Analysis of the Efficacy and Safety of Intratymapanic Dexamethasone for Treating Meniere’s Disease: A Randomized Controlled Trial

Abstract

Objectives

Our objective was to study the efficacy and safety of intratymapanic dexamethasone (ITD) for treating in Méniere’s disease in southern China.

Methods

A total of 124 patients with Méniere’s disease were randomly divided into 2 groups: ITD group (n = 62) and intratympanic lidocaine (ITL) group (n = 62). The ITD group was further randomly divided into 2 groups based on dexamethasone dosage: ITD1 (2 mg/ml) (n = 31) and ITD2 (5 mg/ml) group (n = 31). Symptom alleviation and complications were recorded after every treatment.

Results

Vertigo was improved in 65% of patients who received ITD compared with 55% of patients who received ITL patients (P < .05). Three patients in the ITD2 group had from otomycosis, and 2 of these patients had a perforation; no tympanic membrane perforation was observed in the ITL and ITD1 group.

Conclusions

Compared with lidocaine, dexamethasone is more effective in alleviating vertigo, and a lower concentration of dexamethasone can reduce the occurrence of complications.

Keywords

ear canal microbiology tympanic membrane perforation injection intratympanic adverse effects therapeutic use dexamethasone lidocaine

Introduction

Intratympanic dexamethasone (ITD) is used to treat a number of inner ear diseases, such as Méniere’s disease, sensorineural hearing loss (SNHL), autoimmune inner ear disease, and idiopathic sudden deafness.^1-3 Previous studies have shown that ITD does not cause long-term complications that can affect a patients’ quality of life; minor complications include local pain, bleeding, and temporary dizziness during injection. While ITD is effective for treating inner ear diseases, we have observed that some patients develop otomycosis after ITD, which may be related to the concentration of dexamethasone. In severe cases, we have also observed persistent perforation of the tympanic membrane. As such, ITD can be associated with long-term side effects, and every specialist should master the management of these complications.

The effectiveness of ITD for treating tinnitus associated with Méniere’s disease is 57%.¹ Intratympanic lidocaine (ITL) is also used to treat tinnitus caused by Méniere’s disease, with a reported effective rate of over 67.8%.⁴ ITL is also widely used to treat Méniere’s disease at our center.

The purpose of this study was to compare the effectiveness and safety of ITD and ITL for treating Méniere’s disease.

Material and Methods

Patient Selection

This study was carried out at the Department of Otolaryngology–Head and Neck Surgery of the Third Affiliated Hospital of Sun Yat-sen University from January 2016 to June 2019. Patients with Meniere’s disease who received either ITD or ITL to treat tinnitus associated with Méniere’s disease were enrolled in the study. Patients were divided into an ITD group and ITL group using the random table method. A total of 124 patients were enrolled: 62 in the ITD group and 62 in the ITL group. All patients were diagnosed with Méniere’s disease according to Bárány Society criteria:⁵

(1). Two or more spontaneous episodes of vertigo, each lasting 20 minutes to 12 hours. (2) Audiometrically documented low- to medium-frequency sensorineural hearing loss in one ear, defining the affected ear on at least one occasion before, during, or after an episode of vertigo. (3) Fluctuating aural symptoms (hearing, tinnitus, or fullness) in the affected ear. (4) Symptoms not better accounted for by another vestibular diagnosis.

Exclusion criteria were: (1) External ear, middle ear, and other local inner ear diseases; (2) Systemic disease such as diabetes and hypertension; and (3) Malignancy. Patients who could not complete the follow-up were also excluded. This study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University. All patients provided written informed consent for participation in the study.

