Directional Plasticity Rapidly Improves 3D Vestibulo-Ocular Reflex Alignment in Monkeys Using a Multichannel Vestibular Prosthesis

Bilateral loss of vestibular sensation can be disabling. We have shown that a multichannel vestibular prosthesis (MVP) can partly restore vestibular sensation as evidenced by improvements in the 3-dimensional angular vestibulo-ocular reflex (3D VOR). However, a key challenge is to minimize misalignment between the axes of eye and head rotation, which is apparently caused by current spread beyond each electrode’s targeted nerve branch. We recently reported that rodents wearing a MVP markedly improve 3D VOR alignment during the first week after MVP activation, probably through the same central nervous system adaptive mechanisms that mediate cross-axis adaptation over time in normal individuals wearing prisms that cause visual scene movement about an axis different than the axis of head rotation. We hypothesized that rhesus monkeys would exhibit similar improvements with continuous prosthetic stimulation over time. We created bilateral vestibular deficiency in four rhesus monkeys via intratympanic injection of gentamicin. A MVP was mounted to the cranium, and eye movements in response to whole-body passive rotation in darkness were measured repeatedly over 1 week of continuous head motion-modulated prosthetic electrical stimulation. 3D VOR responses to whole-body rotations about each semicircular canal axis were measured on days 1, 3, and 7 of chronic stimulation. Horizontal VOR gain during 1 Hz, 50 °/s peak whole-body rotations before the prosthesis was turned on was <0.1, which is profoundly below normal (0.94 ± 0.12). On stimulation day 1, VOR gain was 0.4–0.8, but the axis of observed eye movements aligned poorly with head rotation (misalignment range ∼30–40 °). Substantial improvement of axis misalignment was observed after 7 days of continuous motion-modulated prosthetic stimulation under normal diurnal lighting. Similar improvements were noted for all animals, all three axes of rotation tested, for all sinusoidal frequencies tested (0.05–5 Hz), and for high-acceleration transient rotations. VOR asymmetry changes did not reach statistical significance, although they did trend toward slight improvement over time. Prior studies had already shown that directional plasticity reduces misalignment when a subject with normal labyrinths views abnormal visual scene movement. Our results show that the converse is also true: individuals receiving misoriented vestibular sensation under normal viewing conditions rapidly adapt to restore a well-aligned 3D VOR. Considering the similarity of VOR physiology across primate species, similar effects are likely to occur in humans using a MVP to treat bilateral vestibular deficiency.     

Effects of systemic and lateral semicircular canal administration of aminoglycosides on normal and hydropic inner ears.

Streptomycin was injected subcutaneously into guinea pigs (n = 12) with unilateral endolymphatic hydrops. In the unoperated ears, sensory cells were degenerated at the basal ends of all cochleas and to varying extents in the vestibular sense organs. Hydropic ears, in contrast, showed greater ototoxicity in the cochlear and saccular sensory cells, while the drug's effect on the utricular and cristae sensory cells was increased, but less remarkable. In another series of normal animals (n = 16), streptomycin was applied to a fenestra of the lateral semicircular canal. Sensory cells of all three canal cristae and utricular macula were degenerated frequently, but the sensory cells of the cochleas were rarely affected. The vestibular lesions resulting from the canal approach were greater than those produced by systemic injection. Comparison with a former gentamicin-lateral canal series revealed very little difference in action of the two drugs. However, in hydropic ears, gentamicin application to the lateral canal produced increased lesions in all sensory cells, particularly in the organ of Corti. Hydropic ears are vulnerable and a greater caution is needed in administering aminoglycosides by both the systemic and the canal route to patients with Meniere's disease.     

Comparison of vestibular and cochlear ototoxicity from transtympanic streptomycin administration.

