Cochlear Function in Adults with Epilepsy and Treated with Carbamazepine.

BACKGROUND: Epilepsy is a chronic medical disease and is associated with comorbid adverse somatic conditions due to epilepsy itself or its long-term treatment. OBJECTIVES: This study evaluated cochlear function in patients with idiopathic epilepsy and treated with carbamazepine (CBZ). PATIENTS AND METHODS: Included were 47 patients (mean age = 34.56 ± 7.11 years and duration of illness = 17.84 ± 7.21 years) and 40 healthy subjects. They underwent pure-tone audiometry and transient evoked otoacoustic emission (TEOAE) analyses. RESULTS: Hearing loss (mainly bilateral mild) was reported in one third of patients. Compared to controls, patients had lower TEOAE amplitudes at 1.0-4.0 kHz particularly at high frequencies (3 and 4 kHz). Significant correlations were identified between TEOAE amplitudes with CBZ dose (at 3 kHz: r = -0.554, p = 0.008; at 4 kHz: r = -0.347, p = 0.01), its serum level (at 4 kHz: r = -0.280, p = 0.045) and duration of treatment (at 3 kHz: r = -0.392, p = 0.008; at 4 kHz: r = -0.542, p = 0.001). CONCLUSIONS: Long-term CBZ treatment may result in cochlear dysfunction and auditory deficits.

FoxO3a plays a key role in the protective effects of pomegranate peel extract against amikacin-induced ototoxicity.

The use of amikacin (AMK) in present treatment strategies results in severe ototoxicity; however, the underlying molecular mechanisms of this toxicity remain unclear. In this study, we investigated the effectiveness of orally administered pomegranate peel extract (PPE), a strong antioxidant, as a protective agent against AMK-induced ototoxicity. To this end, PPE was orally administered to adult BALB/c mice for 5 days, and the mice were then concurrently treated with AMK (500 mg/kg/day for 15 consecutive days). Auditory threshold shifts induced by AMK were significantly attenuated. The results of immunohistochemical staining and western blot analysis revealed that PPE exerted its protective effects by by downregulating the phosphorylation of Forkhead box O3a (FoxO3a), an important transcription factor which is involved in the responses to oxidative stress. The results also showed that PPE treatment inhibited mitogen-activated protein kinase phosphorylation, prevented the activation of pro-apoptotic protein caspase-3, decreased the levels of apoptosis-inducing Bax protein, and increased the levels of the anti-apoptotic mediator, Bcl-2, induced by AMK in the mouse cochlea. Taken together, our experimental findings suggest that phosphorylated FoxO3a mediates AMK-induced apoptosis in BALB/c mice cochlea. PPE effectively attenuated oxidative stress and ototoxicity by regulating FoxO3a, and may thus prove to be beneficial in protecting auditory cells from ototoxic drugs.

The current state of ototoxicity monitoring in New Zealand.

AIM: To explore medical oncologists' and audiologists' knowledge and attitudes regarding ototoxicity monitoring, and to gain an understanding of monitoring currently being implemented at District Health Boards (DHBs) nationwide. We also aimed to identify ways in which audiological outcomes for patients receiving potentially ototoxic treatments could be improved, including examining whether the formulation and implementation of a national ototoxicity monitoring guideline is necessary. METHOD: Complementary telephonic interviews were conducted with 16 senior or charge audiologists and seven senior medical oncologists from DHBs across New Zealand, and their responses analysed. RESULTS: Responses indicate a comprehensive understanding of ototoxicity across both disciplines; however there is limited familiarity with ototoxicity monitoring protocols. Patients across New Zealand undergo significantly variable ototoxicity monitoring; local practices range from no routine monitoring to audiological assessment prior to each cycle of chemotherapy. No routine audiological follow up is conducted post completion of treatment at any DHB, in contrast with international guidelines. Twenty-two of 23 participants were in favour of development of a national ototoxicity monitoring guideline. CONCLUSION: There is significant discrepancy in how ototoxicity monitoring is conducted across New Zealand, and implementation of a national ototoxicity monitoring protocol may improve audiological outcomes for patients receiving ototoxic chemotherapy.

A prediction model of drug-induced ototoxicity developed by an optimal support vector machine (SVM) method.

