Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health.

Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

Psychometric Validation of a Hearing Screening Questionnaire for Preschoolers based on language development evaluation by caregivers.

INTRODUCTION: This study aimed to validate three age-adjusted versions of a Hearing Screening Questionnaire for Preschoolers, in Brazilian Portuguese, based on parents' perception of their children's hearing and oral language. METHODS: Psychometric validation was conducted on three questionnaires, each comprising nine items with Yes/No responses. Three items focused on hearing screening at birth, and six assessed hearing and oral language. The study included 152 parents and their children, who attended day care centers in Belo Horizonte, Brazil. The children were categorized into three age bands: 12 to 18 months, 19 to 35 months, and 36 to 48 months. Audiological assessments, including tympanometry, transient-evoked otoacoustic emissions (TOAE) and pure-tone audiometry (when applicable), were performed on the children. In case of abnormal findings in the previous exams, auditory brainstem response (ABR) testing was conducted. Descriptive data, false alarm, and false-negative analyses were carried out. RESULTS: Considering any type of hearing loss, whether unilateral or bilateral, the questionnaires showed a false-negative rate of 41.17% (7/17 children). However, when considering only bilateral hearing loss, the questionnaire showed a false alarm rate of 31.69% (45/142) and a false-negative rate of 30.0% (3/10). When focusing exclusively on sensorineural hearing loss, the questionnaire identified two children (1.31%), with a false-negative rate of 0% but a false-positive rate of 33.33%. CONCLUSION: Language-development oriented questionnaires allowed quick screening of potential hearing loss in preschoolers. This study found a robust hit rate with these questionnaires. Their validation signifies a promising and cost-effective tool for conducting hearing screenings in preschool children, especially in nations lacking a comprehensive school screening policy.The validated questionnaire affords an easy-to-apply, low-cost and effective instrument for preschool hearing screening.

Preserved Auditory Steady State Response and Envelope-Following Response in Severe Brainstem Dysfunction Highlight the Need for Cross-Checking.

OBJECTIVES: Commercially available auditory steady state response (ASSR) systems are widely used to obtain hearing thresholds in the pediatric population objectively. Children are often examined during natural or induced sleep so that the recorded ASSRs are of subcortical origin, the inferior colliculus being often designated as the main ASSR contributor in these conditions. This report presents data from a battery of auditory neurophysiological objective tests obtained in 3 cases of severe brainstem dysfunction in sleeping children. In addition to ASSRs, envelope-following response (EFR) recordings designed to distinguish peripheral (cochlear nerve) from central (brainstem) were recorded to document the effect of brainstem dysfunction on the two types of phase-locked responses. DESIGN: Results obtained in the 3 children with severe brainstem dysfunctions were compared with those of age-matched controls. The cases were identified as posterior fossa tumor, undiagnosed (UD), and Pelizaeus-Merzbacher-Like Disease. The standard audiological objective tests comprised tympanograms, distortion product otoacoustic emissions, click-evoked auditory brainstem responses (ABRs), and ASSRs. EFRs were recorded using horizontal (EFR-H) and vertical (EFR-V) channels and a stimulus phase rotation technique allowing isolation of the EFR waveforms in the time domain to obtain direct latency measurements. RESULTS: The brainstem dysfunctions of the 3 children were revealed as abnormal (weak, absent, or delayed) ABRs central waves with a normal wave I. In addition, they all presented a summating and cochlear microphonic potential in their ABRs, coupled with a normal wave I, which implies normal cochlear and cochlear nerve function. EFR-H and EFR-V waveforms were identified in the two cases in whom they were recorded. The EFR-Hs onset latencies, response durations, and phase-locking values did not differ from their respective age-matched control values, indicating normal cochlear nerve EFRs. In contrast, the EFR-V phase-locking value and onset latency varied from their control values. Both patients had abnormal but identifiable and significantly phase-locked brainstem EFRs, even in a case with severely distorted ABR central waves. ASSR objective audiograms were recorded in two cases. They showed normal or slightly elevated (explained by a slight transmission loss) thresholds that do not yield any clue about their brainstem dysfunction, revealing the method's lack of sensitivity to severe brainstem dysfunction. CONCLUSIONS: The present study, performed on 3 sleeping children with severe brainstem dysfunction but normal cochlear responses (cochlear microphonic potential, summating potential, and ABR wave I), revealed the differential sensitivity of three auditory electrophysiological techniques. Estimated thresholds obtained by standard ASSR recordings (cases UD and Pelizaeus-Merzbacher-Like Disease) provided no clue to the brainstem dysfunction clearly revealed by the click-evoked ABR. EFR recordings (cases posterior fossa tumor and UD) showed preserved central responses with abnormal latencies and low phase-locking values, whereas the peripheral EFR attributed to the cochlear nerve was normal. The one case (UD) for which the three techniques could be performed confirms this sensitivity gradient, emphasizing the need for applying the Cross-Check Principle by avoiding resorting to ASSR recording alone. The entirely normal EFR-H recordings observed in two cases further strengthen the hypothesis of its cochlear nerve origin in sleeping children.

