Drug-Drug Interactions in Vestibular Diseases, Clinical Problems, and Medico-Legal Implications.

Peripheral vestibular disease can be treated with several approaches (e.g., maneuvers, surgery, or medical approach). Comorbidity is common in elderly patients, so polytherapy is used, but it can generate the development of drug-drug interactions (DDIs) that play a role in both adverse drug reactions and reduced adherence. For this reason, they need a complex kind of approach, considering all their individual characteristics. Physicians must be able to prescribe and deprescribe drugs based on a solid knowledge of pharmacokinetics, pharmacodynamics, and clinical indications. Moreover, full information is required to reach a real therapeutic alliance, to improve the safety of care and reduce possible malpractice claims related to drug-drug interactions. In this review, using PubMed, Embase, and Cochrane library, we searched articles published until 30 August 2021, and described both pharmacokinetic and pharmacodynamic DDIs in patients with vestibular disorders, focusing the interest on their clinical implications and on risk management strategies.

The Importance of Otoneurological Evaluation in Brazilian Workers Exposed to Pesticides: A Preliminary Study

Introduction: Agrochemicals, also known as pesticides, are widely used in agriculture and in public health. They are organic and inorganic chemical substances with a high level of toxicity not only for the environment, but also for human health. Objective: To verify findings on labyrinthine assessment in endemic disease control agents, and to recommend the inclusion of the vestibular exam in the set of tests for pesticide-exposed populations. Methods: Descriptive, prospective, cross-sectional study with a sample comprising 15 endemic disease control agents, males, mean age of 51.6 years old (standard deviation [SD] = 5.9). All of the participants were submitted to anamnesis, otorhinolaryngological screening, and vestibular assessment. Results: Regarding the most reported complaints, dizziness (73.4%), headache (60%), and tingling in the extremities (53.4%) were observed. The findings of the vestibular exams were normal in 53.3%, while 46.7% showed peripheral vestibular disorder, of which 26.7% were of deficitary type, and 20% of the irritative type. Conclusions: Alteration in the vestibular system was verified in 50% of the workers, with a greater prevalence in the caloric testing. Several disorders related to pesticides intoxication are scientifically known. Actions promoting knowledge and qualification of this population for the proper handling of chemicals are suggested, in addition to the elaboration and inclusion of protocols of vestibular assessment in hearing health programs for the prevention, diagnosis and treatment of vestibular disorders (AU)

Dexamethasone protects against arsanilic acid­induced rat vestibular dysfunction through the BDNF and JNK 1/2 signaling pathways.

The brain­derived neurotrophic factor (BDNF) and c­Jun NH 2­terminal kinase (JNK) signaling pathways are therapeutic targets to prevent degeneration in the central nervous system. Dexamethasone (DXMS), a glucocorticoid, protects against vestibular brain injury, however, the molecular mechanisms have yet to be fully elucidated. To investigate whether the BDNF and JNK signaling pathways are involved in the protective effects of DXMS in rats with vestibular dysfunction, a rat model of severe vestibular deficits was established by middle ear injection of arsanilic acid (AA; 100 mg/ml; 0.05 ml). After 3 days, rat symptoms and behavior scores with vestibular disorders were detected. In brain tissues, histopathological alterations, cell apoptosis, expression levels and patterns of BDNF signaling pathway­associated BDNF, tyrosine receptor kinase B (TrKB) and K+/Cl­ cotransporter isoform 2 (KCC2), and the expression of apoptosis­related cleaved­caspase 3 and the JNK signaling pathway were detected. It was identified that DXMS relieved AA­induced vestibular dysfunction, leading to improvement in rat behavior scores to normal levels, minimizing brain damage at the histopatholojnnkngical level, reducing cell apoptosis, enhancing the expression of BDNF, TrKB and KCC2, and downregulating cleaved­caspase 3 and phosphorylated­JNK1/2 in brain tissues. Together, these findings indicated the protective effect of DXMS on AA­induced rat vestibular dysfunction, and that activating BDNF and inhibiting JNK singling pathways were the underlying mechanisms. In addition, with additional treatment of mifepristone (RU486), a specific glucocorticoid agonist, all the events elicited by DXMS mentioned above in the AA­treated rat rats were reversed. In conclusion, DXMS was identified as a therapeutic agent targeting the BDNF and JNK singling pathways for AA­induced rat vestibular dysfunction.