Drug-induced ototoxicity, as a toxic side effect, is an important issue needed to be considered in drug discovery. Nevertheless, current experimental methods used to evaluate drug-induced ototoxicity are often time-consuming and expensive, indicating that they are not suitable for a large-scale evaluation of drug-induced ototoxicity in the early stage of drug discovery. We thus, in this investigation, established an effective computational prediction model of drug-induced ototoxicity using an optimal support vector machine (SVM) method, GA-CG-SVM. Three GA-CG-SVM models were developed based on three training sets containing agents bearing different risk levels of drug-induced ototoxicity. For comparison, models based on naïve Bayesian (NB) and recursive partitioning (RP) methods were also used on the same training sets. Among all the prediction models, the GA-CG-SVM model II showed the best performance, which offered prediction accuracies of 85.33% and 83.05% for two independent test sets, respectively. Overall, the good performance of the GA-CG-SVM model II indicates that it could be used for the prediction of drug-induced ototoxicity in the early stage of drug discovery.

Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells.

In hair cells of the inner ear, sound or head movement increases tension in fine filaments termed tip links, which in turn convey force to mechanosensitive ion channels to open them. Tip links are formed by a tetramer of two cadherin proteins: protocadherin 15 (PCDH15) and cadherin 23 (CDH23), which have 11 and 27 extracellular cadherin (EC) repeats, respectively. Mutations in either protein cause inner ear disorders in mice and humans. We showed recently that these two cadherins bind tip-to-tip in a "handshake" mode that involves the EC1 and EC2 repeats of both proteins. However, a paucity of appropriate animal models has slowed our understanding both of the interaction and of how mutations of residues within the predicted interface compromise tip link integrity. Here, we present noddy, a new mouse model for hereditary deafness. Identified in a forward genetic screen, noddy homozygotes lack inner ear function. Mapping and sequencing showed that noddy mutant mice harbor an isoleucine-to-asparagine (I108N) mutation in the EC1 repeat of PCDH15. Residue I108 interacts with CDH23 EC2 in the handshake and its mutation impairs the interaction in vitro. The noddy mutation allowed us to determine the consequences of blocking the handshake in vivo: tip link formation and bundle morphology are disrupted, and mechanotransduction channels fail to remain open at rest. These results offer new insights into the interaction between PCDH15 and CDH23 and help explain the etiology of human deafness linked to mutations in the tip-link interface.

"In-bone" utricle cultures--a simplified, atraumatic technique for in situ cultures of the adult mouse (Mus musculus) utricle.

HYPOTHESIS: The "in-bone" method of culturing utricles described here is a reliable and atraumatic technique for culturing mature mouse hair cells and studying hair cell death and protection. BACKGROUND: The current in vitro technique for studying hair cells of the mature mouse utricle involves removal from the temporal bone and free floating culture in media. This technique can be problematic because of variability in the preservation of the sensory epithelium and a steep learning curve that results in injury of the sensory epithelium in less experienced hands. We present a new atraumatic technique of culturing the utricle in situ within the temporal bone. METHODS: Leaving the temporal bone largely intact, a window is opened in the bony vestibule overlying the mouse utricle. The entire temporal bone is then placed into culture media. Utricles were cultured in situ for several days with minimal damage to the epithelium. The utricles are then fixed in situ, removed from the temporal bone, and processed. A standardized aminoglycoside-induced hair cell damage protocol was developed. RESULTS: Mature mouse utricles maintained hair cell numbers for 3 days in culture. Exposure to neomycin resulted in significant dose-dependent hair cell toxicity (p < 0.0001, 1-way analysis of variance). Exposure to the protective drug tacrine resulted in significant protection against neomycin (p < 0.05, 3-way analysis of variance). CONCLUSION: The "in-bone" technique is a reliable and atraumatic method for culturing mature mouse utricles and studying hair cell death and protection. It is easily mastered and can make in vitro study of hair cells accessible to more research groups.

Effect of intratympanic dexamethasone, memantine and piracetam on cellular apoptosis due to cisplatin ototoxicity.

OBJECTIVE: This study aimed to contribute to the literature on the prevention and treatment of ototoxicity due to various drugs and chemicals. MATERIAL AND METHODS: This study compared the histological effects of intratympanic dexamethasone, memantine and piracetam on cellular apoptosis due to cisplatin ototoxicity, in 36 rats. RESULTS: Dexamethasone and memantine had significant effects on the stria vascularis, organ of Corti and spiral ganglion (p < 0.05). Although piracetam decreased the apoptosis rate, this effect was not statistically significant (p > 0.05). CONCLUSION: Dexamethasone and memantine were found superior to piracetam in reducing apoptosis due to cisplatin ototoxicity. Further studies of this subject are needed, incorporating electron microscopy and auditory brainstem response testing.

The protective effect of Ginkgo biloba extract against experimental cisplatin ototoxicity: animal research using distortion product otoacoustic emissions.