Impaired auditory neural performance, another dimension of hearing loss in type-2 diabetes mellitus.

AIM: To evaluate auditory performance in subjects with poorly controlled type-2 diabetes mellitus, using a simple test battery assessing sensitivity to pure tones and neuronal function. METHODS: Enrolled subjects, aged between 23 and 79 years, reported several auditory dysfunctions. They were tested using pure-tone audiometry, otoacoustic emissions for cochlear-function evaluation, and measurement of middle-ear muscle-reflex thresholds in search of an auditory neuropathy. RESULTS: Compared to the standard established for an age-matched normative population, the distribution of averaged pure-tone thresholds in enrolled subjects shifted by about one standard deviation with respect to the normal distribution, in line with past reports of mild sensorineural hearing impairment in diabetes, even though many diabetic subjects fell well within the normative interval of audiometric thresholds. Otoacoustic emissions showed that pure-tone thresholds correctly predicted the status of cochlear sensory cells that, by amplifying sound, ensure normal hearing sensitivity. Whereas the observed hearing losses should not have affected the acoustic levels above which the protective middle-ear muscle reflex is triggered by intense sounds, this reflex was undetectable in around 40% enrolled subjects, a marker of auditory neuropathy. CONCLUSION: Auditory-neural function should be evaluated to identify diabetic subjects whose hearing is impaired. Simple automatic tests are available for this purpose, for example middle-ear muscle reflex detection, which turns out to be more sensitive than the standard audiogram.

Relation between auditory difficulties and bortezomib-induced peripheral neuropathy in multiple myeloma: a single-center cross-sectional study.

PURPOSE: Bortezomib is a neurotoxic drug used in multiple myeloma and responsible for chemotherapy-induced peripheral neuropathy (CIPN). In a previous cross-sectional study, CIPN prevalence was about 26.9% in 67 patients. A second data analysis was performed to explore the relation between CIPN and auditory difficulties. METHODS: Based on 66 multiple myeloma patients from a single center, auditory difficulties were assessed with a self-questionnaire and compared to sensory CIPN (QLQ-CIPN20 questionnaire), patients' characteristics and anticancer treatments. RESULTS: The prevalence of auditory difficulties was about 42.4% (95% CI [30.6-55.2]) of the 66 patients analyzed and was higher in patients with CIPN than without (82.4% vs. 28.6%, p < 0.001). Auditory difficulties were not related to the characteristics of patients and treatments. The severity of auditory difficulties were correlated to CIPN severity (spearman's coefficient: 0.49, p = 0.009). Odds-ratio of auditory difficulties (multivariable analysis adjusted for sensory CIPN, recreation or professional noise exposure, gender, age, and treatments) was significantly associated with CIPN (18.7, 95% CI [3.0-117.1], p = 0.002). CONCLUSION: This relation between CIPN and auditory difficulties raises concerns about hearing safety in multiple myeloma patients treated by bortezomib. TRIAL REGISTRATION NUMBER: NCT03344328.

Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.

The Added Value of Sensitivity to Nonnoxious Stimuli to Predict an Individual's Sensitivity to Pain.