Study Design

ITD Group

The ITD group included 62 patients who were diagnosed with Méniere’s disease (83 ears). Méniere’s disease was strictly diagnosed according to symptoms including episodic vertigo, aural fullness, tinnitus, and hearing loss, based on the criteria previously described. All patients had complete audiologic and caloric examinations. Patients in ITD group were further randomly divided into the ITD1 group (2 mg dexamethasone/ml, n = 31) and ITD2 group (5 mg dexamethasone/ml, n = 31). Dexamethasone was injected into the eardrum under endoscopic guidance, with the patient lying on the side with the affected ear facing upwards. Dexamethasone was added to the middle ear cavity, and the round window membrane was immersed in the solution for an appropriate time. The patient lied with the ear up for 20 minutes so that the round window membrane would be bathed in the solution for a proper time. Patients received ITD every 3 days for a total 10 treatments. Treatment was initiated during hospitalization, and if 10 treatments were not completed by discharged, the remaining treatments were performed in the outpatient department.

ITL Group

A total of 62 patients (91 ears) who met the aforementioned criteria for diagnosis of Méniere’s disease were treated with ITL. The concentration of lidocaine 20 mg/ml, and the method and frequency of injection were the same as the ITD group.

During treatment, all patients in both groups received betahistine 12 mg tid and mecobalamin .5 mg tid orally to improve inner ear microcirculation and neural function.

Follow-up

Before treatment, every patient was given health education indicating the importance of each follow-up visit. Patients received a total of 10 intratympanic injections, 1 every 3 days, and the total follow-up period was 1 month. All injections were given by the same doctor, and injection complications were recorded in detail.

Patients with tinnitus or dizziness were scored using the Tinnitus Handicap Inventory (THI; Newman et al 1996)⁶ or the Dizziness Handicap Inventory (DHI; Jacobson et al 1990),⁷ respectively, before each treatment and the last follow-up. A lower score after treatment is considered an improvement of symptoms. If secretions were present in the external canal they were sent for fungal smear and fungal culture. CHROMagar Candida medium was used to identify Candida species. The diagnostic criteria for otomycosis included: (a) subjective symptoms of one or more of the following: ear itching, ear pain, sensation of foreign matter in the ear, fluid flow in the ear, and hearing loss; (b) otoendoscopy examination showing the skin of the external auditory meatus exhibited flaky, punctate, or blotchy gray or brown fungal hyphae; fungal spores or other lesions; and the skin of the external auditory meatus was congested with yellow, purulent secretions; and (c) positive fungal smear of ear canal secretions.

Patients diagnosed with otomycosis were treated by cleaning the fungal secretions from the external auditory meatus and filling it with antifungal triamcinolone acetonide clotrimazole cream (Parrishon; Yeung Sum Pharmaceutical Co, Xi’an, China). A number of studies have reported the effectiveness of triamcinolone acetonide clotrimazole cream for treating fungal infections of the external auditory meatus.^8,9 After treatment patients were considered cured if they were symptom-free and no abnormal secretions were observed in the external auditory canal by otoendoscopy. Otherwise, the treatment was deemed unsuccessful.

Statistical Analysis

Measurement data were presented as mean ± standard deviation, and Student’s t-test or analysis of variance was used for comparisons between groups. Categorical data were compared with the chi-square test. A value of P < .05 was considered to indicate statistical significance. Statistical analysis was performed with SPSS version 22.0 software.

Results

Data Collection

Of the 124 patients (174 ears) there were 59 males and 65 females with an age range of 21 to 81 years. The time between development of symptoms and treatment ranged from 6 months to 62 months. All patients had been treated with other oral medications prior to treatment with ITD or ITL. Patient demographic and clinical data are summarized in Tables 1 and 2, and comparisons of the ITD and ITL groups before treatment indicated the 2 groups were not statistically different (all comparisons, P > .05).

Table 1.

Comparison of general clinical data between ITD group and ITL group before treatment.