HYPOTHESIS: The relative dose-related cochlear and vestibular ototoxicity produced by transtympanically injected streptomycin (SM) compared to that of gentamicin (GM) was assessed. BACKGROUND: Although SM, the first aminoglycoside used transtympanically, is thought to be selectively vestibulotoxic, it has been replaced by GM in current clinical use. Little experimental data exist that directly demonstrate the relative cochlear and vestibular ototoxicity resulting from transtympanic administration of SM compared to GM. METHODS: Histologic evaluation was performed on inner ears from Mongolian gerbils to study vestibular and cochlear damage. Comparisons were made between animals receiving single (1 x SM) and five daily (5 x SM) injections of SM/Gelfoam-slurry and similarly injected and noninjected controls. These data were compared to results obtained using GM (1 x GM and 5 x GM) reported previously. RESULTS: Two weeks after injection, parallel qualitative and quantitative changes were seen in posterior cristae and cochlear sensory epithelia in the 1 x and 5 x SM injected groups, similar to those resulting from GM injections. Statistically significant decreases in number of hair cells were seen when 5 x SM injected ears were compared to 1 x SM injected ears and control ears. Increased damage was seen with increased dosage of each drug. Whenever damage was observed to the posterior crista sensory cells, damage was also seen in cochlear hair cells. CONCLUSIONS: In this model, SM and GM produced significant cochlear damage when vestibular damage occurred. These results suggest that, in the gerbil, SM and GM are ototoxic but not selectively vestibulotoxic. Increasing the number of transtympanic injections generally increases the damage to sensory hair cells in the posterior crista and the cochlea. A variation in interanimal susceptibility to ototoxic effects exists, but the amount of damage is consistent in cochlear and vestibular hair cells from the same animal. No evidence for selective vestibular ototoxicity from transtympanic SM was found.     

Gentamicin ototoxicity: clinical features and the effect on the human vestibulo-ocular reflex

Conclusions. Gentamicin ototoxicity presents with gait imbalance and oscillopsia, but only rarely with hearing loss and vertigo. Sinusoidal rotational stimuli with high accelerations such as the bedside head-thrust test or rotational step changes in velocity are useful to diagnose bilateral vestibulopathy. Objective. To describe the salient clinical features and vestibular testing results in gentamicin ototoxicity. Patients and methods. A retrospective review of the quantitative vestibular function testing results for patients presenting to the UCLA Neurotology Clinic with gentamicin ototoxicity over the past 10 years (n=35). Results. All patients presented with imbalance and 33 out of 35 had oscillopsia. Three patients reported a noticeable change in hearing and five reported vertigo. Of the 35 patients, 15 were in renal failure at the time of gentamicin administration. Patients with pre-existing peripheral neuropathy compensated poorly. Sinusoidal rotational testing demonstrated profoundly decreased gain and increased phase lead over the entire frequency range, with a subset of patients having relatively preserved gain at the intermediate frequencies (0.8–1.6 Hz) and low acceleration (<30°/s). There was little or no response to high acceleration step changes in velocity. The time constant measured both by sinusoidal and step responses was ultra-low. All patients tested had a positive head-thrust test bilaterally.     

大前庭水管综合征患者人工耳蜗植入效果分析

目的：分析大前庭水管综合征（large vestibular aqueduct syndrome,LVAS）患者人工耳蜗植入的疗效。方法回顾性分析37例行人工耳蜗植入术的LVAS患者（LVAS组）的临床资料,另选择临床资料相匹配37例耳蜗结构正常的人工耳蜗植入患者作为对照组,分别于人工耳蜗植入术前和术后3、6、9、12个月评估其言语识别率、听觉行为分级（categories of auditory performance,CAP）和言语可懂度分级（speech intelligibility rating, SIR）。结果①37例LVAS患者术中有5例（5耳）出现严重井喷,20例（20耳）耳蜗钻孔后出现外淋巴液不同程度波动,对照组均未出现“井喷”现象;两组电极均成功植入;两组术后均无面瘫、脑脊液漏、脑膜炎等并发症;②开机调试时两组电极阻抗值、电极反应阈值（T值）及最大舒适阈值（C值）差异无统计学意义（P＞0．05）,术后3、6、9、12个月两组的言语识别率、CAP、SIR评分均随着康复时间的延长而逐渐提高,在相同的康复时间段,两组之间各项康复指标差异无统计学意义（P＞0．05）;③术中发生“井喷”与未发生“井喷”的LVAS患者之间术后康复效果差异也无统计学意义（P＞0．05）。结论人工耳蜗植入可作为LVAS患者听觉康复的手段,其听觉康复效果与内耳发育正常的人工耳蜗植入患者接近。     

Effects of vestibular prosthesis electrode implantation and stimulation on hearing in rhesus monkeys

