1

Introduction

Meniere’s disease (MD) is pathophysiologically regarded as an endolymphatic hydrops of unknown etiology . It is estimated that 50,000 to 100,000 new cases occur each year in the United States . Clinical diagnosis is established on a history of spontaneous vertigo spells, fluctuating sensorineural hearing loss, tinnitus, and aural fullness . Most often, vertigo is incapacitating, and thus, management is primarily intended to decrease the incidence and severity of vertigo. The management protocol typically comprises dietary recommendations such as a low sodium diet and restriction of caffeine, nicotine, medications and, as a last remedy, surgical approaches . Medical treatment includes diuretics, betahistine, intratympanic (IT) injection of gentamicin or corticosteroids . Quite a lot of papers on betahistine for MD have been issued presenting conflicting results . However, an open trial proved that higher-dosage of betahistine (144 mg/day) is capable to significantly decrease incapacitating vertigo spells in MD . Recently, IT corticoids injections became widespread in clinical practice mainly because minimal side effects were reported in relationship to their use . IT corticosteroids achieve greater inner ear concentrations than those acquired through systemic administration . Although IT gentamicin affords superior vertigo control compared with IT corticoids, it carries a greater risk of hearing loss and imbalance . This is why in clinical practice it appears that IT corticoid injections are extensively prescribed . Some studies have presented encouraging results, while others reported unsatisfactory outcomes associated with IT corticoids .

The aim of the present study was to assess if the combined therapy of IT dexamethasone (ITD) and high dosage of betahistine (HDBH) is able to provide increased vertigo control rates compared to ITD alone.

2

Materials and methods

A multicenter, prospective study assessing the effectiveness of the combined HDBH and ITD in decreasing vertigo spells in MD was performed between January 2009 and June 2013. Five departments with extensive experience in vestibular pathology were involved, including the Departments of Otolaryngology from the Universities of Cluj-Napoca, Timisoara, Iasi, Bucuresti (all clinics from Romania), as well as the Otology and Skull Base Surgery Unit in Siena, Italy. All studies were approved by the respective Institutional Review Boards in accordance with the Guidelines for Protection of Human Subjects. All patients signed an informed consent form before entering the study. Inclusion criteria were adult patients with unilateral definite MD according to the guidelines of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) . According to prior recommendations , patients with episodes of spontaneous vertigo lasting between 20 min and 12 h were included. Further, as previously suggested , to be included, patients had to suffer a mean of four or more vertigo spells per month during the 3 months foregoing management. All these patients failed a trial of 6 months of low-salt diet, dietary restrictions such as caffeine and nicotine avoidance. According to previous studies , exclusion criteria were: bilateral MD, other peripheral or central vestibular syndromes, middle ear pathology, noise-induced hearing loss, previous IT gentamicin or corticosteroid or preceding ablative ear surgery and allergy to betahistine.

Patients underwent a complete neuro-otologic examination. Acoustic neuroma was ruled-out using MRI. Auditory testing comprised pure tone audiometry (PTA) with 4 frequency average (0.5, 1, 2, and 3 kHz) and speech discrimination score (SDS). The Functional Level Score (FLS), Class and vertigo control (class A–F) were defined according to the AAO-HNS criteria . A change of 10 dB or more in PTA or a change of 15% in SDS was considered clinically significant. The Tinnitus Handicap Inventory (THI) was completed in each patient . THI is a 25-item questionnaire designed to assess the severity of tinnitus. Each item was completed with “yes” scoring 4, “sometimes” scoring 2, and “no” scoring 0. The lower the total score, the less was the tinnitus handicap. All of these parameters were obtained before the treatment and at the end of the follow-up.

Patients with definite MD were offered different therapeutic alternatives: IT injection of corticoid or IT injection of gentamicin and vestibular neurectomy. Patients elected ITD injection with or without HDBH as an opportunity that might provide transitory cessation of vertigo spells without the destruction of vestibular system. If complete or substantial vertigo control was not accomplished, another sequence of ITD was offered. In patients with persistent vertigo, despite repeated ITD injections, IT gentamicin injection or ablative surgery was offered.

