Intentional ablation of vestibular function using commercially available topical gentamicin-betamethasone eardrops in patients with Meniere's disease: further evidence for topical eardrop ototoxicity

OBJECTIVE: To determine whether the controversial findings of suspected ototoxicity from commercially available gentamicin sulfate and betamethasone sodium phosphate eardrops can be used in a therapeutic fashion to ablate (or attenuate) vestibular function in patients with unilateral Meniere's disease. STUDY DESIGN: Prospective case review. METHODS: At a tertiary care dizziness unit at the University Health Network, Toronto General Hospital, University of Toronto (Toronto, Ontario, Canada), adults with unilateral Meniere's disease undergoing intratympanic ablation therapy were studied. After insertion of a tympanostomy tube with the patient under local anesthesia, patients instilled gentamicin containing eardrops three times daily until they became vertiginous for longer than 24 hours and then for an additional 2 days longer or for 1 month, whichever came first. Electronystagmographic caloric test responses were measured before treatment using bithermal water caloric and after treatment using air caloric tests. Main outcome measures included clinical titration of drops to the onset of prolonged vertigo. As well, post-treatment findings on electronystagmography and audiometry were compared with pretreatment testing. RESULTS: Twenty patients were available for review. Fifteen patients had a significant reduction in caloric test responses compared with pretreatment values; among them, 10 patients had absent air caloric test responses on the treated side. In 10 patients hearing worsened according to the 1995 American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium Guidelines for reporting in Meniere's disease. CONCLUSIONS: Topical gentamicin-betamethasone eardrops can pass through a tube into the middle ear, where they may prove primarily vestibulo-ototoxic patients with Meniere's disease. The study further confirms clinical observations that gentamicin-containing eardrops might prove ototoxic, especially in noninflamed ears with a tympanic membrane defect.     

Ototoxicity and topical eardrops

Topical aminoglycoside ear drops are theoretically acknowledged to be potentially ototoxic when administered in the presence of a tympanic membrane perforation. Although the development of clinical ototoxicity appears to be rare, nine well-documented and incontrovertible cases (12 ears in total) of iatrogenic topical vestibulotoxicity are presented, representing the largest series in the English language world literature to date. All patients were treated with the topical gentamicin-containing ear drops Garasone^®, (betamethasone sodium phosphate and gentamicin sulphate) for prolonged periods. Toxicity was found to be primarily vestibular rather than cochlear. Further review of five previously reported cases in addition to the findings from another four patients identified with topical ototoxicity are described. Although compensation occurred in unilateral cases the disability in bilateral cases was typically severe and often resulted in litigation.     

Presumed reduction of vestibular function in unilateral Menière's disease with aminoglycoside eardrops

We report the first case in the world literature of deliberate ablation of vestibular function in unilateral Menière's disease with aminoglycoside eardrops (Garasone). These findings give conclusive proof that Garasone eardrops, and by implication, all topical aminoglycoside ear drops can be vestibulotoxic in the presence of a tympanic membrane defect. The lower concentration of gentamicin in Garasone, in comparison to the standard intratympanic preparations for chemical ablation of vestibular function, may also offer a reduction in the potential risk of cochleotoxocity.     

Assessment of vestibular ototoxicity of ear drops by recording of vestibular evoked potentials to acceleration impulses

INTRODUCTION: The cochlear ototoxicity of several ear drops is well documented in the literature, but very few studies exist on the vestibular ototoxicity of these topical drugs. GOAL OF STUDY: To develop an animal model for the assessment of the vestibular ototoxicity of ear drops. MATERIALS AND METHODS: Two animal groups, consisting of five fat sand rats (FSRs) each, underwent unilateral labyrinthectomy. Normal saline was topically applied into the middle ear cavity of rats in the first group for 7 days (control group). Rats in the second group were treated in the same way by topical gentamicin solution. Cochlear function was assessed by the recording of auditory evoked potential (ABPs) thresholds, and vestibular function was assessed by the recording of vestibular evoked potentials (VsEPs) to angular accelerations. RESULTS: In the control group, except for the amplitude of the first wave, there was no significant difference in the VsEPs recorded before and after topical application. In the gentamicin group, VsEPs could not be recorded after 7 days, and ABPs were recorded in one case only, with a threshold of 100 dB sound pressure level (SPL). CONCLUSION: VsEPs seem to be a reliable measure for evaluating the vestibular ototoxicity of topical ear drops.     

