen tension in the early stages of SNHL is 35% of the normal, and by using carbogen inhalation (5% of CO2 and 95% of 02), the tension rose to 175%, suggesting occlusion involves capillary network but spares arterioles.

Membrane Rupture

This concept was introduced by Goodhil [6] and he theorized two possible mechanisms: implosive and explosive. In implosive, the rupture of round window membrane or foot plate happens due to intense pressure in the middle ear; the latter is a result of raised pressure from CSF transmitted to the perilymph leak. Further strengthening this hypothesis, Gussen [7] reported temporal bone findings in two patients showing rupture of the Reissner’s membrane.

Literature Review on Intratympanic Steroids Employed for the Treatment of Sudden Hearing Loss

Intratympanic steroids remain the most appreciated treatment protocol for several years as rescuing treatment for abrupt hearing loss. The most commonly used steroids by clinicians are Methylprednisolone and dexamethasone being used in different combinations. Roberto et al. [8] summarized a list of the literature available since 2004 in their publication in 2010.

Published data on IT steroid administration since 2004 is given in the table below.

Authors	Type of study	No of treated patients	Type of steroid	No of injections	Results	Criteria to assess improvement
Ho et al. 2004 [9]	Salvage	15	Dex 4 mg/mL	1 injection a week for 3 weeks	54%	Furuhashi’s criteria
Slattery et al. 2005 [10]	Salvage	20	MP 62.5 mg/mL	4 injections	55%	PTA > 10 dB SDS 12%
Battista 2005 [11]	Initial	25	Dex 24 mg/mL	4 injections in 2 weeks	8% full 12% partial	Full: in 10 dB baseline Partial: PTA improvement > 50%
Choung et al. 2006 [12]	Salvage	33	Dex 5 mg/mL	2 injections in 2 weeks	38.2%	PTA improvement 10 dB SDS 15%
Dallan et al. 2006 [13]	Salvage	8	MP 40 mg/mL	Single injection	75%	PTA improvement 15 dB
Xenellis et al. 2006 [14]	Salvage	19	MP 40 mg/mL	4 infiltrations in 2 weeks	47%	PTA improvement > 10 dB
Haynes et al. 2007 [15]	Salvage	40	Dex 24 mg/mL	Single injection	27.5%	PTA improvement > 20 dB or SDS 20%
Roebuck and Chang 2006 [16]	Salvage	31	Dex 24 mg/mL	Single injection	PTA: 33% SDS: 38.7%	PTA improvement > 10 dB SDS > 15%
Plaza and Herráiz 2007 [17]	Salvage	9	MP 20 mg/mL	3 injections in a week	55%	PTA improvement > 15 dB SDS > 15%
Kilic et al. 2007 [18]	Salvage	19	MP 62.5 mg/mL	5 infiltrations in 12 days	73.6%	PTA improvement > 10 dB
Ahn et al. 2008 [19]	Salvage	a. 16 early-IT b. 20 mid-IT c. 13 late-IT	Dex 5 mg/mL	4 infiltrations in 15 days	a. 43.8% b. 30% c. 15.4%	PTA improvement > 15 dB
Battaglia et al. 2008 [20]	Initial	a. 17 IT b. 16 HDPT i.v c. 18IT + HDPT i.v	Dex 12 mg/mL	1 infiltration per week for 3 weeks	a. 59% b. 39% c. 88%	PTA improvement > 15 dB

Early IT receiving IT treatment within 2 weeks, mid IT receiving IT treatment between 2 weeks and 1 month, late IT receiving IT treatment between 1 month and 2 months, Dex dexamethasone, MP methylprednisolone, HDPT high dose prednisone taper, SDS speech discrimination score, PTA pure tone audiometry

Summarizing the above literature, it has been observed that there was an improvement of around 20 to 88% [11, 20] in the audiometric gain. This gain is affected by several factors such as—whether the patient has undergone a therapy before, the time lapsed after the initiation of the primary symptoms of hearing loss, the rate and dosage of steroid administration, and most importantly the different distinguishing criteria to mention the improvement in hearing loss. According to the authors of these researches, the frequency of injections per week is one or two and the treatments last for 2 to 4 weeks. Patients in these studies have reported for adverse effects which could be due to the intolerance to components of the injection or due to the presence of benzyl alcohol in its composition.

