1

Introduction

Meniere’s disease (MD) represents the second most frequently encountered causes of peripheral vertigo in clinical practice . Management is aimed in decreasing the frequency of vertigo spells, reducing tinnitus, and preserving or even improving hearing . Various treatments are prescribed in a step-wise approach ranging from low-salt diet, diuretics, betahistine, to intratympanic injection of gentamicin or corticosteroids and even surgery . The management is even more intricate since a complete or partial resolution of vertigo spells could be attained spontaneously after 7–10 years from identification of MD . Betahistine has been extensively used in the treatment of MD with disagreeing results reported . Nevertheless, recently, an open trial demonstrated that a higher-dosage of betahistine (144 mg/day) is able to significantly reduce the number of vertigo attacks in MD . On the other hand, lately the use of intratympanic (IT) corticosteroids became popular . Their usage is grounded on the concept of an immune-mediated pathology in the development of MD . It was demonstrated that IT injected corticosteroids attain higher inner ear concentrations than those obtained through systemic administration . Quite a lot of papers have been published on the use of IT corticosteroids in MD with conflicting results and no consensus on the protocol of IT administration has been reached .

The goal of the present paper was to compare the effectiveness of IT dexamethasone versus high-dosage of betahistine in the treatment of patients with MD.

2

Material and methods

This study was approved by the Institutional Review Board of the two medical centers (Azienda Ospedaliera-Università of Padova, Italy, and Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca) in accordance with the Guidelines for Protection of Human Subjects. All patients were provided with thorough explanations about the risks and benefits associated with the procedures and signed an informed consent form before entering the study. Included in the study were adult patients with unilateral definite MD fulfilling the criteria of the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) . All of these subjects failed a trial of 6 months of low-salt diet and diuretics. Excluded were patients presenting with: a) other peripheral or central vestibular disorders; b) noise-induced hearing loss; c) middle ear diseases; d) previous treatment with IT gentamicin or corticosteroids or previous ablative ear surgery for MD; e) bilateral MD; f) allergy to betahistine; g) simultaneous treatment with diuretics, corticosteroids and vasodilators .

Patients underwent a complete otoneurological examination, and auditory testing consisting of pure tone audiometry (PTA) with 4 frequency average (0.5, 1, 2, and 3 kHz) and speech discrimination score (SDS). Magnetic resonance imaging was obtained in order to rule out a cerebello-pontine pathology. The Functional Level Score (FLS), Class and vertigo control were computed according to the 1995 AAO-HNS guidelines . According to the same guidelines, a change of 10 dB or more in PTA or a change of 15% in SDS was considered clinically significant.

The Dizziness Handicap Inventory was evaluated for every patient . It contains 25 questions divided into physical, emotional, and functional subgroups. Each question was responded with “no” (assigned 0 point), “sometimes” (assigned 2 points), or “yes” (assigned 4 points). The total score ranges from zero (no incapacity) to 100 (severe incapacity). For tinnitus we used the Tinnitus Handicap Inventory (THI), completed by each patient. THI is a 25-item questionnaire designed to assess the harshness of tinnitus frustration . Each point was answered with “yes” giving 4 points, “sometimes” giving 2 points, and “no” 0 point. The lower the total score, the less was the tinnitus handicap. All of these parameters were obtained before the beginning of the treatment and at the end of the follow-up period.

Patients were randomly divided in two groups, each comprising 33 patients. Randomization was performed with a computer-generated number sequence of 0 (Group A) and 1 (Group B) number sets indicating whether the patient was allocated to Group A or B. Randomization was achieved by one investigator only (FC) one day before the injection procedure. Both the surgeons (SA, GB and FT) and the patients were blinded to the treatment. Group A received a combination of IT dexamethasone (DX) and identical-appearing placebo pills while Group B received a combination of high-dosage betahistine and IT saline. Dexamethasone and saline were injected following the well-known procedure: in the supine position, the patient turned the head 45° toward the unaffected ear. Following anesthesia of the eardrum, using a 22-gauge spinal needle, 1 mL of dexamethasone (4 mg/mL) or saline was injected through the tympanic membrane into the middle ear. Patients kept the supine position with the injected ear facing upward for 30 min refraining from swallowing or talking. The injection was repeated for three times with an interlude of 3 days (3 injections every 3 days). High-dosage of betahistine consisted of 144 mg/day (48 mg tid) .

Audiometric testing and completion of questionnaires were performed by different researchers (FC, VT, LM, AN) blinded to the surgeons. During the study period, at two month interval all the patients were surveyed in the clinic. Compliance to treatment was checked through telephone calls by the clinical investigators. On the other hand, at every interim visit, the patient had to return the empty medication packages. Side-effects of the treatment were recorded in each patient.

Another aim of the study was to compare the promptness of vertigo fading in the two treatment arms. Therefore, the mean number of vertigo spells per month was recorded at baseline, at 1, 3 months and then every 3 months for up to 1 year.

Sample size was designed with the software available from DSS Research Tools ( http://www.dssresearch.com/toolkit ). Sample size was calculated to detect differences of 15% in the probability of primary endpoint (the probability of success for Group A was assumed to be 85%, whereas within the Group B, it was assumed to be 70%) with a Type I error of 5% and a statistic power of 80%. For each group, 27 subjects were required. In order to compensate for potential drop-outs, 33 patients were enrolled in each study arm.