Vestibulotoxicity: strategies for clinical diagnosis and rehabilitation.

OBJECTIVE: The purpose of this article is to discuss the most commonly prescribed vestibulotoxic medications and their impact on the vestibular system, to describe the clinical features of vestibular ototoxicity including symptoms reported by patients, and to describe assessment tools that may be used in a monitoring programme, including the functional impact of vestibular loss. Recently published data from a cohort of patients exposed to systemic aminoglycosides (AGS) are summarised, which highlight the importance of monitoring. The role and importance of vestibular rehabilitation in treating affected individuals is discussed. DESIGN: This is a descriptive article. STUDY SAMPLE: Recently published data from 71 patients with cystic fibrosis with AGS exposure are summarised. RESULTS: Recently published data from a cohort of patients exposed to systemic AGS reveal a high prevalence of vestibular system involvement. CONCLUSIONS: Evidence suggests that including assessment of vestibular function in a programme to monitor for ototoxic damage is essential. While suggestions about possible components of a monitoring programme are made, the need for further study in order to determine an ideal protocol for assessing vestibular system function during and following exposure to toxic agents is stressed.

Severe streptomycin ototoxicity in the mouse utricle leads to a flat epithelium but the peripheral neural degeneration is delayed.

The damaged vestibular sensory epithelium of mammals has a limited capacity for spontaneous hair cell regeneration, which largely depends on the transdifferentiation of surviving supporting cells. Little is known about the response of vestibular supporting cells to a severe insult. In the present study, we evaluated the impact of a severe ototoxic insult on the histology of utricular supporting cells and the changes in innervation that ensued. We infused a high dose of streptomycin into the mouse posterior semicircular canal to induce a severe lesion in the utricle. Both scanning electron microscopy and light microscopy of plastic sections showed replacement of the normal cytoarchitecture of the epithelial layer with a flat layer of cells in most of the samples. Immunofluorescence staining showed numerous cells in the severely damaged epithelial layer that were negative for hair cell and supporting cell markers. Nerve fibers under the flat epithelium had high density at the 1 month time point but very low density by 3 months. Similarly, the number of vestibular ganglion neurons was unchanged at 1 month after the lesion, but was significantly lower at 3 months. We therefore determined that the mouse utricular epithelium turns into a flat epithelium after a severe lesion, but the degeneration of neural components is slow, suggesting that treatments to restore balance by hair cell regeneration, stem cell therapy or vestibular prosthesis implantation will likely benefit from the short term preservation of the neural substrate.

The importance of audiometric monitoring in patients with multidrug-resistant tuberculosis

Abstract INTRODUCTION: A total of 771 cases of multidrug-resistant tuberculosis (MDR-TB) were reported in Brazil in 2014. Treatment of MDR-TB with aminoglycosides can produce serious side effects such as permanent and irreversible hearing loss, which occurs in 5-64% of cases, and severely compromise patient quality of life. The goal of this research was to evaluate auditory and vestibular side effects in patients treated for MDR-TB and to identify associations between these complaints and the type of aminoglycoside used. METHODS: We performed a retrospective review of 599 medical records from patients with MDR-TB who were treated at the Hélio Fraga/Fiocruz Reference Center between 2006 and 2010. Cases without auditory or vestibular complaints and patients who were not treated with aminoglycoside drugs were excluded from the study. RESULTS: Of 164 eligible cases, 55 (33.5%) reported an auditory or vestibular complaint and medication was subsequently suspended, although hearing damage was not confirmed in all cases. Audiometric testing confirmed hearing loss in 11 (21.7%) of 12 cases submitted for evaluation. Hearing loss related to ototoxicity was confirmed in 15 (62.5%) cases. Tinnitus was significantly associated with the use of amikacin and streptomycin. CONCLUSIONS: Evaluations of ototoxicity symptoms were not usually reported in the routine care of patients with MDR-TB. Complaints of tinnitus were associated with amikacin and streptomycin use. These results require confirmation in future studies.