Enrolled patients were randomly divided in two distinct groups (Group A and B), each comprising 33 patients. For random assignment of patients, a computer-generated list of random numbers was employed. Randomization was performed by an only investigator (LM) one day before the injection. Both the surgeons and the patients were blinded to the treatment. Group A received a combination of ITD and identical-appearing placebo pills while Group B received a combination of ITD and HDBH. Dexamethasone was injected under the microscope according to the guidelines : in the supine position, the patient turned the head 45° toward the unaffected ear. Local anesthesia of the tympanic membrane was achieved and dexamethasone (4 mg/mL) was injected through a 22-gauge spinal needle and 1-mL syringe to fill the middle ear. Patients were instructed to keep the supine position with the treated ear facing upward for 30 min avoiding swallowing or talking. The ITD protocol consisted of three consecutive daily injections. HDBH consisted in 144 mg/day (48 mg tid).

Audiometric testing and completion of questionnaires were performed by researchers blinded to the surgeons. Throughout the study, all patients kept a diary recording monthly the occurrence of every vertiginous attack. At the follow-up visit, investigators reviewed these diaries. Patients were monitored at 2-month intervals throughout the study. Every patient was monitored for at least 2 years. Both in Romania and Italy betahistine is the most prescribed drug in MD patients. Nevertheless, betahistine is a costly medication in both countries, therefore the tablets were supplied free of charge by the University hospitals involved in the study. Compliance to treatment was tested through regular weekly telephone calls. Moreover, at each intervening visit, patients from both groups had to return the empty medication packages. Treatment side-effects were also recorded.

Sample size was computed with the software available from DSS Research Tools ( http://www.dssresearch.com/toolkit .). Samples were planned to detect differences of 15% in the probability of primary endpoint (the probability of success for Group A was expected to be 50%, whereas for Group B it was presumed to be 75%) with a Type I error of 5% and a statistic power of 80%. For each group, 30 subjects were required. In order to compensate for potential drop-outs, the number was raised to 33 patients.

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 while differences between categorical variables were evaluated using the chi square test. Data were expressed as mean ± standard deviation (SD). A p value of less than 0.05 was considered significant. Differences between groups regarding complete and substantial vertigo control were also analyzed according to the Kaplan–Meier survival method. We used censored observation — if failure did not occur during follow-up, the case was censored. In class A (complete vertigo control) plot, survival was defined as the absence of vertigo spells and failure as recurrent vertigo. In class A + B (substantial vertigo control) plot, survival was defined as substantial vertigo control and failure when vertigo recurred with an incidence greater than 40% of the pre-treatment frequency. The log-rank test was employed to compare survival between groups.

2

Materials and methods

A multicenter, prospective study assessing the effectiveness of the combined HDBH and ITD in decreasing vertigo spells in MD was performed between January 2009 and June 2013. Five departments with extensive experience in vestibular pathology were involved, including the Departments of Otolaryngology from the Universities of Cluj-Napoca, Timisoara, Iasi, Bucuresti (all clinics from Romania), as well as the Otology and Skull Base Surgery Unit in Siena, Italy. All studies were approved by the respective Institutional Review Boards in accordance with the Guidelines for Protection of Human Subjects. All patients signed an informed consent form before entering the study. Inclusion criteria were adult patients with unilateral definite MD according to the guidelines of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) . According to prior recommendations , patients with episodes of spontaneous vertigo lasting between 20 min and 12 h were included. Further, as previously suggested , to be included, patients had to suffer a mean of four or more vertigo spells per month during the 3 months foregoing management. All these patients failed a trial of 6 months of low-salt diet, dietary restrictions such as caffeine and nicotine avoidance. According to previous studies , exclusion criteria were: bilateral MD, other peripheral or central vestibular syndromes, middle ear pathology, noise-induced hearing loss, previous IT gentamicin or corticosteroid or preceding ablative ear surgery and allergy to betahistine.

