Histamine H1 Receptor Contributes to Vestibular Compensation.

Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor, and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the postlesion functional plasticity in the adult CNS. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery in the CNS, but also a novel potential therapeutic target for vestibular disorders.SIGNIFICANCE STATEMENT Vestibular disorders manifest postural imbalance, nystagmus, and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the postlesion functional plasticity in the adult CNS. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery of CNS, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders.

The role of GABAB receptors in the vestibular oculomotor system in mice.

Systemic administration of a gamma-amino butyric acid type B (GABAB) receptor agonist, baclofen, affects various physiological and psychological processes. To date, the effects on oculomotor system have been well characterized in primates, however those in mice have not been explored. In this study, we investigated the effects of baclofen focusing on vestibular-related eye movements. Two rotational paradigms, i.e. sinusoidal rotation and counter rotation were employed to stimulate semicircular canals and otolith organs in the inner ear. Experimental conditions (dosage, routes and onset of recording) were determined based on the prior studies exploring the behavioral effects of baclofen in mice. With an increase in dosage, both canal and otolith induced ocular responses were gradually affected. There was a clear distinction in the drug sensitivity showing that eye movements derived from direct vestibulo-ocular reflex pathways were relatively unaltered, while the responses through higher-order neural networks in the vestibular system were substantially decreased. These findings were consistent with those observed in primates suggesting a well-conserved role of GABAB receptors in the oculomotor system across frontal-eyed and lateral-eyed animals. We showed here a previously unrecognized effect of baclofen on the vestibular oculomotor function in mice. When interpreting general animal performance under the drug, the potential contribution of altered balance system should be taken into consideration.

Can the adverse effects of antiepileptic drugs be detected in saccadic eye movements?

PURPOSE: The objective of this study was to determine whether the adverse effects of antiepileptic-drugs could be assessed by the eye movements of epilepsy patients. METHODS: This study was performed prospectively in a single tertiary hospital. The inclusion criteria for this study were as follows: (1) consecutive patients with epilepsy taking antiepileptic-drugs regularly for at least 1 year, (2) the absence of structural lesions on MRI, (3) an age ≥16 years old, (4) not using medications that could influence eye movement, and (5) a normal neurological examination. The latency, peak velocity and accuracy of the saccades and the gain of the pursuits were recorded by video-based electro-oculography. We analyzed the differences in the parameters of the eye movements for 75 patients with epilepsy and 20 normal controls matched for age and sex. RESULTS: The total latency (1017.7 ± 148.9 ms vs. 1150.7 ± 106.6 ms, p=0.0003) and accuracy [370.7% (95% CI 364.1-376.4%, range 306-408.2%), 92.7% as total accuracy normalized value vs. 383.6% (95% CI 378.8-398%, range 322.9-417.4%), 95.9% as total accuracy normalized value, p=0.0005] were significantly different between the patients with epilepsy and normal controls. For the detection of nystagmus with video-based electro-oculography, the clear cutoff values of total accuracy (≤388.7%, 97.2% as total accuracy normalized value) revealed 93.4% sensitivity and 28.6% specificity, and the clear cutoff values of total latency (≤1005.5 ms) showed 49.2% sensitivity and 78.6% specificity. CONCLUSIONS: The total latency and accuracy of video-based electro-oculography may be screened to identify patients with a high risk of adverse effects with antiepileptic-drugs.

Examining the effect of dl-3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine on the Standardized Field Sobriety Tests.

dl-3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine are commonly used illicit drugs that are thought to impair driving ability. The Standardized Field Sobriety Tests (SFSTs) are utilized widely to detect impairment associated with drugs other than alcohol in drivers, although limited evidence concerning MDMA and methamphetamine consumption on SFST performance exists. The aim of this study was to evaluate whether the SFSTs were a sensitive measure for identifying the presence of the specific isomer d-methamphetamine and MDMA. In a double-blind, within-subject, counter-balanced and placebo-controlled study, 58 healthy and abstinent recreational drugs users were administered three treatments: 100mg of MDMA, 0.42 mg/kg d-methamphetamine, and placebo. For each condition the SFSTs were administered at 4 and 25 h post treatment. d-methamphetamine was not found to significantly impair SFST performance unlike MDMA, which significantly impaired SFST performance in comparison to placebo with 22% of the sample failing the test at the 4h testing time-point. No differences were observed at the 25 h testing time-point for any of the conditions. It was concluded that the SFSTs are not efficient in identifying the presence of low level d-methamphetamine, and are significantly better at detecting the presence of MDMA at the levels assessed.