To investigate the effects of vestibular prosthesis electrode implantation and activation on hearing in rhesus monkeys, we measured auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE) in four rhesus monkeys before and after unilateral implantation of vestibular prosthesis electrodes in each of 3 left semicircular canals (SCC). Each of the 3 left SCCs were implanted with electrodes via a transmastoid approach. Right ears, which served as controls, were not surgically manipulated. Hearing tests were conducted before implantation (BI) and then 4 weeks post-implantation both without electrical stimulation (NS) and with electrical stimulation (S). During the latter condition, prosthetic electrical stimuli encoding 3 dimensions of head angular velocity were delivered to the 3 ampullary branches of the left vestibular nerve via each of 3 electrode pairs of a multichannel vestibular prosthesis. Electrical stimuli comprised charge-balanced biphasic pulses at a baseline rate of 94?pulses/s, with pulse frequency modulated from 48 to 222?pulses/s by head angular velocity. ABR hearing thresholds to clicks and tone pips at 1, 2, and 4?kHz increased by 5-10?dB from BI to NS and increased another ～5?dB from NS to S in implanted ears. No significant change was seen in right ears. DPOAE amplitudes decreased by 2-14?dB from BI to NS in implanted ears. There was a slight but insignificant decrease of DPOAE amplitude and a corresponding increase of DPOAE/Noise floor ratio between NS and S in implanted ears. Vestibular prosthesis electrode implantation and activation have small but measurable effects on hearing in rhesus monkeys. Coupled with the clinical observation that patients with cochlear implants only rarely exhibit signs of vestibular injury or spurious vestibular nerve stimulation, these results suggest that although implantation and activation of multichannel vestibular prosthesis electrodes in human will carry a risk of hearing loss, that loss is not likely to be severe.     

Current and future management of bilateral loss of vestibular sensation - an update on the Johns Hopkins Multichannel Vestibular Prosthesis Project

Bilateral loss of vestibular sensation can disable individuals whose vestibular hair cells are injured by ototoxic medications, infection, Ménière's disease or other insults to the labyrinth including surgical trauma during cochlear implantation. Without input to vestibulo-ocular and vestibulo-spinal reflexes that normally stabilize the eyes and body, affected patients suffer blurred vision during head movement, postural instability, and chronic disequilibrium. While individuals with some residual sensation often compensate for their loss through rehabilitation exercises, those who fail to do so are left with no adequate treatment options. An implantable neuroelectronic vestibular prosthesis that emulates the normal labyrinth by sensing head movement and modulating activity on appropriate branches of the vestibular nerve could significantly improve quality of life for these otherwise chronically dizzy patients. This brief review describes the impact and current management of bilateral loss of vestibular sensation, animal studies supporting the feasibility of prosthetic vestibular stimulation, and a vestibular prosthesis designed to restore sensation of head rotation in all directions. Similar to a cochlear implant in concept and size, the Johns Hopkins Multichannel Vestibular Prosthesis (MVP) includes miniature gyroscopes to sense head rotation, a microcontroller to process inputs and control stimulus timing, and current sources switched between pairs of electrodes implanted within the vestibular labyrinth. In rodents and rhesus monkeys rendered bilaterally vestibulardeficient via treatment with gentamicin and/or plugging of semicircular canals, the MVP partially restores the vestibulo-ocular reflex for head rotations about any axis of rotation in 3-dimensional space. Our efforts now focus on addressing issues prerequisite to human implantation, including refinement of electrode designs and surgical technique to enhance stimulus selectivity and preserve cochlear function, optimization of stimulus protocols, and reduction of device size and power consumption.     