Systemic absorption of gentamicin in the management of active mucosal chronic otitis media

A prospective study was performed on patients with active mucosal chronic otitis media who were being treated with the gentamicin-containing preparation Gentisone HC^TM. In 27 patients plasma gentamicin levels were measured. Detectable levels were found in 7/27 (26%). Pre- and post-treatment audiometry was performed on 16 patients. There was no statistically significant difference in the change of the mean bone conduction thresholds as a result of treatment, between the treatment and control ears (P= 0.07, Wilcoxon signed Ranks Test at 95% C.I.). We conclude that there is evidence of systemic absorption of gentamicin that would ultimately be absorbed into the perilymph. Gentamicin is known to be ototoxic affecting the vestibular system in lower doses and the cochlea in high doses, hence audiometric assessment is not an appropriate screen for ototoxicity when using topical gentamicin-containing drops. Alternative topical preparations should be further investigated.     

Systemic absorption of gentamicin in the management of active mucosal chronic otitis media.

A prospective study was performed on patients with active mucosal chronic otitis media who were being treated with the gentamicin-containing preparation Gentisone HC. In 27 patients plasma gentamicin levels were measured. Detectable levels were found in 7/27 (26%). Pre- and post-treatment audiometry was performed on 16 patients. There was no statistically significant difference in the change of the mean bone conduction thresholds as a result of treatment, between the treatment and control ears (P = 0.07, Wilcoxon signed Ranks Test at 95% C.I.). We conclude that there is evidence of systemic absorption of gentamicin that would ultimately be absorbed into the perilymph. Gentamicin is known to be ototoxic affecting the vestibular system in lower doses and the cochlea in high doses, hence audiometric assessment is not an appropriate screen for ototoxicity when using topical gentamicin-containing drops. Alternative topical preparations should be further investigated.     

Middle ear instillation of gentamicin and streptomycin in chinchillas: morphologic appraisal of selective ototoxicity.

OBJECTIVE: To determine selective cochlear and vestibular ototoxicity of two aminoglycoside antibiotics (gentamicin and streptomycin) in the chinchilla model. Middle ear application of these agents mirrors the clinical practice of chemical vestibular ablation used in Meniere's disease. BACKGROUND: Middle ear instillation of gentamicin or streptomycin has become a popular form of vestibular ablative treatment for disabling Meniere's disease. The vestibular selectivity of these two drugs applied in this fashion has clinical support but is not fully established in humans. Our understanding in this regard has largely been limited to animal models exposed to systemic infusion of aminoglycosides. METHOD: Ten chinchillas underwent left middle ear instillation of one of three agents using variable dosing schedules: gentamicin (n = 6), streptomycin (n = 2), and saline (n = 2) as control. Animals were sacrificed for temporal bone studies using scanning electron microscopy. Morphologic changes in the cochlear and vestibular neuroepithelia were identified. RESULTS: Widespread cochlear and vestibular neuroepithelial injuries were observed with both gentamicin and streptomycin. Contralateral ototoxicity was variable and not related to the total dose of drug delivered. The effect of these two aminoglycosides on the dark cells of the vestibular system appeared negligible. CONCLUSION: We were unable to confirm the selective damage of vestibular end-organ in the chinchilla by either gentamicin or streptomycin, a phenomenon that is generally perceived to occur in humans. Chinchillas, like other small mammals, may not be an ideal model for the study of human ototoxicity.     