Assessment of D-methionine protecting cisplatin-induced otolith toxicity by vestibular-evoked myogenic potential tests, ATPase activities and oxidative state in guinea pigs.

To date, inadequate study has been devoted to the toxic vestibular effects caused by cisplatin. In addition, no electrophysiological examination has been conducted to assess cisplatin-induced otolith toxicity. The purposes of this study are thus two-fold: 1) to determine whether cervical vestibular-evoked myogenic potentials (VEMPs) and ocular VEMPs are practical electrophysiological methods of testing for cisplatin-induced otolith toxicity and 2) to examine if D-methionine (D-met) pre-injection would protect the otolith organs against cisplatin-induced changes in enzyme activities and/or oxidative status. Guinea pigs were intraperitoneally treated once daily with the following injections for seven consecutive days: sterile 0.9% saline control, cisplatin (5 mg/kg) only, D-met (300 mg/kg) only, or a combination of d-met (300 mg/kg) and cisplatin (5 mg/kg), respectively, with a 30 minute window in between. Each animal underwent the oVEMP and cVEMP tests before and after treatment. The changes in the biochemistry of the otolith organs, including membranous Na(+), K(+)-ATPase and Ca(2+)-ATPase, lipid peroxidation (LPO) levels and nitric oxide (NO) levels, were also evaluated. In the cisplatin-only treated guinea pigs, the mean amplitudes of the oVEMP tests were significantly (p<0.05) decreased when compared to the other three groups. In guinea pigs receiving both D-met and cisplatin, the amplitudes of their oVEMP tests were significantly larger (p<0.05) than those of the cisplatin-only group, but smaller (p<0.05) than those of the saline control or D-met-only group. However, no significant difference of the amplitudes of cVEMP tests was noted among the four groups. In comparison with the other three groups, the cisplatin-only group had the lowest (ps<0.05) mean Na(+), K(+)-ATPase and Ca(2+)-ATPase, and the highest (ps<0.05) LPO and NO levels. The oVEMP tests were feasible for the evaluation of cisplatin-related otolith dysfunction. D-Met attenuated the reduced ATPase activities and increased oxidative stress induced by cisplatin toxicity in the otolith organs.

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity.

Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations.

[Current aspects of ototoxicity. Ototoxic substances and their effects]. / Aktuelle Aspekte zur Ototoxizität : Ototoxische Substanzen und deren Effekte.

Ototoxicity describes reversible or irreversible disorders of inner ear functions due to the influence of chemical, biological, or physical substances. Ototoxicity should be kept in mind during differential diagnosis of hearing loss, tinnitus, dizziness, and vertigo. In clinical practice, drug-induced ototoxic effects play a major role. The otorhinolaryngologist should also be involved in interdisciplinary cooperation, e.g., during treatment with antineoplastic chemotherapeutic agents with potential ototoxic side effects. In clinical practice, multimedication and interactions between different agents can complicate precise correlation in individual cases. Recent studies also show that noncellular components, such as otoconia, are extremely sensitive to chemical attacks.

Vestibular loss promotes procedural response during a spatial task in rats.

Declarative memory refers to a spatial strategy using numerous sources of sensory input information in which visual and vestibular inputs are assimilated in the hippocampus. In contrast, procedural memory refers to a response strategy based on motor skills and familiar gestures and involves the striatum. Even if vestibular loss impairs hippocampal activity and spatial memory, vestibular-lesioned rats remain able to find food rewards during complex spatial memory task. Since hippocampal lesions induce a switch from declarative memory to procedural memory, we hypothesize that vestibular-lesioned rats use a strategy other than that of hippocampal spatial response to complete the task and to counterbalance the loss of vestibular information. We test, in a reverse T-maze paradigm, the types of strategy vestibular-lesioned rats preferentially uses in a spatial task. We clearly demonstrate that all vestibular-lesioned rats shift to a response strategy to solve the spatial task, while control rats use spatial and response strategies equally. We conclude that the loss of vestibular informations leading to spatial learning impairments is not offset at the hippocampus level by integration process of other sense mainly visual informations; but favors a response strategy through procedural memory most likely involving the striatum, cerebellum, and motor learning.