Characteristics	Group ITD	Group ITL	X²/t	P value
Characteristics	(n = 62)	(n = 62)	X²/t	P value
Sex (n/%)			X² = .292	.589
Male	30	27
Female	32	35
Age (y)	45.57 ± 9.23	43.77 ± 11.89	t = 1.275	.762
Side(n/%)			X² = .414	.520
Left	37	45
Right	46	46
Decibels(dB)	52.37 ± 14.68	53.77 ± 15.59	t = 1.527	.528
Accompanied Symptoms			X² = .127	.938
Vertigo	51	53
Tinnitus	47	45
Aural fullness	32	34

Table 2.

Comparison of general clinical data between ITD 1 gorup (2mg/ml dexamethasone)and ITD 2 group (5mg/ml dexamethasone) before treatment.

Characteristics	Group ITD1	Group ITD2	X²/t	P value
Characteristics	(n = 31)	(n = 31)	X²/t	P value
Sex (n/%)			X² = 1.033	.309
Male	13	17
Female	18	14
Age (y)	44.62 ± 12.73	46.35 ± 1.73	X² = 1.469	.592
Side(n/%)			X² = .318	.573
Left	17	20
Right	24	22
Decibels (dB HL)	51.38 ± 15.74	52.99 ± 13.69	t = 1.109	.795
Accompanied Symptoms			X² = .074	.964
Vertigo	25	26
Tinnitus	22	25
Aural fullness	15	17

Complications in ITD and ITL groups

Treatment complications of the ITD and ITL groups are summarized in Table 3. Compared with the ITL group, the incidence of external auditory meatus mycosis was significantly higher in the ITD group (P = .029). In addition, 2 patients in the ITD group developed a perforation accompanied by external auditory meatus mycosis (described below). No tympanic membrane perforation was observed in the ITL group. There was no statistical difference in the incidence of vertigo, pain, tongue numbness, tinnitus, and other complications between the 2 groups (all, P > .05).

Table 3.

Comparison of the incidence of complications in ITD group and ITL group.

	Group ITD(83 ears)	Group ITL(91 ears)	P value
Otomycosis	3	0	.029*
Perforation	2	0	.035*
Transient dizziness and vertigo	7	9	.153
Pain	17	21	.368
Bleeding	7	10	.289
Tongue numbness	8	10	.227
Tinnitus	7	3	.072

Otomycosis

Three patients in the ITD2 group developed otomycosis after treatment. One patient developed otomycosis 12 days after the beginning of treatment and was observed as a thick black fungus silk on the left tympanic membrane. Fungal culture was positive for Aspergillus niger. The patient was treated with triamcinolone acetonide and econazole cream injected into the external auditory canal for 4 weeks. The treatment was effective at eliminating the fungal infection, and ITD treatments were resumed (Figure 1A).

Figure 1.

Images of otomycosis after ITD.

The second patient developed a fungal infection in the external canal after 21 days after beginning treatment. Initially, a large amount of white, brown, and yellow fungi were noted in the right external canal. Fungal culture was positive for Aspergillus flavus. The patient developed right otitis 7 days later. He was treated with antibiotics, and applied triamcinolone acetonide and econazole cream injected into the external canal. The infection was controlled after 14 days later, but he experienced a perforation of the eardrum after 3 months. Treatment with triamcinolone acetonide and econazole cream was continued weekly for 4 weeks; the fungal infection resolved but a persistent perforation remained (Figure 1B).

The third patient developed otomycosis 18 days after beginning treatment. She had received the first 2 injections over 7 days she was an inpatient. A 18 days she complained of itching, loss of hearing in the right ear, and some green secretions from the ear. Endotoscope examination showed mycoses were so thick that they covered all the membrane, as well as white, brown, and black secretions. After clearing the ear canal, a needle-like perforation in the anterior-inferior quadrant of tympanic membrane was noted, and membrane atrophy/thinning was seen around the perforation. Fungal culture was positive for Aspergillus niger. She was treated with triamcinolone acetonide and econazole cream in the external canal weekly for 4 weeks. After treatment, the fungal infection was resolved and the perforation was healed (Figures 1C and 1D).