BACKGROUND: Simple tools are needed to predict postoperative pain. Questionnaire-based tools such as the Pain Sensitivity Questionnaire (PSQ) are validated for this purpose, but prediction could be improved by incorporating other parameters. OBJECTIVES: To explore the potency of sensitivity to nonpainful stimuli and biometric data to improve prediction of pain. STUDY DESIGN: Transversal exploratory study. SETTING: Single clinical investigation center. METHODS: Eighty-five healthy volunteers of both genders underwent a multimodal exploration including biometry, questionnaire-based assessment of anxiety, depression, pain catastrophizing, sensitivity to smell, and the PSQ, followed by a psychophysical assessment of unpleasantness thresholds for light and sound, and sensitivity to mechanical, heat, and cold pain. These last 3 parameters were used to calculate a composite pain score. After a multi-step selection, multivariable analyses identified the explanative factors of experimental pain sensitivity, by including biometric, questionnaire-based, and psychophysical nonnociceptive sensitivity parameters, with the aim of having each domain represented. RESULTS: Female gender predicted mechanical pain, a younger age and dark eyes predicted cold pain, and the PSQ predicted heat pain. Sensitivity to unpleasantness of sound predicted mechanical and heat pain, and sensitivity to unpleasantness of light predicted cold pain. Sensitivity to smell was unrelated. The predictors of the composite pain score were the PSQ, the light unpleasantness threshold, and an interaction between gender and eye color, the score being lower in light-eyed men and higher in all women. The final multivariable multi-domain model was more predictive of pain than the PSQ alone (R2 = 0.301 vs 0.122, respectively). LIMITATIONS: Sensitivity to smell was only assessed by a short questionnaire and could lack relevance. Healthy volunteers were unlikely to elicit psychological risk factors such as anxiety, depression, or catastrophizing. These results have not been validated in a clinical setting (e.g., perioperative). CONCLUSION: The predictive potential of the PSQ can be improved by including information about gender, eye color, and light sensitivity. However, there is still a need for a technique suitable for routine clinical use to assess light sensitivity.

Prevalence of Chemotherapy-Induced Peripheral Neuropathy in Multiple Myeloma Patients and its Impact on Quality of Life: A Single Center Cross-Sectional Study.

Bortezomib is a pivotal drug for the management of multiple myeloma. However, bortezomib is a neurotoxic anticancer drug responsible for chemotherapy-induced peripheral neuropathy (CIPN). CIPN is associated with psychological distress and a decrease of health-related quality of life (HRQoL), but little is known regarding bortezomib-related CIPN. This single center, cross-sectional study assessed the prevalence and severity of sensory/motor CIPN, neuropathic pain and ongoing pain medications, anxiety, depression, and HRQoL, in multiple myeloma patients after the end of bortezomib treatment. Paper questionnaires were sent to patients to record the scores of sensory and motor CIPNs (QLQ-CIPN20), neuropathic pain (visual analogue scale and DN4 interview), anxiety and depression (HADS), the scores of HRQoL (QLQ-C30 and QLQ-MY20) and ongoing pain medications. Oncological data were recorded using chemotherapy prescription software and patient medical records. The prevalence of sensory CIPN was 26.9% (95% CI 16.7; 39.1) among the 67 patients analyzed and for a mean time of 2.9 ± 2.8 years since the last bortezomib administration. The proportion of sensory CIPN was higher among patients treated by intravenous and subcutaneous routes than intravenous or subcutaneous routes (p = 0.003). QLQ-CIPN20 motor scores were higher for patients with a sensory CIPN than those without (p < 0.001) and were correlated with the duration of treatment and the cumulative dose of bortezomib (coefficient: 0.31 and 0.24, p = 0.01 and 0.0475, respectively), but not sensory scores. Neuropathic pain was screened in 44.4% of patients with sensory CIPN and 66.7% of them had ongoing pain medications, but none were treated with duloxetine (recommended drug). Multivariable analysis revealed that thalidomide treatment (odds-ratio: 6.7, 95% CI 1.3; 35.5, p = 0.03) and both routes of bortezomib administration (odds-ratio: 13.4, 95% CI 1.3; 139.1, p = 0.03) were associated with sensory CIPN. Sensory and motor CIPNs were associated with anxiety, depression, and deterioration of HRQoL. Sensory CIPN was identified in a quarter of patients after bortezomib treatment and associated with psychological distress that was far from being treated optimally. There is a need to improve the management of patients with CIPN, which may include better training of oncologists regarding its diagnosis and pharmacological treatment.

Decreased Reemerging Auditory Brainstem Responses Under Ipsilateral Broadband Masking as a Marker of Noise-Induced Cochlear Synaptopathy.