Vestibular and balance findings in nonsymptomatic workers exposed to styrene and dichloromethane.

OBJECTIVE: The aim of our study was to assess the vestibular and balance system in non-symptomatic workers exposed to styrene and dichloromethane at the workplace. DESIGN: Subjects underwent videonystagmography including saccades, smooth pursuit (SP), optokinetic test (OKN), gaze nystagmus assessment, bithermal caloric test, and static posturography. STUDY SAMPLE: Study groups included 74 workers in plastics manufacturing, aged 40 (SD 8) years, exposed to styrene and dichloromethane, and the reference group of 49 non-exposed subjects, aged 36 (SD 10) years. RESULTS: More than 60% of exposed and non-symptomatic workers revealed abnormal results of vestibular tests. Saccadic latency elongation (p = 0.0098), lower gain in SP (p = 0.0037) and OKN (p = 0.0000) were more common in the exposed group, as well as lower reactivity (p = 0.0337) and mean slow phase velocity of caloric nystagmus. Static posturography revealed higher sway velocities in the test with eyes closed, on foam and worse results of three from five limit of stability tests. No relationship between chemicals exposure and vestibular and balance test results was found. CONCLUSIONS: In principle, our findings indicate the possibility of high-level deficits in the central part of vestibular system. Lower vestibular reactivity may suggest that bilateral vestibular hypofunction might also be the possible consequence of solvent exposure.

Baclofen, motion sickness susceptibility and the neural basis for velocity storage.

Reduction of the dominant time constant (T(VOR)) of the angular vestibulo-ocular reflex (aVOR) by habituation is associated with a decrease in motion sickness susceptibility. Baclofen, a GABA(b) agonist, reduces the time constant of the velocity storage integrator in the aVOR in a dose-dependent manner. The high frequency aVOR gain is unaltered by baclofen. Here we demonstrate that the reduction in T(VOR) produced by oral administration of 20 mg of baclofen causes a significant reduction in motion sickness susceptibility, tested with roll while rotating (RWR). These data show that motion sickness susceptibility can be pharmacologically manipulated with a GABA(b) agonist and support our conclusion that motion sickness is generated through velocity storage. We also show how baclofen acts on velocity storage at the neural level. A vestibular-plus-saccade (VPS) neuron was recorded in the rostral medial vestibular nucleus (rMVN) of a cynomolgus monkey, an area where we postulate that velocity storage is generated. The cell had a time constant during steps of velocity that was close to that of the T(VOR). After parenteral administration of baclofen, there was a similar decrease in the time constants of the VPS neuron and the T(VOR). This is the first demonstration of the concurrence of unit and aVOR time constants before and after baclofen. The data support the hypothesis that the velocity storage integrator is generated through activity of vestibular-only (VO) and VPS neurons in rMVN and suggest that GABA(b) synapses on VO and VPS neurons are likely to be involved in the baclofen-induced reduction in motion sickness susceptibility.

The efficacy of ketamine for the treatment of postoperative shivering.

BACKGROUND: There are few reports on the utility of ketamine for the prevention of postoperative shivering. We thus established the efficacy of two doses of ketamine compared with meperidine for the treatment of postoperative shivering. METHODS: This is a prospective, randomized double-blind study involving 90 ASA I-II patients after general anesthesia. Patients with shivering grade 3-4 were allocated to receive either meperidine 25 mg, ketamine 0.5 mg/kg, or ketamine 0.75 mg/kg IV. Shivering and side effects were monitored at set time intervals. RESULTS: Shivering grades for the first 4 min after treatment were lower in the ketamine groups; however, nystagmus and feeling like "walking in space" was experienced with both doses of ketamine. CONCLUSION: Ketamine 0.5-0.75 mg/kg is more rapid than meperidine (25 mg) for the reduction of postoperative shivering, but the side effect profile may limit its usefulness.

[Oculomotor anomalies from medications]. / Les anomalies oculomotrices dues aux médicaments.