Curative Effect Analysis

Three patients in the ITD2 group developed otomycosis during treatment and 2 of them also had a perforation of the tympanic membrane. These 3 patients did not complete all 10 intratympanic injections; all of the other patients in both groups completed the 10 injections. Patients who completed all 10 injections were evaluated by the DHI and THI scales; thus, 59 patients in ITD group (31 ITD1 group and 28 ITD2 group) and 62 patients in ITL group were evaluated. There was no significant difference in the frequency of tinnitus improvement between the groups. Improvement of vertigo was significantly higher in the ITD group compared to the ITL group (χ² = 4.545, P = .033). There was no significant difference in the rate of vertigo improvement between the ITD1 and ITD2 groups (Table 4, Table 5).

Table 4.

Vertigo and tinnitus improvement between ITD group and ITL group after treatment.

Characteristics	Group ITD	Group ITL	X²	P value
Characteristics	(n = 59)	(n = 61)	X²	P value
Vertigo improvement	31/48(.65)	23/53(.43)	4.545	.033*
Tinnitus improvement	29/44(.66)	28/45(.62)	.131	.717

Table 5.

Vertigo and tinnitus improvement between ITD 1 gorup (2mg/ml dexamethasone)and ITD 2 group (5mg/ml dexamethasone) after treatment.

Characteristics	Group ITD1	Group ITD2	X²	P value
Characteristics	(n = 31)	(n = 28)	X²	P value
Vertigo improvement	16/25(.64)	15/23(.65)	.008	.930
Tinnitus improvement	14/22(.64)	15/22(.68)	.101	.750

With respect to the DHI scale, there were no significant differences in subscale scores before treatment between the ITD and ITL group; however, there was a significant difference in physical and functional subscale scores after treatment (both, P < .05). There were no statistical differences in THI catastrophic, functional, and emotional subscale scores between the ITD and ITL groups after treatment. There were no statistical differences in DHI and THI subscale scores between the ITD1 and ITD2 groups after treatment (Table 6, Table 7).

Table 6.

DHI and THI subscale for ITD and ITL group.

	pre II		P value	post II		P value
	ITD	ITL	P value	ITD	ITL	P value
DHI subscale
Physical	22.32 ± 4.76	23.65 ± 5.02	.113	15.72 ± 3.56	17.53 ± 3.96	.032*
Emotional	30.33 ± 7.58	29.17 ± 6.89	.082	23.95 ± 5.65	24.72 ± 5.95	.128
Functional	28.33 ± 7.58	27.43 ± 7.08	.187	22.77 ± 6.72	24.96 ± 5.03	.045*
THI subscale
Catastrophic	14.76 ± 4.77	13.87 ± 3.98	.231	1.52 ± 3.88	11.32 ± 4.21	.423
Emotional	25.66 ± 5.85	25.78 ± 6.88	.321	20.76 ± 4.82	19.11 ± 4.32	.232
Functional	34.62 ± 8.84	35.98 ± 9.24	.254	28.76 ± 6.87	29.65 ± 7.83	.342

Abbreviations: THI, Tinnitus Handicap Inventory; DHI, Dizziness Handicap Inventory; II, Intratympanic injection.

Table 7.

DHI and THI subscale for ITD 1 gorup (2mg/ml dexamethasone)and ITD 2 group (5mg/ml dexamethasone).

	Group ITD1		P value	Group ITD2		P value
	pre IT	post IT	P value	pre IT	post IT	P value
DHI subscale
Physical	22.49 ± 3.46	22.67 ± 3.58	.081	16.32 ± 3.97	15.13 ± 3.21	.142
Emotional	29.13 ± 7.12	30.97 ± 7.38	.321	22.57 ± 5.65	24.72 ± 5.95	.324
Functional	29.72 ± 6.77	28.01 ± 8.12	.127	23.27 ± 5.67	21.93 ± 4.98	.214
THI subscale
Catastrophic	14.01 ± 4.23	15.36 ± 3.62	.173	10.07 ± 3.21	10.77 ± 3.72	.085
Emotional	23.74 ± 6.52	24.38 ± 7.33	.443	19.55 ± 5.66	20.93 ± 5.27	.162
Functional	33.72 ± 7.65	35.19 ± 8.56	.321	29.15 ± 6.12	27.39 ± 7.10	.261

