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.     

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 degrees/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.     

Gentamicin ototoxicity induced apoptosis of the vestibular hair cells of guinea pigs

To clarify mechanisms of inner ear cell death induced by aminoglycosides, we used an in situ nick-end labelling method to examine guinea pig vestibular epithelia after chronic systemic treatments with gentamicin to produce apoptosis. Such changes occurred in damaged hair cells, suggesting that this process may be crucial for subsequent repair and cell regeneration.     

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.     

The ototoxicity of repetitive chronic aminoglycoside administration. An experimental study

To determine whether previous exposure to an aminoglycoside antibiotic would predispose an individual to more severe ototoxic reactions upon subsequent administration, guinea pigs were given up to three courses of gentamicin at a dose of 50 or 100 mg/kg. Each course was separated by a period of 4 weeks, and animals were killed 4 weeks after the date of last injection. Cochlear pathology was assessed by the surface preparation technique and phase contrast microscopy. Detailed counts of sensory hair cell populations were recorded and statistically analysed. No significant ototoxic hair cell loss occurred following the repetition of 50 mg/kg. At 100 mg/kg, repetitive administration produced a significant and cumulative destruction of the most basal outer and inner hair cells. Using this protocol, it was concluded that if the initial exposure proved ototoxic, further administration of gentamicin increased subsequent sensory hair cell loss.     

Gentamicin ototoxicity in the saccule of the lizard Podarcis Sicula induces hair cell recovery and regeneration

There is little information available on the susceptibility of reptilian saccule hair cells to ototoxin-induced sensory damage. In this study, we report morphological evidence of hair cell recovery and regeneration after damage induced by gentamicin in the saccule of a lizard. We perform morphological analysis using scanning electron microscopy and confocal laser scanning microscopy with actin and calbindin as markers for hair cells and tubulin as a marker for supporting cells. The data were consistent: gentamicin induced damage in the hair cells, and the damage increased with increasing duration of treatment. Initially, the saccule appeared unhealthy. Subsequently, the sensory hair cells became compromised, with fused stereovilli, followed by widespread loss of hair cell bundles from the hair cells. Finally, numerous hair cells were lost. Morphologically, the saccule appeared normal 28days after gentamicin treatment. Using a mitogenic marker, we tested whether or not there is hair cell regeneration following administration of gentamicin. We found evidence of bromodeoxyuridine incorporation first in supporting cell nuclei and subsequently in hair cell nuclei. This indicates that a process of sensory epithelium repair and hair cell regeneration occurred, in both extrastriolar and striolar regions, and that the recovery was due to both the proliferation of supporting cells and, as seems likely, self-repair of hair cell bundles.     

Delay in hearing loss following drug administration. A consistent feature of amikacin ototoxicity

The time course of threshold increase in the VIII nerve compound action potential was studied in guinea pigs following amikacin administration at four different constant infusion rates. Despite the wide range of dosing durations required to achieve drug ototoxicity (2-24 days), the full development of both high and low frequency hearing loss was invariably found to be delayed with respect to the time of drug removal. The greatest degree of delayed hearing loss generally occurred within the first 7 days after drug removal, with smaller losses occurring during later time intervals. The delay showed a tendency to decrease as the ototoxic dose was increased. Using the data from the two highest dosing rates, it was estimated that a minimum of 4 days had to elapse before any hearing loss could be detected, once an ototoxic amount of drug had been administered. These data suggest that hearing loss is always substantially delayed with respect to the receipt of an ototoxic dose of amikacin, and that this must be taken into account when conducting animal experiments and when monitoring hearing in patients for the early detection of ototoxicity.     