OBJECTIVES: In mammals, a 2-hr exposure to an octave-band noise (OBN) at 100 to 108 dB SPL induces loss of synaptic ribbons between inner hair cells and auditory nerve fibers with high thresholds of response (hiT neurons), that encode high-intensity sounds. Here, we tackle the challenge of diagnosing this synaptopathy by a noninvasive functional audiological test, ultimately in humans, despite the expected absence of auditory-threshold elevation and of clear electrophysiological abnormality, hiT neuron contributions being hidden by those of more sensitive and robust neurons. DESIGN: The noise-induced synaptopathy was replicated in mice (at 94, 97, and 100 dB SPL; n = 7, 7, and 8, respectively, against 8 unexposed controls), without long-lasting auditory-threshold elevation despite a twofold decrease in ribbon-synapse number for the 100-dB OBN exposure. Auditory brainstem responses (ABRs) were collected using a simultaneous broadband noise masker just able to erase the ABR response to a 60-dB tone burst. Tone burst intensity was then increased up to 100 dB SPL for eliciting reemerging ABRs (R-ABRs), dependent on hiT neurons as more sensitive neurons are masked. RESULTS: In most ears exposed to 97-dB-SPL and all ears exposed to 100-dB-SPL OBN, contrary to controls, R-ABRs from the overexposed region have vanished, whereas standard ABR distributions widely overlap. CONCLUSIONS: R-ABRs afford an individual noninvasive marker of normal-auditory-threshold cochlear synaptopathy. A simple modification of standard ABRs would allow hidden auditory synaptopathy to be searched in a patient. ABBREVIATIONS: ABR: auditory brainstem response; dB SPL: decibel sound pressure level; DPOAE: distortion-product otoacoustic emission; hiT neuron: high-threshold neuron; IHC: inner hair cell; loT neuron: low-threshold neuron; OBN: octave-band noise; OHC: outer hair cell; PBS: phosphate buffer saline; R-ABR: reemerging ABR.

In-Depth Characterization of Somatic and Orofacial Sensitive Dysfunctions and Interfering-Symptoms in a Relapsing-Remitting Experimental Autoimmune Encephalomyelitis Mouse Model.

Among the many symptoms (motor, sensory, and cognitive) associated with multiple sclerosis (MS), chronic pain is a common disabling condition. In particular, neuropathic pain symptoms are very prevalent and debilitating, even in early stages of the disease. Unfortunately, chronic pain still lacks efficient therapeutic agents. Progress is needed (i) clinically by better characterizing pain symptoms in MS and understanding the underlying mechanisms, and (ii) preclinically by developing a more closely dedicated model to identify new therapeutic targets and evaluate new drugs. In this setting, new variants of experimental autoimmune encephalomyelitis (EAE) are currently developed in mice to exhibit less severe motor impairments, thereby avoiding confounding factors in assessing pain behaviors over the disease course. Among these, the optimized relapsing-remitting EAE (QuilA-EAE) mouse model, induced using myelin oligodendrocyte glycoprotein peptide fragment (35-55), pertussis toxin, and quillaja bark saponin, seems very promising. Our study sought (i) to better define sensitive dysfunctions and (ii) to extend behavioral characterization to interfering symptoms often associated with pain during MS, such as mood disturbances, fatigue, and cognitive impairment, in this optimized QuilA-EAE model. We made an in-depth characterization of this optimized QuilA-EAE model, describing for the first time somatic thermal hyperalgesia associated with mechanical and cold allodynia. Evaluation of orofacial pain sensitivity showed no mechanical or thermal allodynia. Detailed evaluation of motor behaviors highlighted slight defects in fine motor coordination in the QuilA-EAE mice but without impact on pain evaluation. Finally, no anxiety-related or cognitive impairment was observed during the peak of sensitive symptoms. Pharmacologically, as previously described, we found that pregabalin, a treatment commonly used in neuropathic pain patients, induced an analgesic effect on mechanical allodynia. In addition, we showed an anti-hyperalgesic thermal effect on this model. Our results demonstrate that this QuilA-EAE model is clearly of interest for studying pain symptom development and so could be used to identify and evaluate new therapeutic targets. The presence of interfering symptoms still needs to be further characterized.

Subcortical neural generators of the envelope-following response in sleeping children: A transfer function analysis.