Transtympanic gentamicin for meniere's syndrome

Objectives: Study the impact of transtympanic gentamicin on patients with unilateral Meniere's syndrome. Partial chemical labyrinthectomy is a relatively recent concept for the treatment of Meniere's syndrome. It uses the ototoxic effect of gentamicin to reduce the symptom of vertigo and maintain cochlear function. Study Design: A prospective study using transtympanic gentamicin was begun in January 1994. Patients selected had failed medical therapy, but were not incapacitated. Patients had preinjection audiometric and electronystagmography data. Most had an imaging study. All had one injection, about half had more than one. Patients were seen 1 month after therapy and repeat studies were obtained. Repeat injection was performed if indicated. Follow-up from the chart or by telephone was obtained. Data were tabulated using the 1995 American Academy of Otologaryngology—Head and Neck Surgery guidelines. Results: Through December 1996 43 patients with unilateral Meniere's syndrome were treated. The pretherapy function level was 3 through 5. After therapy the function level was 1 or 2. There was almost no change in cochlear function and no patient became deaf. Many patients had mild ataxia or dysequilibrium during the first 2 weeks following therapy. Most patients showed some decrease in labyrinthine function measured on electronystagmography. No attempt was made to ablate labyrinthine function. Seventeen of 18 patients had a vertigo index in the class A or B category after 2 years. Conclusions: Transtympanic gentamicin has become the treatment of choice for patients who fail medical therapy for Meniere's syndrome at the authors' institution. Laryngoscope, 108:1446–1449, 1998     

Ototoxicity after use of neomycin eardrops is unrelated to A1555G point mutation in mitochondrial DNA

Ear drops containing neomycin only rarely cause ototoxicity. The authors report on three patients with a tympanic membrane perforation who developed severe ototoxicity after use of eardrops containing 0.35 per cent neomycin. Mitochondrial DNA analysis revealed that there was no A1555G point mutation in these patients. This finding indicates that application of low concentration neomycin to the middle ear can cause severe inner ear damage even in humans who are not hyper-susceptible to aminoglycosides.     

Middle ear instillation of gentamicin and streptomycin in chinchillas: electrophysiological appraisal of selective ototoxicity

The purpose of this study was to investigate selective vestibular ototoxicity of gentamicin and streptomycin in the chinchilla model. In total, 10 chinchillas underwent left middle ear instillation of one of three agents: gentamicin, streptomycin and saline. Electrophysiological data (otoacoustic emissions (OAEs), auditory brainstem evoked response (ABRs), and ice-water electronystagmography were recorded before and after instillation. Animals were sacrificed for temporal bone studies using scanning electron microscopy. Morphological changes in the cochlear and vestibular neuroepithelia were correlated with electrophysiological changes. Widespread ipsilateral cochlear and vestibular neuroepithelial injuries were observed and correlated with loss of OAEs, ABRs and ice-water caloric response. This study provides no evidence of selective vestibular ototoxicity of gentamicin or streptomycin. Morphological damage correlates with, but precedes loss of electrophysiological parameters. Chinchillas, like other small mammals, may not be an ideal model for the study of human ototoxicity.     

Endoscope-assisted vestibular neurectomy

Objective/Hypothesis: In some instances endoscopes offer better visualization than the microscope and frequently allow less invasive surgery. This study was undertaken to determine whether endoscopy is safe and effective during neurectomy of the vestibular nerve. Method: Ten patients with intractable unilateral Meniere's disease underwent a retrosigmoid craniotomy for neurectomy of the vestibular nerve. Endoscopy with a Hopkins telescope was used during each procedure to study posterior fossa anatomic relationships and to assist the neurectomy. Preoperative and postoperative audiometric evaluation was performed in all patients undergoing vestibular neurectomy. Nine of these patients had preoperative electronystagmography, and four patients completed postoperative electronystagmography. The 1995 American Academy of Otolaryngology—Head and Neck Surgery's Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere's disease were used. Results: Complete neurectomy was achieved in all 10 patients. Endoscopy allowed improved identification of the nervus intermedius and the facial, cochlear, and vestibular nerves and adjacent neurovascular relationships without the need for significant retraction of the cerebellum or brainstem. In addition, endoscopic identification of the cleavage plane between the cochlear and vestibular nerves medial to or within the internal auditory canal (n = 3) was not made with the 0-degree endoscope; however, identification was made with the 30- or 70-degree endoscope in all cases. In all patients with Meniere's disease, elimination of the recurrent episodes of vertigo (n = 10) or otolithic crisis of Tumarkin (n = 1) was achieved. Conclusions: Posterior fossa endoscopy can be performed safely. Endoscope-assisted neurectomy of the vestibular nerve may offer some advantages over standard microsurgery including increased visualization, more complete neurectomy, minimal cerebellar retraction, and a lowered risk of cerebrospinal fluid leakage.     