Many medicines, mainly with neurological purpose, interfere with the oculomotricity. The biochemistry of the oculomotor systems and thus, the mechanisms of action of these drug interferences are not completely clarified. Most medicines impair the eye movements at the level of their fine adjustment by feed-back loops implying the cerebellum. Quite often, the interferences remain asymptomatic, restricted to a saccadic pursuit, hypometric saccades or an end-point nystagmus. Sometimes however, symptoms of dizziness or oscillopsia appear, due to loss of the vestibulo-ocular reflexes efficiency. A diplopia or a blurred vision by double outline could be suggestive of an ocular motor paresis or a loss of the binocular fusion due to drugs action.

Impact of alcohol on vestibular function in relation to the legal limit of 0.25 mg/l breath alcohol concentration.

The aim of this study was to investigate the effect of alcohol on sacculocollic and vestibulo-ocular reflex systems, when the breath alcohol concentration (BrAC) is close to the legal limit of 0.25 mg/l. Twenty healthy male volunteers underwent vestibular evoked myogenic potential and caloric coupled with visual suppression tests. These tests were conducted prior to imbibing alcohol at a dosage of 0.5 g/kg to achieve a peak BrAC of around 0.25 mg/l. Once the peak BrAC was reached, these tests were performed again. Predosing and postdosing analytical results were compared, as were those with BrAC levels > or = 0.25 mg/l and <0.25 mg/l. After ingesting alcohol, 36 ears (90%) showed vestibular evoked myogenic potential responses, with a significantly increased latency of peak p13. The mean slow-phase velocity of caloric nystagmus in 40 ears after dosing was significantly reduced, and that with BrAC > or =0.25 mg/l was significantly less than that with BrAC <0.25 mg/l. Likewise, the visual suppression index decreased considerably after alcohol ingestion. In conclusion, from the perspective of vestibular function, the 0.25-mg/l BrAC limit gains clinical significance, because the vestibulo-ocular reflex performance deteriorates further, when the BrAC exceeds 0.25 mg/l. However, impaired performance of sacculocollic reflex and vestibulocerebellar interaction has occurred, when the BrAC was <0.25 mg/l, suggesting that a lower legal threshold is appropriate.

Streptomycin action to the mammalian inner ear vestibular organs: comparison between pigmented guinea pigs and rats.

Streptomycin is the antibiotic of choice to treat tuberculosis and other infectious diseases but it causes vestibular malfunction and hipoacusia. Rodents are usually employed as models of drug action to the inner ear and results are extrapolated to what happens in humans. In rats, streptomycin destroys macular sensory cells and does not affect cochlear ones, whereas in guinea pigs the contrary is true. Action on the vestibular cristae cells involved in vestibulo-ocular reflex integrity is less clear. Thus, we compared this response in both pigmented guinea pigs (Cavia cobaya) and rats (Rattus norvegicus) after parallel streptomycin chronic treatment. In guinea pigs, the reflex was obliterated along treatment time; in rats this behavior was not observed, suggesting that the end organ target was diverse. In recent studies, streptidine, a streptomycin derivative found in the blood of humans and rats treated with streptomycin, was the actual ototoxic agent. The putative streptomycin vestibular organ target observed in humans corresponds with the guinea pig observations. Results observed in rats are controversial: streptidine did not cause any damage either to vestibular cristae nor auditory cells. We hypothesize differential drug metabolism and distribution and conclude that results in laboratory animals may not always be applicable in the human situation.

Effects of vestibular training on motion sickness, nystagmus, and subjective vertical.

Pitch head-and-trunk movements during constant velocity rotation are a provocative vestibular stimulus that produces vertigo and nausea. When exposed to this stimulus repeatedly, motion sickness symptoms diminish as the subjects habituate. Acetylleucine is a drug that is used to treat acute vestibular vertigo. In this study, we wanted to ascertain whether this drug (a) lessened motion sickness or delayed habituation; (b) accelerated the recovery following habituation; and (c) whether changes in the subjective vertical accompanied habituation. Twenty subjects were administered acetylleucine or placebo in a double-blind study during a five-day vestibular training. Horizontal vestibulo-ocular reflex, optokinetic nystagmus, smooth pursuit, and subjective visual vertical were evaluated before, during, and up to two months after the vestibular training. Based on Graybiel's diagnostic criteria, motion sickness decreased steadily in each vestibular training session, and there was no difference between the scores in the acetylleucine and placebo groups. Post-rotatory nystagmus peak velocity and time constant also declined in both groups at the same rate. Thus, acetylleucine neither reduced the nausea associated with this provocative stimulus, nor hastened the acquisition or retention of vestibular habituation of motion sickness and nystagmus. There was no difference in optokinetic nystagmus and smooth pursuit between the acetylleucine and placebo groups. However, subjects showed larger error in the subjective visual vertical after habituation, which indicates that spatial orientation is also affected by vestibular training.