Our study aims to determine the effectiveness of methylprednisolone for sudden hearing loss in terms of audiometric gain with the special attention for the correlation between hearing recovery and time of onset of therapy and frequency of hearing loss. It also evaluates the effect on hearing outcomes on days lapsed before beginning the methylprednisolone therapy.

Methodology

The cases who presented with a sudden audiometrically proved hearing loss of 30 dB or more were covered in the study. A total of 33 patients were reviewed. A dose of 0.8 mL methylprednisolone + 0.2 mL of 2% Xylocaine was administered to these patients. Subjects diagnosed with Meniere disease, retro cochlear disease, autoimmune hearing loss, trauma, fluctuating hearing loss, or any other similar problems for sudden hearing were excluded from the study. Pre-treatment and post-treatment audiometric assessments including pure-tone average (PTA) were studied for audiometric gain. The obtained variables of recovery were evaluated.

Treatment outcomes in relation to age of the subjects, time of onset of therapy, audiometric gain at low, medium and high frequencies were the parameters used to evaluate the subjects.

Statistical Package for Social Sciences (SPSS) is used for data analysis. Written consent was taken from all participants of the study. All patients attending the clinic between 2016 and 2017 were a part of the study.

Results

Thirty-three patients fulfilled the selection criteria to be included in this study. Table 1 shows the hearing gain in these patients after injecting methylprednisolone intratympanically at different hearing loss frequencies. A significant improvement in the mean hearing gain value of 23.58 dB, 27.53 dB, and 23.50 dB was seen after the injection at low (35.62 from 59.20), medium (40.25 from 67.78) and high (57.52 from 81.02) hearing frequencies respectively. This indicates the efficacy of intratympanic methylprednisolone injection in the treatment of sudden hearing loss. A considerable gain of 15 dB or more was seen in 78% of patients at the low hearing frequency, 72% at the medium hearing frequency and 56.67% at the high hearing frequency.

Table 1.

Hearing gains attained after intratympanic injection of methylprednisolone at different frequencies of hearing loss

Mean hearing value before the injection (dB)	Hearing loss frequency	Mean hearing value after the injection (dB)	Difference in the mean values	Patients with a gain of 15 dB or more (%)
59.20	Low	35.62	23.58	78
67.78	Medium	40.25	27.53	72
81.02	High	57.52	23.50	56.67

It was also found that intratympanic injection of methylprednisolone had a greater impact on the treatment if given within 4 days post hearing loss. The difference in the mean value within 4 days and after 4 days of hearing loss showed a significant improvement at low (13.56 from 29.77), medium (7.45 from 39.81) and high (5.97 from 34.91) hearing frequencies (p < 0.05; Table 2).

Table 2.

Audiometric gain after injecting methylprednisolone intratympanically within and after 4 days post hearing loss at different frequencies of hearing loss

Hearing loss frequency	Mean Value of the audiometric gain after injection within 4 days post hearing loss	Mean value of the audiometric gain after injection 4 days post hearing loss	p value
Low	29.77	13.56	0.01
Medium	39.81	7.45	0.00
High	34.91	5.97	0.00

Table 3 compares the mean value of the audiometric gain in patients less than 50 years of age with those more than 50 years of age. It is found that intratympanic injection of methylprednisolone causes no significant difference in the treatment outcome in these patients (p > 0.05). This indicates that the efficacy of the drug in the treatment of sudden hearing loss does not change with age.

Table 3.

Comparison of audiometric gains in patients of age less and more than 50 years of age after intratympanic injection of methylprednisolone at different frequencies of hearing loss

Hearing frequency	Mean hearing value at age < 50 years	Mean hearing value at age > 50 years	p value
Low	23.89	19.21	0.50
Medium	28.66	20.93	0.43
High	23.12	18.91	0.64

Discussion

Glucocorticoids or mineralocorticoid receptors present in the inner ear are thought to be responsible for improving the hearing process in sudden sensorineural hearing loss [21]. Tumor Necrosis Factor (TNF)-∝ and Nuclear Factor NF-κB are inflammatory mediators that have harmful effects on the cochlea and steroids are said to have a protective mechanism against them. The TNF-∝ and NF-κB gets elevated during infection and inflammation [22] resulting in an increase of blood flow in the cochlea [23] so as to prevent ischemia in the cochlea [24], and avoiding noise actuated hearing problems [25], and managing protein synthesis in the auditory organs [26].