Guidelines for the treatment of tympanostomy tube otorrhea

Treatment of tympanostomy tube otorrhea has evolved with numerous studies demonstrating the superiority of topical therapy in the form of eardrops over systemic antibiotic therapy. Many physicians have been concerned about ototoxicity with antibiotic eardrops because several ototopical agents have a risk of vestibular and cochlear damage, which may be permanent. An expert round table of pediatric and general otolaryngologists, pediatricians, and family physicians met in Quebec City in May 2004 to develop practical Canadian guidelines for the safe treatment of tympanostomy tube otorrhea. The recommendations and guidelines are outlined.     

Topical gentamicin and ethacrynic acid: Effects on cochlear function

Objective: To determine whether concurrent intravenous administration of the loop diuretic ethacrynic acid potentiates the toxicity of the aminoglycoside antibiotic gentamicin applied topically on the round window. Study Design: The authors studied the effects on cochlear sensitivity of co-administered intracardiac ethacrynic acid (40 mg/kg) and high-dose topical gentamicin solution (100%) applied to the round window. Comparisons were made with animals receiving ethacrynic acid plus systemic gentamicin (100 mg/kg); topical gentamicin alone; systemic gentamicin alone; and intravenous ethacrynic acid alone. Methods: Experiments were carried out on pigmented guinea pigs weighing 400 to 500 g. Changes in cochlear function were characterized by monitoring shifts in compound action potential (CAP) thresholds by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results: After 20 days animals receiving ethacrynic acid in combination with topical gentamicin to the round window failed to demonstrate a significant deterioration in cochlear sensitivity, whereas all animals receiving systemic gentamicin plus ethacrynic acid experienced profound increases in CAP thresholds. Conclusions: This study supports the contention that ethacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph. In addition, this study answers important clinical concerns regarding the safety of the use of topical aminoglycoside agents in combination with loop diuretics.     

A randomised controlled trial of active chronic otitis media comparing courses of eardrops versus one‐off topical treatments suitable for primary,secondary and tertiary healthcare settings