Treatment of the gravity dependence of downbeat nystagmus with 3,4-diaminopyridine.

The authors examined the effect of 3,4-diaminopyridine (DAP) on the gravity-dependent (GD) vertical ocular drift component of downbeat nystagmus in 11 patients with idiopathic cerebellar ataxia. With the head tilted downward (45 degrees ), DAP reduced slow phase velocity (SPV) in 7 of 11 patients by 36%. Its efficacy correlated with the GD modulation. DAP minimizes the gravity-independent velocity bias and may improve deficient inhibitory cerebellar control on overacting otolith-ocular reflexes.

The systemic application of diazepam facilitates the reacquisition of a well-balanced vestibular function in a unilateral vestibular re-input model with intracochlear tetrodotoxin infusion using an osmotic pump.

Diazepam is a popular medicine used in the treatment of acute vertigo. In the past, many studies investigating the effect of diazepam in peripheral vestibular destruction have been reported. However, no previous study has yet investigated the effect of diazepam on a model with a transient and reversible vestibular function similar to recurrent vertigo as seen in Meniere's disease. We thus made a peripheral vestibular re-input model by the unilateral intracochlear administration of tetrodotoxin (TTX) using an osmotic pump and then examined the influence of diazepam on the vestibular system in this model. Hartley white guinea pigs were intracochlearly administered with TTX on the right side for 3 days by an osmotic pump. Animals were divided into three groups, TTX alone (control group (n = 7)), TTX and an intraperitoneal diazepam injection once a day for 3 days (diazepam group (n = 6)) and vehicle injection (vehicle group (n = 6)). A caloric response and vestibuloocular reflex (VOR) were observed at 7 and 14 days after completing 3 days of TTX administration. Seven days after vestibular re-input, a directional preponderance of the nystagmus (DP) to the TTX-treated side was observed in the control and vehicle groups on VOR examination. DP was not observed in the diazepam group on any examined day. The R/L time ratio of caloric response showed no statistical difference between three groups on any examined day. These results suggest that diazepam may thus be useful for patients in an acute stage of peripheral vestibular vertigo by decreasing their vertiginous symptoms.

Diazepam tolerance effects on vestibular function testing, part II: vestibulo-ocular reflex parameters during rotational testing.

OBJECTIVES: The purpose of this prospective study was to determine whether clinical doses of diazepam (DZ; 10 mg/d) administered for 14 days result in tolerance as measured by the sinuosidal harmonic acceleration (SHA) rotational test. It has been shown that repeated dosing with DZ leads to accumulation and tolerance in outcome measures that assess memory, sedation, and psychomotor tasks. METHODS: In a double-blinded, repeated-measures design, 30 normal male subjects who ranged in age from 20 to 36 years were randomly assigned to a placebo group or a DZ group and participated in 6 SHA rotational sessions over a 2-week period. Analysis of drug-placebo differences in percent change from baseline was performed with a 1-way analysis of variance. RESULTS: Vestibulo-ocular reflex gain and phase frequencies at 0.01, 0.02, 0.04, and 0.08 Hz were significant (p < .05) for treatment group. No significant effect was observed for gain and phase frequency at 0.16 Hz--a finding that indicates selective effects on different central nervous system mechanisms. There was no statistical significance for time. CONCLUSIONS: Clinically, the DZ subjects' scores remained within the normal ranges for vestibulo-ocular phase and gain, suggesting that patients in whom drug cessation is problematic may not have to discontinue DZ before testing with the SHA rotational system.

An evaluation of the sensitivity of the standardised field sobriety tests to detect the presence of amphetamine.