Discussion

The intratympanic injection technique was first reported by Schuknecht in 1956 when he used intratympanic streptomycin to treat Ménière’s disease.¹⁰ In 1985, Fradis used IT lidocaine to treat Méniere’s disease, and 67.8% of patients had an improvement of tinnitus.⁴ In 1987, Sakata used IT dexamethasone to treat the Méniere’s disease in 61 patients, and 74% had an improvement of tinnitus. Currently, ITD and ITL are commonly used to treat Méniere’s disease.¹¹ Neither of the 2 reports from the 1980s mention complications of IT, and both concluded that ITD or ITL were safe and effective. However, current research has suggested that there may be some adverse effects with this method.

Complications

Intratympanic steroid injection has become a regular treatment for Méniere’s disease, sudden hearing loss, autoimmune inner ear diseases, and SNHL. In our study, we observed some minor complications of intratympanic injections such as transient dizziness and vertigo, pain, tongue numbness, and tinnitus. Other researchers have also reported side effects of the intratympanic steroid injections. Guan-min et al¹² studied 39 patients who received intratympanic steroid injections, and reported one patient developed acne and another patient developed vertigo immediately after the injection, and recovered after 2 hours of rest. Plontke et al¹³ followed 23 patients who received intratympanic steroid injections for 2 weeks, and found 2 patients developed otalgia, 1 patient a headache, 1 patient an ear canal skin defect, and 1 patient developed vertigo. Park et al¹⁴ followed 88 patients who received intratympanic steroid injections for 3 months, and found 25 patients (28.4%) had complications including otalgia (11/88), transient dizziness (9/88), ear fullness (8/88), and headache (5/88). Wu et al¹⁵ followed 55 patients who received intratympanic steroid injections for a month and found that 18 patients had transient dizziness and 1 patient had a temporary tympanic membrane perforation. In our study, despite nearly one-fifth of the overall study population developing complications, the majority of them were technique-related, very transient, and self-resolving. They included transient dizziness/vertigo post-injection, and ear fullness and slight otalgia during injection, which can be all caused by the injection technique. Given that patients recovered after only a few minutes, we believe the transient vertigo attacks are due to the introduction of warm or cold liquids into the external ear canal.

Otomycosis

In our study, some patients developed external auditory meatus mycosis. In our literature search, we did not find any reports of mycosis of the external auditory canal after intratympanic injections. While we did not find any report of mycosis of the external auditory canal, we noted that some patients developed mycosis after ITD. The possible reason is that our vertigo center admits a large number of patients from southern China, including more than 250 Méniere’s disease patients every year. Due to the large number of patients, it is not unusual that some rare complications are observed. We speculate that otomycosis after intratympanic injection may be related to the following 3 factors.

Dexamethasone

In our study, only patients that received ITD developed mycosis of the external auditory canal. As such, dexamethasone injection into the tympanic cavity may increase the risk for immunosuppression and opportunistic infection. Leav et al¹⁶ reported a case of invasive pulmonary aspergillosis in a patient with asthma who was treated with high-dose inhaled fluticasone (1,760 mg daily), which is significantly higher than the standard dosage (440 mg twice daily). This suggests that steroids can lead to immunosuppression, and the higher the concentration, the greater the chance of an opportunistic infection. This is consistent with what we observed in our study. All the patients who developed a fungal infection were treated with 5 mg/ml of dexamethasone; no patients treated with 2 mg/ml developed a fungal infection. This suggests that the lowest effective concentration of dexamethasone should be used. We also noted that the rate of tinnitus improvement was similar between the ITD1 and ITD2 groups. Therefore, our results indicate that 2 mg/ml dexamethasone reduces the chance of otomycosis without reducing treatment effectiveness. Nonetheless, previous studies using higher concentrations of dexamethasone ranging from 10 mg/ml to 24 mg/ml for the treatment of Ménière’s disease have not reported an increase of external auditory meatus mycosis.^17-19 A possible reason is that most patients in the studies received injections only 1–5 times per month; not as frequent as in our study.