BACKGROUND: Cisplatin, an effective therapeutic agent for various human cancers, has dose-limiting side effects of ototoxicity and nephrotoxicity. Cisplatin ototoxicity is thought to result from increased amounts of toxic free radicals or cell membrane changes leading to increased intracellular calcium content. Ginkgo biloba extract prevents lipid peroxidation, decreases intracellular free oxygen radical levels, regulates the cell membrane calcium transport mechanism and prevents cell death. This study aimed to investigate the protective effect of Ginkgo biloba extract against cisplatin-induced ototoxicity in rats. METHODS: Twenty Wistar albino rats with normal hearing (confirmed by distortion product otoacoustic emission testing prior to cisplatin application) were randomly allocated to two groups. Both groups received a single intraperitoneal dose of cisplatin (12 mg/kg). Group two also received daily intraperitoneal doses of Ginkgo biloba extract (100 mg/kg) for 10 days. Distortion product otoacoustic emission measurements were repeated on days 10 and 17 and signal-to-noise ratios were compared. RESULTS: Compared with group one, group two had significantly better distortion product otoacoustic emission results at 3, 4, 6 and 8 kHz on days 10 and 17. CONCLUSION: These findings suggest that Ginkgo biloba extract protects the inner ear against cisplatin-induced ototoxicity.

Ototoxicity of Burow solution on the guinea pig cochlea.

PURPOSE OF THE STUDY: The aim of the present study was to evaluate the ototoxicity of Burow solution. PROCEDURES: Compound action potentials (CAPs) of the eighth nerve were measured before and 30 minutes after the application of the Burow solution in the middle ear cavity. RESULTS: Use of the original Burow solution (pH 3.5) for 30 minutes caused a significant reduction of click sounds. A 2-fold diluted Burow solution (pH 4.4) for 30 minutes caused no reduction in CAP threshold. Burow solution, pH adjusted to 4.5, caused no changes in CAP threshold at 30 minutes. At 24 hours, Burow solution (pH 3.5) caused complete abolition of CAP. CONCLUSIONS: Burow solution is ototoxic in the guinea pig when applied in the middle ear cavity for 30 minutes or longer. In the clinical settings, it is advisable to avoid allowing the solution to contact the round window for extended times.

Topical application of the antiapoptotic TAT-FNK protein prevents aminoglycoside-induced ototoxicity.

We previously demonstrated that an artificial protein, TAT-FNK, has antiapoptotic effects against cochlear hair cell (HC) damage caused by ototoxic agents when applied systemically. To examine the feasibility of topical protein therapy for inner ear disorders, we investigated whether gelatin sponge soaked with TAT-FNK and placed on the guinea pig round window membrane (RWM) could deliver the protein to the cochlea and attenuate aminoglycoside (AG)-induced cochlear damage in vivo. First, we found that the immunoreactivity of TAT-myc-FNK was distributed throughout the cochlea. The immunoreactivity was observed from 1-24 h after application. When Tat-FNK was applied 1 h before ototoxic insult (a combination of kanamycin sulfate and ethacrynic acid), auditory brainstem response threshold shifts and the extent of HC death were significantly attenuated. When cochlear organotypic cultures prepared from P5 rats were treated with kanamycin, TAT-FNK significantly reduced the extent of caspase-9 activation and HC death. These findings indicate that TAT-FNK topically applied on the RWM can enter the cochlea by diffusion and effectively prevent AG-induced apoptosis of cochlear HCs by suppressing the mitochondrial caspase-9 pathway.

Drug-mediated ototoxicity and tinnitus: alleviation with melatonin.

This review evaluates the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear. A thorough search of the literature was performed using available databases for the purpose of uncovering articles applicable to the current review. Cochlear function was most frequently evaluated by measuring otoacoustic emissions and their distortion products after animals were treated with cytotoxic drugs alone or in combination with melatonin. Vestibular damage due to aminoglycosides was evaluated by estimating hair cell loss in explanted utricles of newborn rats. Tinnitus was assessed in patients who received melatonin using a visual analogue scale or the Tinnitus Handicap Inventory. Compared to a mixture of antioxidants which included tocopherol, ascorbate, glutathione and N-acetyl-cysteine, melatonin, also a documented antioxidant, was estimated to be up to 150 times more effective in limiting the cochlear side effects, evaluated using otoacoustic emission distortion products, of gentamicin, tobramycin and cisplatin. In a dose-response manner, melatonin also reduced vestibular hair cell loss due to gentamicin treatment in explanted utricles of newborn rats. Finally, melatonin (3 mg daily) limited subjective tinnitus in patients. These findings suggest the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin's low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage.

High dose combination pertussis toxin induces autoimmune inner ear disease in Sprague-Dawley rats.