RATIONALE: The Standardised Field Sobriety Tests (SFSTs), designed and validated to assess impairment associated with alcohol intoxication, are currently being employed by the Victoria Police (Australia) for the identification of driving impairment associated with drugs other than alcohol. OBJECTIVES: The aim of this study was to evaluate whether the SFSTs are a sensitive measure for identifying the presence of dexamphetamine and methamphetamine. METHODS: Three studies each employed a repeated-measures, counterbalanced, double-blind placebo-controlled design. In each study, 20 healthy volunteers completed two treatment conditions: either 0.42 mg/kg d,l-dexamphetamine and placebo, 0.42 mg/kg d,l-methamphetamine and placebo, or 0.42 mg/kg d-methamphetamine and placebo. Performance was assessed using the SFSTs, consisting of the Horizontal Gaze Nystagmus test, the Walk and Turn test, and the One Leg Stand test. Blood and saliva samples were obtained before and immediately after the administration of the SFSTs (120 and 170 min post drug administration). RESULTS: At 120 and 170 min post drug administration, d,l-dexamphetamine blood levels were 83.16 and 98.42 ng/ml, respectively; d,l-methamphetamine levels were 90 and 95 ng/ml, respectively; and d-methamphetamine blood levels were 72 and 67 ng/ml, respectively. None of the three amphetamine doses impaired performance on the SFSTs. Using the SFSTs, the presence of dexamphetamine was identified in 5% of cases, d-methamphetamine in 5%, and d,l-methamphetamine in 0% of cases. CONCLUSIONS: Under these conditions, the SFSTs are not a sensitive measure for detecting the presence of low levels of amphetamine.

Effect of 4-aminopyridine on upbeat and downbeat nystagmus elucidates the mechanism of downbeat nystagmus.

The potassium channel blocker 4-aminopyridine (4-AP) restored vertical smooth pursuit and gaze holding in light in one patient with upbeat (UBN) and in one with downbeat nystagmus (DBN). Without a visible target, however, 4-AP had no effect on UBN, but DBN vanished. We hypothesize that this difference in the effects of 4-AP, which is known to increase the excitability of cerebellar Purkinje cells, can be attributed to the different lesion sites involved in UBN and DBN.

Effects of chronic infusion of a GABAA receptor agonist or antagonist into the vestibular nuclear complex on vestibular compensation in the guinea pig.

The aim of this study was to determine the effects of chronic infusion of a GABA(A) receptor agonist/antagonist into the ipsilateral or contralateral vestibular nuclear complex (VNC) on vestibular compensation, the process of behavioral recovery that occurs after unilateral vestibular deafferentation (UVD). This was achieved by a mini-osmotic pump that infused, over 30 h, muscimol or gabazine into the ipsilateral or contralateral VNC. Spontaneous nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT) were measured. Infusion of muscimol or gabazine into either the ipsilateral or the contralateral VNC had little effect on SN compensation. In contrast, infusion of muscimol (250, 500, and 750 ng) into the contralateral VNC and gabazine (31.25, 62.5, and 125 ng) into the ipsilateral VNC significantly affected YHT and RHT (p < 0.05), but not their rate of compensation (p > 0.05). Interestingly, the effects of muscimol and gabazine on YHT and RHT were consistent throughout the first 30 h post-UVD. Infusion of muscimol (62.5, 125, and 250 ng) into the ipsilateral VNC and gabazine (125, 375, and 750 ng) into the contralateral VNC had little effect on YHT and RHT or their rate of compensation. These results suggest that the ipsilateral gabazine and contralateral muscimol infusions are modifying the expression of the symptoms without altering the mechanism of compensation. Furthermore, the neurochemical mechanism responsible for vestibular compensation can cope with the both the GABA(A) receptor-mediated and the UVD-induced decrease in resting activity.

Treatment of vertigo due to acute unilateral vestibular loss with a fixed combination of cinnarizine and dimenhydrinate: a double-blind, randomized, parallel-group clinical study.