Vascular stria is the site of injury in the sudden SNHL which is also responsible for maintaining endocochlear potential through Sodium/Potassium (Na/K) secretion [27]. Corticosteroids help in improving the function of vascular stria and in preserving its morphology [28]. Many studies have indicated the use of corticosteroids as safe without making any histological changes [11, 29–33].

Intratympanic steroids have been demonstrated to protect vascular stria in otitis media [34]. Studies have also illustrated that corticosteroids when used intratympanically enhance ionic homeostasis, multiply the cochlear blood flow [29] and prevent aminoglycoside toxicity [35] thereby restoring adequate cochlear function [32]. However, intratympanic corticosteroids are not helpful in treating cases of tinnitus as evident in otoacoustic emissions [30, 32].

In this study, the hearing improvement was analyzed according to the hearing loss frequency. Intratympanic steroids spread into the perilymph through the round window present. This makes it obvious that hearing improvement must be better at higher frequencies (basal turn of the cochlea) than at low frequency (apex of the cochlea). This contradiction is explained by the differential vulnerability of basal and apical hair cells. The basal turn of the cochlea is found to be more vulnerable to trauma and free radicals in comparison to the apical turn. It is seen that cochlear base is affected in case of hearing loss from noise, ototoxic drugs or trauma in the high frequential range. Also, the outer and the inner hair cells present at the base of the cochlea develop ultrastructural anomalies more quickly in comparison to the apical turns following severe or total cochlear ischemia [36, 37].

Cochlear Pharmacokinetics

Steroids, when administered orally or intravenously are not able to attain an as high concentration in the perilymph when administered intratympanically [38, 39]. A number of studies have demonstrated a non-uniform flow and inter-scalar tract for intratympanically infused bodies [40–43]. Researchers have shown with the use of biomarkers such as phenyl ammonia [44] and peroxidase that a non-linear distribution of substances occur, in which the higher concentration is found at the round window or basal gyrus in comparison to the apical gyri. Salt in his studies has shown that materials could transcend the vestibule by using extracellular pathways present between scalae and the spiral ligament [41, 42].

Shaia and Sheehy [45] have demonstrated significant improvements in the subjects within 7 days of initiation of hearing loss. They illustrated that the treatment also proved beneficial for those patients also in whom the therapy had started after 3 months. Fuse et al. [46] have mentioned that most of the patients suffering from OCT cured completely in a week to 10 days after administering steroid medication. Another observation in the study was made with prolonged follow up with patients for 3 months to 2 years—the results declared that all the patients regained the hearing loss, who had not shown profound results in the short-term study. The patients who recovered slowly were corticosteroid resistant.

In our study, we found that treatment with methylprednisolone must be started as early as possible in order to gain maximum benefits from the therapy. Injections given within 4 days are more beneficial for recovery in hearing loss. Also, we found that audiometric gains are achieved more for lower and middle frequencies.

Future Directions

The successful administration of intratympanic injections has shown a promising future for the management of cochlear abnormalities. New techniques are being attempted to deliver the drugs to the inner ear. Gene vehicles can be effectively used for gene delivery to the middle ear using the round window. Inhibitors of calpain, JNK, and liquid peroxidation can be used to protect the ear from loud sounds through the intratympanic delivery of antibodies and steroids. Glycovir and infliximab when used intratympanically, can be employed to reduce the inflammation of inner ear by attaching with TNF-∝ which is proinflammatory. Another intratympanic procedure uses Gadolinium to envisage the middle ear in Meniere’s disease to investigate the endolymphatic hydrops. Thus, the use of intratympanic methods of delivery will pave the way for better interventions in the future.

Conclusion

Intratympanic Methylprednisolone is proven to be a trusted treatment for treating sudden hearing loss. A gain of 15 dB or more can be achieved in around 75% patients. The treatment is found to be more effective at low and medium hearing frequencies. Further, the results show that the earlier the injection is given, the more beneficial it is. Injection is given within 4 days of hearing loss results in better improvement in hearing (showing a statistically significant association) strongly advocating the use of intratympanic injection of methylprednisolone in the treatment of sudden hearing loss. Factors like age and gender do not affect the efficacy of the drug in the treatment of the sudden hearing loss.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.