Clin. Otolaryngol. 2012, 37 , 261–270 Objective: Primary: to compare one‐off administration of boric acid powder with courses of 1% acetic acid and ciprofloxacin eardrops in treating active chronic otitis media. Secondary: to evaluate the effectiveness of Quadriderm® cream in resistant active chronic otitis media; and to document side effects of these treatments, especially hearing loss. Study design: Randomised controlled trial. Setting: Outpatient department of a tertiary ENT unit. Participants: Hundred and fifty‐nine patients over 6 years old with active chronic mucosal (without cholesteatoma) otitis media randomised to receive one of the three primary agents. Method: All techniques employed were suitable for primary healthcare givers as well as specialists. After confirming eligibility, patients were randomly allocated to treatment. All ears underwent toilet with irrigation using clean water, a syringe and ambient light, with or without dry mopping, until the perforation was visible. The randomised solution was flushed through the middle ear and eustachian tube using a ‘tragal pump’ technique: saline was used as the solution for flushing in the boric acid powder arm. Patients allocated topical ear medication were given a bottle of eardrops to administer (six drops twice daily, ‘pumped in’) until finished. Those allocated boric acid powder had the external ear canals filled as a one‐off treatment. Patients were followed up monthly thereafter. Outcome measures: Primary: Dry (inactive) middle ears as assessed by the doctor. Secondary: Patient assessment of success; microbiologic culture and sensitivity; audiologic changes because of treatment; complications of treatment; costs of therapies. Results: Ciprofloxacin eardrops and boric acid powder were statistically superior to 1% acetic acid eardrops in rendering active chronic otitis media inactive (73% dry ears for ciprofloxacin; 67% for boric acid powder; and 24% for acetic acid). There was no difference between the success rates of ciprofloxacin eardrops and boric acid powder. Quadriderm cream was effective in 85% of patients failing first‐line therapy. No agent caused significant complications and specifically no hearing loss. Conclusions: This study showed a single application of boric acid powder following external auditory canal irrigation until the perforation was visible to be as effective as the current best practice of topical quinolone eardrops in active chronic otitis media. Boric acid powder is inexpensive and does not require patient compliance. Boric acid powder is a viable, less costly alternative to topical antibiotic/steroid ear drops in the developing world for active chronic otitis media. Acetic acid eardrops 1% are ineffective. Quadriderm cream, given as a one‐off therapy, also appears to be effective.     

Experimental investigations on the influence of anemia on gentamicin ototoxicity

Summary The purpose of this study was to determine whether or not anemic patients have a higher risk of gentamicin ototoxicity. Using the laboratory rat as an animal model with auditory brain-stem response measurements and surface preparations of the organ of Corti, it could be shown that cochlear damage in anemic rats treated with gentamicin was significantly higher (P< 0.05) than in the nonanemic ones treated with the same dosages of antibiotic. Doses of gentamicin used were 50 mg/kg for 30 days and 40 mg/kg for another 75 days. Offprint requests to: P. Federspil     

Determination of ototoxicity of common otic drops using isolated cochlear outer hair cells.

OBJECTIVES: Otic drops are commonly used not only for otitis externa, but also for otorrhea in the presence of tympanostomy tubes or tympanic membrane perforations. Many studies have demonstrated the ototoxicity of common otic preparations such as Cortisporin otic drops (Monarch Pharmaceuticals, Bristol, TN). The purpose of this study was to assess the relative ototoxicity of common otic preparations by direct exposure to isolated cochlear outer hair cells (OHCs). METHODS: OHCs from adult chinchilla cochlea were exposed to standard bathing solution (control), acetic acid, Acetasol HC (Alpharma USPD Inc., Baltimore, MD), Gentacidin (CIBA Vision Ophthalmics, Atlanta, GA), and Tobradex (Alcon, Fort Worth, TX). The cells were observed using an inverted microscope, and the images were recorded in digital still-frame and video, and analyzed on the Image Pro-Plus 3.0 program (Media Cybernetics, Silver Spring, MD). RESULTS AND CONCLUSIONS: As measured by time to cell death and change in morphology of OHCs, acetic acid with or without hydrocortisone was most toxic to OHCs. Cortisporin was more cytotoxic than gentamicin and Tobradex.     