Hearing loss and vestibular dysfunction among children with cancer after receiving aminoglycosides.

BACKGROUND: Children undergoing cancer therapy often receive aminoglycosides to treat febrile neutropenia or gram-negative infections. The magnitude of the risk of developing aminoglycoside-induced ototoxicity and the dose threshold at which that risk significantly increases are unknown. PROCEDURE: Eligible cancer patients received the aminoglycoside amikacin at Children's Medical Center between 2004 and 2007. They were aged 3-8 years; were without prior hearing loss; had no platinum-based chemotherapy, cranial radiation, nor bone marrow transplant; and received no loop diuretics within 6 weeks of testing. Consenting patients underwent complete hearing and vestibular testing. RESULTS: We tested 23 patients who had significant amikacin exposure. Three (13%) had abnormal hearing tests, and four (17%) had subclinical vestibular dysfunction; none had both. Of those with hearing loss, two were known to have developed hearing loss after aminoglycoside exposure, but the third had moderate to severe high-frequency sensorineural hearing loss bilaterally that had been undiagnosed. We observed clear dose-dependent ototoxicity; of the eight patients who received amikacin for a cumulative total of more than 50 days, five (68%) developed toxicity. Similarly, of the seven who received a cumulative total of more than 1,200 mg/kg, five developed toxicity. CONCLUSIONS: These data highlight the risks of prolonged aminoglycoside administration and warrant further validation in a larger group of patients. Patients to be treated with prolonged aminoglycoside therapy may benefit from prospective hearing screening.

Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report.

Mefloquine is a 4-methanolquinoline anti-malarial that in recent years has fallen out of favor for use as chemoprophylaxis against infection with chloroquine-resistant Plasmodium falciparum malaria owing in part to growing concerns of side effects and potential neurotoxicity. Despite over 20 years of licensed use, the pathophysiological mechanisms underlying mefloquine's neuropsychiatric and physical side effects and the clinical significance of the drug's neurotoxicity have remained poorly understood. In this report, an adverse reaction to mefloquine chemoprophylaxis is described characterized by prodromal symptoms of anxiety with subsequent development of psychosis, short-term memory impairment, confusion and personality change accompanied by complaints of disequilibrium and vertigo, with objective findings of central vestibulopathy. It is posited that these effects represent an idiosyncratic neurotoxic syndrome of progressive limbic encephalopathy and multifocal brainstem injury caused by the drug. This case provides insights into the clinical significance of mefloquine neuronal gap junction blockade and neurotoxicity demonstrated in animal models, points to recommendations for the management of affected patients including diagnostic considerations and appropriate referrals, and highlights critical implications for the continued safe use of the medication.

Lead and cadmium levels and balance and vestibular dysfunction among adult participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2004.

BACKGROUND: Few studies have been conducted to identify risk factors for balance and vestibular dysfunction in general populations, but previous studies have reported evidence of adverse effects of lead and cadmium on balance control in high-risk groups. OBJECTIVE: We evaluated the relationship between blood lead and cadmium levels and balance and vestibular dysfunction in a general population study. METHODS: We analyzed data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) of 5,574 adults ≥ 40 years of age. Balance dysfunction was evaluated by the Romberg Test of Standing Balance on Firm and Compliant Support Surfaces, which examines the ability to stand unassisted using four test conditions to evaluate vestibular system, vision, and proprioception inputs that contribute to balance. Blood levels of lead and cadmium were measured by atomic absorption spectrometry. Associations were estimated using logistic regression models adjusted for potential confounders. Associations with time to loss of balance were estimated using adjusted Cox proportional hazard models. RESULTS: The adjusted odds ratio (OR) for balance dysfunction in association with the highest quintile (3.3-48 µg/dL) versus the lowest quintile (< 1.2 µg/dL) of lead was 1.42 [95% confidence interval (CI): 1.07, 1.89]. The corresponding OR for cadmium (0.9-7.4 µg/L vs. < 0.2 µg/L) was 1.27 (95% CI: 1.01, 1.60). The adjusted hazard ratio for time to failure for the most physiologically challenging balance test among subjects with the highest vs. lowest quintiles of blood lead was 1.24 (95% CI: 1.04, 1.48). Cadmium levels were not associated with time to failure. CONCLUSIONS: Our findings suggest that blood lead and cadmium levels may be associated with balance and vestibular dysfunction in a general sample of U.S. adults.