CONCLUSION: A better animal model of autoimmune inner ear disease (AIED) in Sprague-Dawley rats has been developed by combination with high dose of pertussis toxin. This study also indicated that inner ear-specific antigens can be involved in autoimmune reactions. Cell-mediated immune injury can play an important role in the induction of AIED, at least in the earlier stage. OBJECTIVES: The purpose of this study was to develop a more suitable rat model that demonstrated closer resemblance to the pathophysiological process in AIED. METHODS: Ninety-six female Sprague-Dawley rats were divided into four groups. They were subcutaneously immunized with crude inner ear antigen/complete Freund's adjuvant (CIEAg/CFA), or intraperitoneal injection of 500 ng pertussis toxin (PT), or injection of CIEAg/CFA+PT, or phosphate-buffered saline (PBS) alone. The auditory function, histopathology of the inner ear, and autoantibodies were examined. RESULTS: Significant differences in the time course of auditory brainstem response (ABR) threshold and mean score of cellular infiltration were demonstrated in the CIEAg/CFA+PT group of animals. Missing hair cells, degeneration of the spiral ganglion cells, endolymphatic hydrops, and autoantibodies were all noted after immunization. There were no significant differences in ABR threshold or histopathology in any other group of animals.

Balance dysfunction resulting from acute inner ear energy failure is caused primarily by vestibular hair cell damage.

Inner ear energy failure is associated with disorders such as inner ear ischemia. Recently, we used the mitochondrial toxin 3-nitropropionic acid (3-NP) to establish an animal model of inner ear energy failure that presents with auditory dysfunction. Here we investigated the mechanisms underlying balance disorders in the 3-NP animal model. Spontaneous nystagmus peaked 6 hr after treatment with either 300 mM or 500 mM 3-NP. The nystagmus attenuated gradually and disappeared 3 days after 3-NP treatment. A caloric test using ice water was performed to evaluate residual vestibular function 7 days after 3-NP treatment. The response to caloric stimulation was reduced to approximately 40% of the response of the untreated ear following 300 mM 3-NP and was undetectable following 500 mM 3-NP. Structural changes in the peripheral vestibular organs were analyzed by light and electron microscopy. Severe loss of stereocilia was observed following 500 mM 3-NP, whereas disorganized and mildly reduced stereocilia were observed following 300 mM 3-NP. There was severe loss and degeneration of vestibular hair cells following 500 mM 3-NP but only slight loss and degeneration of hair cells following 300 mM 3-NP. These results indicate that acute inner ear energy failure causes balance dysfunction mainly by damaging hair cells in the vestibule, which is distinct from the mechanism underlying auditory disorders.

Damage and functional recovery of the Atlantic cod (Gadus morhua) inner ear hair cells following local injection of gentamicin.

This study addresses the ultrastructural and functional damage and subsequent recovery of the inner ear in the Atlantic cod following intrasaccular gentamicin injection. Inner ear damage was assessed using SEM and measurements of AEP following 250-Hz pure-tone stimuli. Data from gentamicin-treated fish were compared with control (no injection) and sham (injection of saline) fish. Control fish had normal response thresholds associated with well-developed hair cell bundles in their macula sacculi. Sham fish had higher response thresholds compared with control fish during the first week post-intervention, but response thresholds were subsequently normal. Treated fish displayed significant inner ear damage associated with an increased average AEP threshold on the third day following treatment. Thereafter, inner ear tissue displayed signs of progressive regeneration until it was comparable to controls from the 14th day. Response thresholds were similar to those of control fish from the 17th day following treatment. These observations suggest that the macula sacculi of Atlantic cod can regenerate towards a near-complete functional and ultrastructural recovery within 17-21 days following ototoxic gentamicin treatment.

Sudden hearing loss caused by labyrinthine hemorrhage.

Sudden sensorineural hearing loss is relatively frequent. In most cases, the etiology is not discovered. One of the possible causes for sudden deafness is inner labyrinth bleeding, which was difficult to diagnose before the advent of magnetic resonance imaging. The purpose of this paper is to report a case of sudden hearing loss caused by a labyrinthine hemorrhage, and to present a review of the literature on this topic.

Surdez súbita causada por hemorragia intralabiríntica / Sudden hearing loss caused by labyrinthine hemorrhage

A surdez súbita sensorioneural é uma perda auditiva súbita ou rapidamente progressiva. Na maioria dos casos a etiologia não é descoberta. Uma das causas possíveis de surdez súbita é a hemorragia intralabiríntica que, antes do surgimento da ressonância magnética, não era corretamente diagnosticada. O objetivo deste trabalho é relatar um caso de surdez súbita causada por hemorragia intralabiríntica e realizar uma revisão da literatura sobre este assunto.