Use of the Round Window Microcatheter in the Treatment of Meniere's Disease

Objectives/Hypothesis Transtympanic gentamicin is an increasingly popular treatment for Meniere's disease. The present report examines the 2‐year follow‐up of our first 27 patients with Meniere's disease treated with the use of microdose gentamicin through the Round Window Microcatheter. We applied the 1995 American Academy of Otolaryngology—Head and Neck Surgery criteria to this patient group to analyze the results of treatment. Study Design This study is an evaluation of consecutive patients with predetermined data collection on each patient. Methods Patients with confirmed Meniere's disease underwent placement of the Round Window Microcatheter, which was filled with 10 mg/mL gentamicin, after placement into the round window niche was confirmed. Ten milligrams per milliliter of gentamicin was injected into the catheter by hand on two occasions after device placement in the first several patients. The remaining patients had continuous infusion of 10 mg/mL gentamicin at 1μL/h for the next 10 days. The catheter was removed 10 days after placement. All patients underwent an extensive set of hearing and vestibular tests on several occasions before, during, and after treatment. Results In the patients in the study, vertigo was eliminated in 92.6%, with 3.7% of patients (1/27) demonstrating a mild permanent threshold shift in hearing. Tinnitus and pressure were significantly reduced in more than 65% of patients. Only one patient demonstrated a reduction of vestibular function after treatment. Conclusions Results of this study on this group of patients indicate that vertigo can be controlled in the long term using microdose gentamicin without a significant reduction in cochlear or vestibular function in most of the patients in our series. Our results are compared with the published literature examining transtympanic injection. In addition, the underlying science supporting this type of treatment is examined.     

Topical vancomycin for chronic suppurative otitis media with methicillin-resistant Staphylococcus aureus otorrhoea

There has been a steady increase in the number of cases of methicillin-resistant Staphylococcus aureus (MRSA) otorrhoea; this is a growing concern. The purpose of this study was to evaluate the efficacy of topical vancomycin treatment in patients with MRSA otorrhoea. Fifty-five patients with MRSA otorrhoea were prospectively enrolled into the study. Thirty-five patients were treated with vancomycin eardrops as outpatients. The concentration of the locally prepared vancomycin solution was 25 mg/ml. The dose of vancomycin was two drops three times daily for 10 days. As a control group, 20 patients were treated with gentamicin 0.3% solution. Data were analysed by the Mann-Whitney U test to compare the efficacy of vancomycin eardrops and gentamicin eardrops. In the vancomycin group, the otorrhoea was significantly reduced in 33 ears (94%); in the gentamicin group, in four ears (20 per cent); this reduction was statistically significant (P < 0.03). The use of topical vancomycin treatment was effective for patients with MRSA otorrhoea refractory to conventional antibiotic treatment.     

Diagnostic and therapeutic strategies for Meniere's disease of the Japan Society for Equilibrium Research

ObjectiveWe provided diagnostic and therapeutic strategies for Meniere's disease in accordance with Japanese Clinical Practice Guideline of Meniere's disease and delayed endolymphatic hydrops 2nd ed. Tokyo: Kanehara Shuppan; 2020 edited by the Japan Society for Equilibrium Research.MethodsThe Committee for Clinical Practice Guidelines was entrusted with a review of the scientific literature on the above topic. Clinical Questions (CQs) concerning the treatment for Meniere's disease were produced, and the literature according to each of them including CQ was searched. The recommendations are based on the literature review and the expert opinion of a subcommittee.ResultsDiagnosis criteria of Meniere's disease are classified into Meniere's disease with typical cochlear and vestibular symptoms, and atypical Meniere's disease with either cochlear symptoms or vestibular symptoms. Treatment of Meniere's disease was composed of lifestyle changes, medications such as anti-vertigo drugs and diuretics, middle ear positive pressure treatment, and selective destruction of the vestibule.ConclusionMeniere's disease is diagnosed based on clinical histories and examination findings after processes of differential diagnosis. Treatment option of the disease should be selected in order of invasiveness, according to the severity of the disease and the response to each treatment.     

Gefährden Ohrentropfen die Innenohrfunktion? Eine tierexperimentelle Untersuchung

Summary Damages to inner ear function can be induced by improper application of ear drops. Which of the many substances combined in commercial otological preparations is mainly responsible, still remains a matter of controversy.In guinea pigs a defined amount of different ear drops is applied to the round window over a constant time period and, at the same time, the inner ear function is determined by continuous recording of the compound action potentials and cochlear microphonics. In this way, the relative intratympanic ototoxicity of neomycin and tetracain concentration series can be compared with commercial aminoglycoside containing ear drops.However, there are some ear drops which contain highly ototoxic substances, they show no significant differences of hearing loss to other.