Statistical analysis was performed using SPSS ver. 20.0 (SPSS Inc, Chicago, IL). The Student t-test was used to detect significant differences between groups, after a Kolmogorov–Smirnov (K–S) test for normality. Differences between categorical variables were assessed using the chi square test. Data were expressed as mean ± standard deviation (SD). A p value of less than 0.05 was considered significant.

2

Material and methods

This study was approved by the Institutional Review Board of the two medical centers (Azienda Ospedaliera-Università of Padova, Italy, and Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca) in accordance with the Guidelines for Protection of Human Subjects. All patients were provided with thorough explanations about the risks and benefits associated with the procedures and signed an informed consent form before entering the study. Included in the study were adult patients with unilateral definite MD fulfilling the criteria of the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) . All of these subjects failed a trial of 6 months of low-salt diet and diuretics. Excluded were patients presenting with: a) other peripheral or central vestibular disorders; b) noise-induced hearing loss; c) middle ear diseases; d) previous treatment with IT gentamicin or corticosteroids or previous ablative ear surgery for MD; e) bilateral MD; f) allergy to betahistine; g) simultaneous treatment with diuretics, corticosteroids and vasodilators .

Patients underwent a complete otoneurological examination, and auditory testing consisting of pure tone audiometry (PTA) with 4 frequency average (0.5, 1, 2, and 3 kHz) and speech discrimination score (SDS). Magnetic resonance imaging was obtained in order to rule out a cerebello-pontine pathology. The Functional Level Score (FLS), Class and vertigo control were computed according to the 1995 AAO-HNS guidelines . According to the same guidelines, a change of 10 dB or more in PTA or a change of 15% in SDS was considered clinically significant.

The Dizziness Handicap Inventory was evaluated for every patient . It contains 25 questions divided into physical, emotional, and functional subgroups. Each question was responded with “no” (assigned 0 point), “sometimes” (assigned 2 points), or “yes” (assigned 4 points). The total score ranges from zero (no incapacity) to 100 (severe incapacity). For tinnitus we used the Tinnitus Handicap Inventory (THI), completed by each patient. THI is a 25-item questionnaire designed to assess the harshness of tinnitus frustration . Each point was answered with “yes” giving 4 points, “sometimes” giving 2 points, and “no” 0 point. The lower the total score, the less was the tinnitus handicap. All of these parameters were obtained before the beginning of the treatment and at the end of the follow-up period.

Patients were randomly divided in two groups, each comprising 33 patients. Randomization was performed with a computer-generated number sequence of 0 (Group A) and 1 (Group B) number sets indicating whether the patient was allocated to Group A or B. Randomization was achieved by one investigator only (FC) one day before the injection procedure. Both the surgeons (SA, GB and FT) and the patients were blinded to the treatment. Group A received a combination of IT dexamethasone (DX) and identical-appearing placebo pills while Group B received a combination of high-dosage betahistine and IT saline. Dexamethasone and saline were injected following the well-known procedure: in the supine position, the patient turned the head 45° toward the unaffected ear. Following anesthesia of the eardrum, using a 22-gauge spinal needle, 1 mL of dexamethasone (4 mg/mL) or saline was injected through the tympanic membrane into the middle ear. Patients kept the supine position with the injected ear facing upward for 30 min refraining from swallowing or talking. The injection was repeated for three times with an interlude of 3 days (3 injections every 3 days). High-dosage of betahistine consisted of 144 mg/day (48 mg tid) .

Audiometric testing and completion of questionnaires were performed by different researchers (FC, VT, LM, AN) blinded to the surgeons. During the study period, at two month interval all the patients were surveyed in the clinic. Compliance to treatment was checked through telephone calls by the clinical investigators. On the other hand, at every interim visit, the patient had to return the empty medication packages. Side-effects of the treatment were recorded in each patient.

Another aim of the study was to compare the promptness of vertigo fading in the two treatment arms. Therefore, the mean number of vertigo spells per month was recorded at baseline, at 1, 3 months and then every 3 months for up to 1 year.

Sample size was designed with the software available from DSS Research Tools ( http://www.dssresearch.com/toolkit ). Sample size was calculated to detect differences of 15% in the probability of primary endpoint (the probability of success for Group A was assumed to be 85%, whereas within the Group B, it was assumed to be 70%) with a Type I error of 5% and a statistic power of 80%. For each group, 27 subjects were required. In order to compensate for potential drop-outs, 33 patients were enrolled in each study arm.

Statistical analysis was performed using SPSS ver. 20.0 (SPSS Inc, Chicago, IL). The Student t-test was used to detect significant differences between groups, after a Kolmogorov–Smirnov (K–S) test for normality. Differences between categorical variables were assessed using the chi square test. Data were expressed as mean ± standard deviation (SD). A p value of less than 0.05 was considered significant.

3

Results

Between January 2007 and January 2012, 66 patients with unilateral definite MD presenting at the two mentioned Departments met the inclusion criteria and were included in the study. The mean age was 50.2 years (SD ± 14.3 years) in Group A, and mean age was 51.5 years (SD ± 14.3 years) in Group B. The baseline demographic and functional characteristic distributions among the two groups are presented in Table 1 . No statistically significant difference was observed between all the above parameters among the two groups. One can see that no MD patient with stage 1 and/or FLS below 3 is included in the present study. This is to certify that patients with possible and probable MD, with mild vestibular dysfunction were excluded from the present analysis.

Table 1

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