Sudden sensorineural hearing loss is relatively frequent. In most cases, the etiology is not discovered. One of the possible causes for sudden deafness is inner labyrinth bleeding, which was difficult to diagnose before the advent of magnetic resonance imaging. The purpose of this paper is to report a case of sudden hearing loss caused by a labyrinthine hemorrhage, and to present a review of the literature on this topic.

Drug-related nephrotoxic and ototoxic reactions : a link through a predictive mechanistic commonality.

BACKGROUND: Drug-induced ototoxicity is a subject of interest because many diseases are treated with drugs that have potential toxic effects on the ear. There is evidence that both inner ear and kidney tissue are immunologically, biochemically and functionally related. It has been suggested that drugs that influence the transport of sodium and/or potassium change ionic homeostasis in the inner ear and, hence, induce functional disturbances such as hearing loss, tinnitus and vertigo. OBJECTIVES: To assess whether renal suspected adverse drug reactions (sADRs) have predictive value for ear and labyrinth adverse drug reactions (ADRs) and whether drug classes involved have influence ion transport systems. STUDY DESIGN: Data were obtained from the Netherlands Pharmacovigilance Centre Lareb. The study base comprised all reports of sADRs up until 1 January 2007. Cases were all sADRs for relevant renal disorders and all sADRs for relevant ear disorders. All other reported sADRs were selected as 'non-cases'. The relationship between drug classes and renal, ear and labyrinth sADRs was evaluated by calculating reporting odds ratios (RORs). An ROR > or = 1.50 was regarded as a cut-off value for an association. Drug classes were classified into four groups: (A) ROR kidney <1.50 and ROR ear <1.50 or no reports on ear sADRs (reference group); (B) ROR kidney <1.50 and ROR ear > or = 1.50; (C) ROR kidney > or = 1.50 and ROR ear <1.50 or no reports on ear sADRs; and (D) ROR kidney > or = 1.50 and ROR ear > or = 1.50. For each group, we calculated odds ratios (ORs) for the association between the group classification and the effect on ion channels/ion transport systems in kidney and ear tissues. RESULTS: Of 193 drug classes with relevant ADRs for renal disorders, 120 drug classes also had reports on ototoxic reactions. Fourteen out of 120 drug classes had an ROR > or = 1.50 for the association between the drug class and both renal and ear sADRs. Among these drug classes were several with a well known ability to induce renal (adverse) effects and ear and labyrinth disorders, such as loop diuretics, aminoglycosides and quinine. We found that one mechanistic commonality of the drug classes mentioned in the reports was the ability to affect ion transport systems. The percentage of drugs having this property differed between the four groups. The ORs for groups D and B were significantly higher compared with the reference group (OR 12.2, 95% CI 3.0, 30.5 and OR 8.7, 95% CI 2.4, 18.7, respectively), whereas there was no association for group C. CONCLUSION: Our data suggest that renal sADRs as such are not a marker for drug-induced ear and labyrinth disorders. However, the ability of drugs to act on ion channels or ion transport systems and, therefore, have an influence on ionic homeostasis in the kidney and ear might be a predictor for the possible occurrence of drug-related ototoxicity.

Sensory reweighting as a method of balance training for labyrinthine loss.

BACKGROUND AND PURPOSE: Instability is a significant risk factor for falls in individuals with a bilateral labyrinthine deficit. The purpose of this case report is to describe an intervention that we found to improve balance in a patient with bilateral labyrinthine deficit using a training paradigm based on the sensory reweighting hypothesis. CASE DESCRIPTION: The participant was a female and 10 years post-onset of bilateral labyrinthine deficit. The participant was instructed to focus on the motion of her hips and knees while standing on a dynamic platform that was either stationary or matched to the excursion of her center of mass (COM) but in the opposite direction and with gradually increasing amplitude. She was tested for her ability to maintain her balance under conditions of sensory conflict both before the training and on two periods after training. OUTCOMES: Decreases in anteroposterior and mediolateral motion of the COM were observed between the pretest and both posttests with a stationary and a moving platform when in the dark and under conditions of sensory conflict. Using the method of approximate entropy, we found that the complexity of the center of pressure (COP) response increased in both the anteroposterior and medolateral directions from the pretest to both posttests when on the platform matched to the COM motion. SUMMARY: Results indicated that training on a dynamic platform diminished the destabilizing effect of conflicting sensory signals. Additionally, a relationship was observed between decreased COM motion and increased complexity in COP, which represents a more self-organized system. This finding suggests that improved stability may be associated with an increased complexity in the COP trajectory.