Patients underwent a complete neuro-otologic examination. Acoustic neuroma was ruled-out using MRI. Auditory testing comprised pure tone audiometry (PTA) with 4 frequency average (0.5, 1, 2, and 3 kHz) and speech discrimination score (SDS). The Functional Level Score (FLS), Class and vertigo control (class A–F) were defined according to the AAO-HNS criteria . A change of 10 dB or more in PTA or a change of 15% in SDS was considered clinically significant. The Tinnitus Handicap Inventory (THI) was completed in each patient . THI is a 25-item questionnaire designed to assess the severity of tinnitus. Each item was completed with “yes” scoring 4, “sometimes” scoring 2, and “no” scoring 0. The lower the total score, the less was the tinnitus handicap. All of these parameters were obtained before the treatment and at the end of the follow-up.

Patients with definite MD were offered different therapeutic alternatives: IT injection of corticoid or IT injection of gentamicin and vestibular neurectomy. Patients elected ITD injection with or without HDBH as an opportunity that might provide transitory cessation of vertigo spells without the destruction of vestibular system. If complete or substantial vertigo control was not accomplished, another sequence of ITD was offered. In patients with persistent vertigo, despite repeated ITD injections, IT gentamicin injection or ablative surgery was offered.

Enrolled patients were randomly divided in two distinct groups (Group A and B), each comprising 33 patients. For random assignment of patients, a computer-generated list of random numbers was employed. Randomization was performed by an only investigator (LM) one day before the injection. Both the surgeons and the patients were blinded to the treatment. Group A received a combination of ITD and identical-appearing placebo pills while Group B received a combination of ITD and HDBH. Dexamethasone was injected under the microscope according to the guidelines : in the supine position, the patient turned the head 45° toward the unaffected ear. Local anesthesia of the tympanic membrane was achieved and dexamethasone (4 mg/mL) was injected through a 22-gauge spinal needle and 1-mL syringe to fill the middle ear. Patients were instructed to keep the supine position with the treated ear facing upward for 30 min avoiding swallowing or talking. The ITD protocol consisted of three consecutive daily injections. HDBH consisted in 144 mg/day (48 mg tid).

Audiometric testing and completion of questionnaires were performed by researchers blinded to the surgeons. Throughout the study, all patients kept a diary recording monthly the occurrence of every vertiginous attack. At the follow-up visit, investigators reviewed these diaries. Patients were monitored at 2-month intervals throughout the study. Every patient was monitored for at least 2 years. Both in Romania and Italy betahistine is the most prescribed drug in MD patients. Nevertheless, betahistine is a costly medication in both countries, therefore the tablets were supplied free of charge by the University hospitals involved in the study. Compliance to treatment was tested through regular weekly telephone calls. Moreover, at each intervening visit, patients from both groups had to return the empty medication packages. Treatment side-effects were also recorded.

Sample size was computed with the software available from DSS Research Tools ( http://www.dssresearch.com/toolkit .). Samples were planned to detect differences of 15% in the probability of primary endpoint (the probability of success for Group A was expected to be 50%, whereas for Group B it was presumed to be 75%) with a Type I error of 5% and a statistic power of 80%. For each group, 30 subjects were required. In order to compensate for potential drop-outs, the number was raised to 33 patients.

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 while differences between categorical variables were evaluated using the chi square test. Data were expressed as mean ± standard deviation (SD). A p value of less than 0.05 was considered significant. Differences between groups regarding complete and substantial vertigo control were also analyzed according to the Kaplan–Meier survival method. We used censored observation — if failure did not occur during follow-up, the case was censored. In class A (complete vertigo control) plot, survival was defined as the absence of vertigo spells and failure as recurrent vertigo. In class A + B (substantial vertigo control) plot, survival was defined as substantial vertigo control and failure when vertigo recurred with an incidence greater than 40% of the pre-treatment frequency. The log-rank test was employed to compare survival between groups.