The effect of intratympanic vitamin C administration on cisplatin-induced ototoxicity

The Objective of this study is to investigate the effect of intratympanic injection of vitamin C on cisplatin-induced ototoxicity. The study included 24 albino adult female rats (48 ears). The study animals were divided into four groups each of which was composed of six animals including a control (intraperitoneal cisplatin), a cisplatin–saline (saline intratympanic + intraperitoneal cisplatin), a C vit (intratympanic vitamin C) and a cisplatin–C vit group (intraperitoneal cisplatin + intratympanic vitamin C). As two animals had died due to cisplatin-induced ototoxicity (one in the control and one in the cisplatin-saline group) they were excluded from the study. The experiment was terminated, performing distortion product otoacoustic emission (DPOAE) measurement prior to procedures and at the end of the experiment. The results of the statistical analysis were evaluated. In the cisplatin–C vit group, there were no significant decreases in DPOAE amplitudes at 2 kHz (p > 0.05). Although a decrease was observed in DPOAE amplitudes at 2.8, 4, 6, and 8 kHz frequencies, these amplitude reductions were significantly lower than the control group (p < 0.05). Intratympanic vit C infusion provided a protective effect against cisplatin-induced ototoxicity primarily at 2 kHz and at other frequencies (2.8, 4, 6, and 8 kHz), and it did not produce a toxic effect in the cochlea.     

Tobramycin ototoxicity: a second look.

Tobramycin was administered intravenously to guinea pigs and was shown to produce an impairment of the alternating current cochlear potential. This effect is temporary and occurs only when the blood pressure has been severely lowered. We conclude that these data do not represent the onset of ototoxicity of tobramycin as reported by others, but only represents the cochlear effect of the pronounced fall in blood pressure that is produced by the tobramycin.     

Cisplatin vestibular ototoxicity: Preliminary report.

Sixteen patients were monitored for vestibular ototoxicity while receiving cisplatin in dosages of 180 mg/M². The incidence of preexisting vestibular functional abnormalities (31%) was higher than the incidence of ototoxicity (18%). Although the number of patients was not large enough for meaningful statistical comparison, the incidence of vestibular ototoxicity from cisplatin was low for the dosage levels employed. Based upon the results of this study, the following recommendations are made for monitoring cisplatin vestibular ototoxicity. 1. All patients should receive vestibular tests prior to cisplatin administration. 2. Subjects, who have reduced (or asymmetric) vestibular function upon pretherapy testing, should be monitored at least weekly for any change in function while receiving cisplatin. 3. Subjects who are normal prior to therapy need to be tested only when cumulative doses exceed 400 mg. The severe nausea and vomiting associated with cisplatin chemotherapy is not related to vestibular ototoxicity.     

Vestibulotoxicity and ototoxicity of gentamicin in newborns at risk

Gentamicin is a potentially ototoxic drug routinely used for treatment of life-threatening infectious diseases in neonatology. In study 1, of 8,333 children examined for hearing disorders, 134 (1.6%) had received previous treatment with gentamicin. Only eight (6.0%) suffered from various extents of sensorineural hearing impairment, and all eight had a history of other risk factors of hearing loss (e.g., perinatal asphyxia, acidosis, icterus gravis, or meningitis). In study 2, 30 children (mean age, 13.2 months) with normal hearing had received gentamicin during the newborn phase, and 30 healthy children of similar age without previous gentamicin treatment were examined for vestibular function. Neither in the number of spontaneous eye movements nor in the means of the nystagmus parameters of the rotatory test did the data show any significant difference between the groups. The results indicate that gentamicin in controlled therapeutic doses has a less ototoxic and vestibulotoxic effect in newborns than it does in older children or in adults.     

Effect of intratympanic dexamethasone administration on cisplatin-induced ototoxicity in adult guinea pigs

Objective

To evaluate the effect and safety of intratympanic dexamethasone administration on cisplatin-induced ototoxicity in adult male guinea pigs and to assess the differences between early and late protection from this ototoxicity.

Methods

Forty eight adult male guinea pigs were divided as follows: group I served as control group. Group II was subjected to intratympanic saline (subgroup IIa) or dexamethasone (subgroup IIb) injection. Group III was intraperitoneally injected with cisplatin. Groups IV and V were subjected first to intratympanic dexamethasone administration in both ears for 5 days starting 1 day and 1 h – respectively – before cisplatin intraperitoneal injection.

Results

Dexamethasone intratympanic injection revealed similar functional and structural results compared with control. Cisplatin intraperitoneal injection resulted in a profound cochlear functional and structural damage in group III. Non-significant otoprotection resulted from intratympanic dexamethasone administration one day before cisplatin. Intratympanic dexamethasone injection 1 h before cisplatin treatment resulted in a significant preservation of the functional and structural properties of the cochlea.