Side effects of aminoglycosides on the kidney, ear and balance in cystic fibrosis.

Aminoglycoside antibiotics are a central component of the treatment of pulmonary exacerbations of cystic fibrosis (CF) and slow the decline in lung function which ultimately causes the death of most patients. The prognosis of CF has improved, and thus side effects of treatments have become increasingly important. Observational studies suggest that the morbidity from side effects of aminoglycosides is disturbingly common, and that aggressive treatment may lead to more side effects. This review of the current literature on side effects of aminoglycosides considers the pathophysiological mechanisms, epidemiology and risk factors, investigation of side effects and preventative strategies. Treatments which have shown early promise are identified and areas of future research are discussed.

An animal model of ocular vestibular-evoked myogenic potential in guinea pigs.

This study aimed to establish an animal model of ocular vestibular-evoked myogenic potential (oVEMP) in guinea pigs. Ten healthy and 10 gentamicin-treated guinea pigs underwent oVEMP test using a hand-held bone-conducted vibrator placed on the animal's forehead. All 10 healthy animals exhibited bilateral oVEMPs at the stimulus intensity of 139 dB force level (FL), with a mean threshold and latencies of peak nI and pI of 130 +/- 4 dBFL, 3.17 +/- 0.37 ms and 4.72 +/- 0.38 ms, respectively. Similar to response rate, the nI-pI amplitude decreased markedly in magnitude as stimulus intensity decreased. Another 10 animals administered with gentamicin (2 mg) on the left ear 1 week after surgery had 100% clear oVEMPs beneath the left eye (ipsilateral to the lesion side), whereas oVEMPs were absent and reduced beneath the right eye (opposite to the lesion side) in 7 and 3 animals, respectively. Morphological study of animals with absent oVEMPs identified substantial damage to the hair cells of the utricular macula. Quantitative analysis revealed that histological density of intact hair cells of the utricular macula from control and lesion ears were 194 +/- 15 and 66 +/- 9 per 130 x 130 microm(2) field, respectively, showing a 68% reduction in the latter. Further, the stereocilia of the residual hair cells were either fused or deformed, and pointed outward randomly. In conclusion, this study establishes the animal model of oVEMP in guinea pigs using bone-conducted vibration stimuli, which sets the stage for investigating the pathophysiology of the utricular disorders.

Assessment of gentamicin-induced vestibulotoxicity by click and galvanic vestibular-evoked myogenic potentials: a guinea pig investigation.

OBJECTIVE: The aim of this investigation carried out with guinea pigs was to study the possible effects of a gentamicin treatment on the saccular macula and on its afferent vestibular ganglion neurons. METHODS: The gentamicin-induced impairment was analyzed using vestibular-evoked myogenic potentials (VEMPs) elicited by both click and galvanic vestibular stimulations (GVS). Fifty microl of saline or gentamicin solution (40 mg/ml) was dropped over the round window membrane of the right (control) and left (lesion) cochleae, respectively. Four weeks after surgery, the VEMPs elicited with clicks and GVS were evaluated for each animal. Then, the animals were sacrificed in order to perform morphological and anti-Nav1.8 immunocytochemical analyses. RESULTS: Click- and GVS-VEMPs were obtained in all of the controls, whereas no potentials were obtained from gentamicin-treated animals. Lesions of sensory cells were observed in the saccular macula. In the injured vestibular ganglion, the percentage of voltage-gated sodium channel Nav1.8-like immunoreactive (Nav1.8-LI) neurons was significantly lower (38.9+/-0.7) than that (53.6+/-3.2) calculated in controls. CONCLUSIONS: Gentamicin-induced impairments of the saccular macula and afferents of guinea pigs can be evaluated by recording both click- and GVS-VEMPs. Both tests provide information on the sacculo-collic reflex pathway and could help a clinical diagnosis of gentamicin intoxication by conventional eardrops in the patient with a perforated eardrum.