BACKGROUND: Acute unilateral vestibular loss is a balance disorder that is accompanied by vertigo symptoms and concomitant vegetative symptoms, including nausea and vomiting. Patients are frequently confined to bed rest but may continue to experience vertigo symptoms. A well-established antivertiginous therapy consisting of cinnarizine and dimenhydrinate at low doses may offer rapid relief of acute vertigo symptoms due to acute vestibular loss, without inhibiting physiological compensation processes. OBJECTIVE: The purpose of this study was to compare the clinical efficacy and tolerability of a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg versus monotherapy with its respective components in the treatment of acute vertigo symptoms due to acute unilateral vestibular loss. METHODS: In this prospective, single-center, randomized, double-blind, parallel-group clinical study, 50 patients with acute vestibular vertigo were randomly assigned to receive 4 weeks of treatment (1 tablet 3 times daily) with a fixed combination of 20 mg cinnarizine and 40 mg dimenhydrinate, 20 mg cinnarizine alone, or 40 mg dimenhydrinate alone. All patients received a 15% mannitol infusion as standard therapy during the first 6 days of treatment. Efficacy was determined by the patients' assessments of vertigo symptoms after 1 and 4 weeks of treatment using a verbal rating scale (vertigo score) and by vestibulo-ocular and vestibulospinal tests. The primary efficacy criterion was defined as the relief of vertigo symptoms after 1 week of treatment. RESULTS: After 1 week of treatment, the fixed combination was significantly more effective than 20 mg cinnarizine (P < 0.001) and 40 mg dimenhydrinate (P < 0.01). After 4 weeks, the fixed combination was still significantly more effective than cinnarizine in reducing vertigo symptoms (P < 0.01) and significantly more effective than dimenhydrinate in improving the patients' balance while standing (P < 0.05). The tolerability of the fixed combination was rated good or very good by 100% of the patients (cinnarizine alone, 82.4%; dimenhydrinate alone, 94.4%). No serious adverse events occurred. Four patients in the fixed combination and the cinnarizine groups, and 6 patients in the dimenhydrinate group reported nonserious adverse events. CONCLUSIONS: The results of this study suggest a distinct benefit in using a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg versus the respective monotherapies in this population of patients with acute vestibular vertigo.

Vestibular destruction by slow infusion of gentamicin into semicircular canals.

Intratympanic or round window application of gentamicin is often used to alleviate disabling vertigo arising from unilateral Meniere's disease; however, treatment is often accompanied by hearing loss because the drug initially enters the cochlea before diffusing to the vestibular system. In order to enhance vestibular damage and reduce the risk of hearing loss, gentamicin was infused directly into the vestibular system. An osmotic pump containing 50, 100, 200 or 400 microg/ml of gentamicin was infused into the superior semicircular canal of the chinchilla for 7 days. Afterwards, vestibular damage was evaluated by measuring the decline in hair cell density in the utricle, saccule and superior semicircular canals. Auditory damage was assessed with distortion product otoacoustic emissions (DPOAE) and outer hair cell (OHC) and inner hair cell (IHC) loss. Infusion with the two lowest gentamicin concentrations resulted in significant hair cell loss and reduced duration of the nystagmus response, but had little or no effect on OHC or DPOAE. Higher doses of gentamicin damaged cochlear hair cells and reduced the DPOAE. In conclusion, slow infusion of a low dose of gentamicin into the semicircular canals mainly damages the vestibular hair cells and inactivates the nystagmus response without damaging cochlear hair cells or DPOAE.

Inner ear changes with intracochlear gentamicin administration in Guinea pigs.

OBJECTIVES/HYPOTHESIS: Transtympanic administration of gentamicin is reported to be a useful treatment for vertigo in such conditions as Meniere's disease, and determining appropriate clinical dosage of gentamicin is difficult. The authors examined the relation between gentamicin dosages and inner ear function in guinea pigs. STUDY DESIGN: This study is a basic science project designed to examine cochlear and vestibular function in animal models. METHODS: Various concentrations of gentamicin solution were infused into the right inner ear of guinea pigs by osmotic pumps. Caloric nystagmus as a marker of vestibular function and the change in auditory brainstem response (ABR) threshold as a marker of cochlear function were observed. RESULTS: After 14 days of treatment, high gentamicin concentrations of 40 mg/mL caused canal paralysis and a rapid shift in ABR threshold. Animals exposed to low gentamicin concentrations of 4 mg/mL showed no obvious change in either vestibular or cochlear function. Animals exposed to moderate gentamicin concentrations of 12 mg/mL showed a moderate shift in ABR threshold and caloric malfunction. Histopathological examination revealed that after 14 days of treatment with 40 mg/mL gentamicin, severe cytoplasmic damage occurred in both vestibular and cochlear end organs. In animals treated with 12 mg/mL gentamicin, hair cells remained in the cochlear third turn and ampulla of the lateral semicircular canal. CONCLUSION: The authors established an animal model that showed the moderate damage of inner ear with moderate-dose gentamicin. The study results indicated that the appropriate administration of gentamicin could establish a stable effect on the inner ear. It may be important to select the protocol that delivers a stable dosage of gentamicin to treat patients with Meniere's disease safely and effectively.