Conclusion

Intratympanic dexamethasone administration is a safe, easy and efficient way to protect from cisplatin ototoxicity especially when administered 1 h before cisplatin treatment.     

Reduction of cisplatin ototoxicity in rats by oral administration of pomegranate extract

The aim of this study was to investigate the effectiveness of the oral administration of pomegranate extract (PE) as a protective agent against cisplatin-induced ototoxicity. The study included a prospective, controlled animal study Group 1 (n = 6), received no cisplatin or PE, and group 2 (n = 6) received cisplatin at 8 mg/kg/day for 3 consecutive days. Group 3 (n = 6) received not only cisplatin at 8 mg/kg/day for 3 consecutive days, but also received PE (100 μL/day) via gavage for 5 days prior to the cisplatin injection and for 3 days concomitantly with the cisplatin injections. To measure cisplatin ototoxic effects, “distortion product otoacoustic emissions” (DPOAE) were analyzed 3 days before and after the cisplatin injections. Histological changes in the cochleas were observed by light microscopy. Compared with group 3, the DPOAE amplitudes of group 2 decreased significantly. Among the groups, there was a statistically significant difference in basal and mid turn external ciliated cells (ECC) number, but there was no statistically significant difference in apical turn. Differences in stria vascularis (SV) changes were statistically significant between the groups, and the median score for SV injury was significantly greater in group 2 than in group 3. Differences in the median scores for SGC changes being significantly greater in group 2 than in group 3. In conclusion, these results indicated that oral administration of PE afforded statistically significant protection to the cochlea in rats from cisplatin toxicity, and thus, oral experimental dose of PE administration may have a protective effect against cisplatin ototoxicity in rats.     

Aspirin ototoxicity in the guinea pig.

Aspirin ototoxicity has been studied on guinea pigs by shiver-audiometry and histological investigation of the cochlear duct. One dose of 350 mg/kg has provoked, after 7 h, a mean hearing loss of 18-24 dB at 0.25-8 kHz, followed by complete recovery in 3 days. The difference between the administration of 50 mg/kg/day and 350 mg/kg/day consists of a wide extension of the frequencies involved, and in about 10 dB a greater hearing loss. In both cases, no appreciable recovery of hearing was observed after 22 days (the histological investigations were negative). The biochemical pathogenesis of aspirin ototoxicity is discussed and periodical audiometric controls before and during salicylate treatment are recommended.     

Inhalation of hydrogen gas attenuates cisplatin-induced ototoxicity via reducing oxidative stress

Objective

Cisplatin, an anticancer drug used extensively to treat a broad range of tumors, has strong ototoxic side effects induced by reactive oxygen species (ROS). Recently, it has been reported that hydrogen gas (H₂) is a new antioxidant by selectively reducing hydroxyl radical, the most cytotoxic ROS. The present study was designed to investigate whether H₂ treatment is beneficial to cisplatin-induced ototoxicity via reducing oxidative stress.

Methods

The animals were intraperitoneally given a 30 min infusion of 16 mg/kg cisplatin or the same volume of saline. H₂ treatment was given twice with 2% H₂ inhalation for 60 min starting at 1 h and 6 h after cisplatin or saline injection, respectively. The hearing status of all animals was evaluated by auditory brainstem responses (ABR). The hair cell damage was observed by phalloidin staining. In addition, the levels of oxidative products in serum and cochlear tissue were measured.

Results

We found that H₂ treatment significantly attenuated cisplatin-induced hearing loss evaluated by click-evoked and tone burst ABR threshold. Furthermore, histological analysis revealed that 2% H₂ treatment significantly alleviated cisplatin-induced hair cell damage in the organ of corti. In addition, cisplatin significantly increased the levels of malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α) in serum and cochlear tissue, which was attenuated by H₂ treatment.

Conclusion

These results demonstrate that H₂ is beneficial to cisplatin-induced ototoxicity via reducing oxidative stress. Therefore, H₂ has potential for improving the quality of life of patients during chemotherapy by efficiently mitigating the cisplatin ototoxicity.