Climate: Warm and Humid

The warm and humid environment in southern China favors the development of fungal infection of the external auditory meatus. Fungi can easily reproduce in a warm environment. Our hospital is located in a subtropical region, with an average temperature of over 22.5°C, and the appropriate growth temperature of fungi is between 20-35°C. Second, Guangzhou is close to the ocean and there are barriers (e.g., big mountains) to prevent the warm and humid air flow coming from the ocean from reaching Guangzhou. This warm and humid environment is very favorable for the growth of fungi.²⁰ It is because of this geography that fungal external auditory meatus infection is not common in northern China, and doctors in areas where the infection is not common may lack understanding of the disease, resulting in some missed diagnosis of otomycosis.

The clinical characteristics of otomycosis include obvious ear itching accompanied by a sense of ear blockage. Endotoscopy may show a thick white fungal silk on the tympanic membrane, or a white, brown, yellow, or black mycosis mass blocking the external auditory canal. Microscopic examination of the mass will reveal fungal spores.²¹

Iatrogenic Infections

The third factor may be iatrogenic infections, which may be because the whole treatment process is not standardized, nor is the use of antifungal drugs. If the syringe is not properly sterilized during drug extraction, a small number of fungal spores may be iatrogenic into the eardrum or external auditory canal, which may cause local propagation and spread of the fungus. Thus, more attention needs to be given to standardizing procedures to reduce the possibility of iatrogenic infection. Treatment with fungus-contaminated steroids is one of the most common causes of fungal infection. Kauffman et al²² reported that in 2012, 751 patients developed fungal meningitis, stroke, spinal or paraspinal infection, or peripheral osteoarticular infection and 64 died. In the end, they found that most patients had undergone epidural injection or osteoarticular injections with fungus-contaminated methylprednisolone acetate, resulting in a significant number of intracranial and intra-articular infections. Fungal infections can also be caused by contaminated drugs injected into the ear, so aseptic procedures should be followed and the government must carry out the most stringent quality control requirements for the production of drugs.

Curative Effect Analysis

Our results showed that with the same number of injections there was no significant difference in rate of tinnitus improvement between the ITD group and the ITL group, but there was a significant advantage in the improvement of vertigo in the ITD group. There was no significant difference in the rate of tinnitus or vertigo improvement between ITD1 and ITD2 groups. Patients in the ITD2 group were more likely to have complications such as otomycosis and tympanic membrane perforation. These findings suggested that dexamethasone has a better therapeutic effect than lidocaine, and a lower concentration of dexamethasone can reduce the occurrence of complications. Therefore, we recommend that a concentration of 2 mg dexamethasone/ml be used.

Conclusions

In this study, we found that otomycosis, though rare, is a complication of ITD, and this has not been previously reported. Notably, a concentration of 2 mg dexamethasone/ml can reduce the occurrence of fungal external auditory meatus infection while also improving tinnitus. Mycosis of the external auditory canal can be cured by active treatment. ITD is still the recommended treatment for Ménière’s disease, but the concentration should be reduced to 2 mg/ml. Because the number of patients in this study was relatively low, study with a larger number is needed to support our conclusions.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Science and Technology Program of Guangzhou, China (Grant No. 201704030081).

Ethical Standards

All procedures/treatment in this study and the treatment of patients comply with the ethical standards of the relevant national and institutional committees on human experimentation, and with the Helsinki Declaration of 1975, as revised in 2008.

ORCID iD

Gendi Yin

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