Vestibular impairment and cochlear implantation

Conclusion. Cochlear implantation (CI) may induce vestibular impairment soon after surgery as well as after implant activation. This impairment seems to be independent from the cause of deafness and can be considered a possible complication from the intra-operative trauma and, to minor degree, from the ongoing electric stimulation. It would also seem that vestibular damage occurs independently from the likelihood of post-operative hearing deterioration. In unilateral selected CI cases, vestibular examination can be proposed as additional pre-operative exam for selection of the ear to be implanted. Objectives. This study has been planned in order to get evidence of eventual impairment of the vestibular apparatus after cochlear implantation as well as to verify whether the impairment could be related to different variables, such as cause of deafness, concomitant hearing deterioration, surgical trauma and duration of electrical stimulation. Method. Charts from two different populations of implantees have been reviewed, 21 from a prospective, 72 from a retrospective study, respectively. All the patients were implanted with Clarion® devices of different generation. Vestibular testing was based on rotatory, caloric (when possible) and stabilometric measurements, which were carried out pre-operatively and at the following different times: 5 weeks after CI surgery, and 30, 60 and 90 days after CI activation. Hearing thresholds were also assessed in those patients who showed signs of vestibular impairment as well as in a group of patients without vestibular disorders (control). Patients belonging to the retrospective group were all asked to fill a questionnaire regarding their balance condition. Results. In 14.3% of the prospective study group, a grade I and II spontaneous nystagmus was evidenced pre-operatively and remained unchanged during the whole assessment period. A grade II spontaneous nystagmus was present in 3 patients (21.4%) of the same group after surgery. In the immediate post-operative period, vestibular impairment was displayed as true rotational vertigo in 21.4% and unsteadiness in 42.8% of the study group. Severe unsteadiness was present during the first 2 days after activation in 14.3% of the subjects. In 21.4% of the patients a VPPB episode occured. In the retrospective study group, 26.4% of the subjects referred pre-operative dizziness and 25 patients (34.7%) referred immediate post-operative vertigo episodes, which remained in a milder form after CI activation in 12% of them. The hearing threshold showed to deteriorate in both vestibular-impaired and control CI population without significant difference.     

儿童感音神经性聋77例分析

对７７例感音性神经性聋患儿的病因，前庭，听功能进行分析，中重度以上耳聋者１０９耳，平衡及半规管异常者占８８．９％。大前庭导水管综合征１９例３８耳均呈重度聋，为胚胎发育性疾病，平均年龄７．１岁，在言语形成期以后发病者有一定的言语表达能力，若早期发现进行相应的防范，可保存听力，当听力重度障碍应辅以助听器，帮助言语康复；药物中毒性聋１５例中，１３例２６耳中重工聋且呈聋哑状态，平均年龄２．８岁，此种后天获     

End-point indicators of low-dose intra-tympanic gentamicin in management of Ménière’s disease

Conclusions: One-shot, low-dose intra-tympanic gentamicin (ITG) treatment was effective and safe for Ménière’s disease (MD) patients. Head thrust test (HTT) and vestibular evoked myogenic potentials (VEMPs) test could be used as endpoint indicators for vertigo control in MD patients.

Objectives: The present study is to explore end-point indicators of ITG injection in MD.

Methods: Patients with MD were reviewed from June 2012 to March 2014. Single-shot ITG at a concentration of 30?mg/ml was administered to patients. The sensitivity and specificity of HTT and VEMPs for vertigo control were measured.

Results: All 37 patients with a median follow-up of 26 months were included. Of those 37 patients, 24 patients (64.9%) obtained class A vertigo control and seven patients (18.9%) obtained class B vertigo control. Only six patients had class C control (16.2%). The sensitivity and specificity of HTT for vertigo control were 74.2% and 50.0%. Meanwhile, the sensitivity and specificity of VEMPs threshold were 83.9% and 33.3%. When combined HTT and VEMPs, sensitivity and specificity were 93.5% and 66.7%. Based on the four-tone average thresholds at 0.5, 1, 2, 3?kHz, 78.4% patients had no significant change in PTA and 16.2% patients experienced significant improvement.     

Protective effects of alpha-tocopherol against gentamicin-induced Oto-vestibulo toxicity: an experimental study

OBJECTIVE: Free radicals are involved in gentamicin ototoxicity and vestibular dysfunction and it has been demonstrated that free radical scavengers, such as alpha-tocopherol, are able to inactive free radicals, attenuating tissue damage This study was designed to investigate the possible protective effects of alpha-tocopherol against gentamicin-induced oto-vestibulo toxicity. MATERIAL AND METHODS: Adult albino guinea pigs were divided into four groups and were treated for 2 weeks as follows: Group A, controls; Group B, gentamicin plus corn oil; Group C, gentamicin only; and Group D, gentamicin plus alpha-tocopherol. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VORs), respectively. Electrocochleographic recordings were performed using an implanted round window electrode. The compound action potentials (CAPs) at 2, 4, 8 and 16 kHz were measured every 5 days Morphological changes were analysed by means of scanning electron microscopy. RESULTS: Gentamicin induced a consistent reduction in VOR responses and a progressive high-frequency hearing loss of 50-60 dB sound pressure level. Alpha-Tocopherol co-therapy slowed the progression of hearing loss and significantly attenuated the final threshold shifts The impairment of vestibular function was reduced, as evidenced by an increased VOR gain. The massive loss of outer hair cells in the cochlear basal turn and of cristae ampullaris stereocilia in gentamicin-treated animals was not observed in the cochlea of animals protected with alpha-tocopherol. CONCLUSION: This study supports the hypothesis that alpha-tocopherol interferes with gentamicin-induced free radical formation, and suggests that this drug may be useful in preventing aminoglycoside oto-vestibulo toxicity.     

Instrumental head impulse test changes after intratympanic gentamicin for unilateral definite Ménière’s disease: A systematic review and meta-analysis

Objective

To estimate how much could intratympanic gentamicin (ITG) interfere with the vestibular-ocular reflex (VOR) parameters on instrumental head impulse test (HIT), either with scleral search coil or video head impulse test and, eventually, foresee the control of vertigo crisis in unilateral intractable Ménière’s disease (MD).

Glutamate-like Immunoreactivity During Hair Cell Recovery After Gentamicin Exposure in the Chinchilla Vestibular Sensory Periphery

Objective: Determine the expression of glutamate by immunohistochemistry in normal and recovering vestibular hair cells in the chinchilla crista ampullaris after gentamicin ototoxicity. Study Design: In five groups of three animals each, ototoxicity was produced by placing gentamicin (50 μg)-impregnated Gelfoam pellets within the perilymphatic space of the superior semicircular canal. Animals were sacrificed at 1, 2, 4, 8, and 16 weeks after treatment. A group of normal (n=3) animals was also processed. Methods: For the detection of glutamate the inner ears of these animals were dissected, and the horizontal cristae ampullaris embedded in plastic. Two-micron-thick tissue sections were obtained and incubated with monoclonal antibodies against glutamate. The immunoreaction was detected using the avidinbiotiny-lated-complex technique and diaminobenzidine was the chromogen. Results: Normal sensory epithelia demonstrated type I and type II hair cells with moderate glutamate-like immunoreactivity. Supporting cells demonstrated no glutamate-like immunoreactivity. Afferent nerve fibers and calyxes surrounding type I hair cells demonstrated strong glutamate-like immunoreactivity. At 1 and 2 weeks after treatment the few type II hair cells surviving ototoxic treatment (15%–18%) contained moderate glutamate-like immunoreactivity, supporting cells showed no immunoreactivity, and nerve terminals and fibers displayed strong immunoreactivity. At 4 and 8 weeks after treatment, recovered hair cells (80%) had greater glutamate-like immunoreactivity when compared with normal hair cells, supporting cells displayed no glutamate-like immunoreactivity, and afferent fibers contained strong glutamate-like immunoreactivity. At 16 weeks, glutamate-like immunoreactivity in hair cells returned to normal level. Conclusion: Glutamate may be used as an indicator of hair cell differentiation and as an index of the molecular recovery of hair cells after ototoxicity.     

大前庭水管综合征患儿人工耳蜗植入效果分析

目的比较大前庭水管综合征（1arge vestibular aqueduct syndrome,LVAS）和内耳结构正常人工耳蜗植入术后最大舒适阈值（most comfortab lelevel,M值）和神经反应成像阈值（neural response imaging threshold,tNRI值）,为LVAS患者进行人工耳蜗植入术的可行性提供依据。方法将38例耳聋患儿根据CT检查结果分为A、B两组,A组32例,内耳结构正常;B组6例,双侧前庭导水管扩大,但不伴有其他内耳结构异常。所有患儿均植入美国Advanced Bionics公司生产的HiRes90K人工耳蜗系统。术后1个月左右安装体外设备并进行测试,使用与患儿年龄相应的行为测试方法进行舒适阈的测试;同时用SoundWave1．4调机软件行神经反应成像（neural response imaging,NRI）检测,记录tNRI值。结果两组术后1月开机时3、7、11和15号电极的M值和tNRI值的差异均无统计学意义（P〉0．05）。结论LVAS患儿并非人工耳蜗植入的禁忌,且术后调试时各指标的设定可参考内耳结构正常患儿的数值。     

Loss of Afferent Vestibular Input Produces Central Adaptation and Increased Gain of Vestibular Prosthetic Stimulation

Implanted vestibular neurostimulators are effective in driving slow phase eye movements in monkeys and humans. Furthermore, increases in slow phase velocity and electrically evoked compound action potential (vECAP) amplitudes occur with increasing current amplitude of electrical stimulation. In intact monkeys, protracted intermittent stimulation continues to produce robust behavioral responses and preserved vECAPs. In lesioned monkeys, shorter duration studies show preserved but with somewhat lower or higher velocity behavioral responses. It has been proposed that such changes are due to central adaptive changes in the electrically elicited vestibulo-ocular reflex (VOR). It is equally possible that these differences are due to changes in the vestibular periphery in response to activation of the vestibular efferent system. In order to investigate the site of adaptive change in response to electrical stimulation, we performed transtympanic gentamicin perfusions to induce rapid changes in vestibular input in monkeys with long-standing stably functioning vestibular neurostimulators, disambiguating the effects of implantation from the effects of ototoxic lesion. Gentamicin injection was effective in producing a large reduction in natural VOR only when it was performed in the non-implanted ear, suggesting that the implanted ear contributed little to the natural rotational response before injection. Injection of the implanted ear produced a reduction in the vECAP responses in that ear, suggesting that the intact hair cells in the non-functional ipsilateral ear were successfully lesioned by gentamicin, reducing the efficacy of stimulation in that ear. Despite this, injection of both ears produced central plastic changes that resulted in a dramatically increased slow phase velocity nystagmus elicited by electrical stimulation. These results suggest that loss of vestibular afferent activity, and a concurrent loss of electrically elicited vestibular input, produces an increase in the efficacy of a vestibular neurostimulator by eliciting centrally adapted behavioral responses without concurrent adaptive increase of galvanic afferent activation in the periphery.     

Permanent gentamicin vestibulotoxicity.

OBJECTIVE: To determine the natural history of permanent gentamicin vestibulotoxicity. STUDY DESIGN: Retrospective; comparison of retrospective and prospective studies. SETTING: Tertiary neurotology clinic. Clinical research and technology center. SUBJECTS: Thirty-three subjects with permanent gentamicin-induced vestibulotoxicity. INTERVENTIONS: Medical records review, neurotologic examination, and vestibular and auditory function tests. MAIN OUTCOME MEASURES: Vestibular and auditory function test results at least 1 year after discontinuation of gentamicin, clinical examination results, serum gentamicin levels, and serum creatinine levels. RESULTS: Thirty-three subjects had vestibular function test results consistent with permanent gentamicin ototoxicity. All complained of dysequilibrium, 32 described oscillopsia, and 23 had tinnitus. All 33 subjects had complained of symptoms consistent with ototoxicity within 1 to 3 weeks of initiation of gentamicin therapy; however, gentamicin vestibulotoxicity was not recognized before hospital discharge in 32 of 33 subjects. Serum peak and trough gentamicin levels did not correlate with the development of vestibulotoxicity, nor did observance of recommended "safe" dosage ranges. Of 17 subjects whose serum creatinine levels were recorded, 6 experienced abnormal elevations in serum creatinine in conjunction with gentamicin use. CONCLUSION: Gentamicin can cause permanent vestibular and auditory ototoxicity. There is no safe dose of gentamicin. Serum gentamicin levels are of no value in predicting the onset, occurrence, or severity of vestibulotoxicity or cochleotoxicity. Termination of gentamicin on appearance of signs or symptoms of ototoxicity may reduce the incidence of permanent vestibular ototoxicity. When possible, other antibiotics should be administered.     

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.     

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.     

Quantitative Study of Vestibulotoxicity Induced by Gentamicin or Cisplatin in the Guinea Pig

Although aminoglycoside vestibulotoxicity is well established, the question of cisplatin vestibulotoxicity is controversial. The goals of this study were 1. to determine whether cisplatin induces vestibulotoxicity as measured histologically, and 2. to compare the vestibulotoxicity between gentamicin and cisplatin. Guinea pigs' vestibular end-organ hair bundles in control, gentamicin, and cisplatin groups were compared. In the lateral cristae of the cisplatin group, hair bundles decreased 21% on the central apex portion. In the gentamicin group, a slight decrease (17%) of hair bundles on the striola from the utricular maculae was observed, as was severe damage on the entire cristae, especially on the central apex (70%). These results indicate that gentamicin and cisplatin may not influence vestibular function of the otolithic membrane. However, gentamicin may severely damage and cisplatin may slightly damage the crista ampullaris hair bundles.     

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.