Multiple auditory structures, from cochlea to cortex, phase-lock to the envelope of complex stimuli. The relative contributions of these structures to the human surface-recorded envelope-following response (EFR) are still uncertain. Identification of the active contributor(s) is complicated by the fact that even the simplest two-tone (f1&f2) stimulus, targeting its (f2-f1) envelope, evokes additional linear (f1&f2) and non-linear (2f1-f2) phase-locked components as well as a transient auditory brainstem response (ABR). Here, we took advantage of the generalized primary tone phase variation method to isolate each predictable component in the time domain, allowing direct measurements of onset latency, duration and phase discontinuity values from which the involved generators were inferred. Targeting several envelope frequencies (0.22-1 kHz), we derived the EFR transfer functions along a vertical vertex-to-neck and a horizontal earlobe-to-earlobe recording channels, yielding respectively EFR-V and EFR-H waveforms. Subjects (N= 30) were sleeping children with normal electrophysiological thresholds and normal oto-acoustic emissions. Both EFR-H and EFR-V phase-locking values (PLV) transfer functions had a low-pass profile, EFR-V showing a lower cut-off frequency than EFR-H. We also computed the frequency-latency relationships of both EFRs onset latencies. EFR-H data fitted a power-law function incorporating a frequency-dependent traveling wave delay and a fixed one amounting to 1.2 ms. The fitted function nicely fell within five published estimations of the latency-frequency function of the ABR wave-I, thus pointing to a cochlear nerve origin. The absence of phase discontinuity and overall response durations that were equal to that of the stimulus indicated no contribution from a later generator. The recording of an entirely similar EFR-H response in a patient who had severe brainstem encephalitis with a normal, isolated, ABR wave-I but complete absence of later waves, further substantiated a cochlear nerve origin. Modeling of the EFR-V latency-frequency functions indicated a fixed transport time of 2 ms with respect to EFR-H onset, suggesting a cochlear nucleus (CN) origin, here also, without indication for multiple generators. Other features of the EFR-V response pointing to the CN were, at least for the EFR frequency below the cut-off values of the transfer functions, higher PLVs coupled with increased harmonic distortion. Such a behavior has been described in the so-called highly-synchronized neurons of the ventral cochlear nucleus (VCN). The present study compellingly demonstrated the advantage of isolating the EFR in the temporal domain so as to extract detailed spectro-temporal parameters that, combined with orthogonal recording channels, shed new light on the involved neural generators.

Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis.

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

Generalization of the primary tone phase variation method: An exclusive way of isolating the frequency-following response components.

The primary tone phase variation (PTPV) technique combines selective sub-averaging with systematic variation of the phases of multitone stimuli. Each response component having a known phase relationship with the stimulus components phases can be isolated in the time domain. The method was generalized to the frequency-following response (FFR) evoked by a two-tone (f 1 and f 2) stimulus comprising both linear and non-linear, as well as transient components. The generalized PTPV technique isolated each spectral component present in the FFR, including those sharing the same frequency, allowing comparison of their latencies. After isolation of the envelope component f 2 - f 1 from its harmonic distortion 2f 2 - 2f 1 and from the transient auditory brainstem response, a computerized analysis of instantaneous amplitudes and phases was applied in order to objectively determine the onset and offset latencies of the response components. The successive activation of two generators separated by 3.7 ms could be detected in all (N = 12) awake adult normal subjects, but in none (N = 10) of the sleeping/sedated children with normal hearing thresholds. The method offers an unprecedented way of disentangling the various FFR subcomponents. These results open the way for renewed investigations of the FFR components in both human and animal research as well as for clinical applications.

Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin.

Neurotoxicity remains the most common adverse effect of oxaliplatin, limiting its clinical use. In the present study, we developed a mouse model of chronic oxaliplatin-induced neuropathy, which mimics both sensory and motor deficits observed in patients, in a clinically relevant time course. Repeated oxaliplatin administration in mice induced both cephalic and extracephalic long lasting mechanical and cold hypersensitivity after the first injection as well as delayed sensorimotor deficits and a depression-like phenotype. Using this model, we report that riluzole prevents both sensory and motor deficits induced by oxaliplatin as well as the depression-like phenotype induced by cumulative chemotherapeutic drug doses. All the beneficial effects are due to riluzole action on the TREK-1 potassium channel, which plays a central role in its therapeutic action. Riluzole has no negative effect on oxaliplatin antiproliferative capacity in human colorectal cancer cells and on its anticancer effect in a mouse model of colorectal cancer. Moreover, riluzole decreases human colorectal cancer cell line viability in vitro and inhibits polyp development in vivo. The present data in mice may support the need to clinically test riluzole in oxaliplatin-treated cancer patients and state for the important role of the TREK-1 channel in pain perception.

Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation may reveal subclinical alterations in human T-cell lymphotropic virus type 1-associated myelopathy.

BACKGROUND: Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation (galvanic-VEMP) evaluates the motor spinal cord and identifies subclinical myelopathies. We used galvanic-VEMP to compare spinal cord function in individuals infected with human T-cell lymphotropic virus type 1 (HTLV-1) from asymptomatic status to HTLV-1-associated myelopathy (HAM). METHODOLOGY/PRINCIPAL FINDINGS: This cross-sectional study with 122 individuals included 26 HTLV-1-asymptomatic carriers, 26 individuals with possible HAM, 25 individuals with HAM, and 45 HTLV-1-seronegative individuals (controls). The groups were similar regarding gender, age, and height. Galvanic stimuli (duration: 400 ms; intensity: 2 mA) were applied bilaterally to the mastoid processes and VEMP was recorded from the gastrocnemius muscle. The electromyographic parameters investigated were the latency and amplitude of the short-latency (SL) and medium-latency (ML) responses. While SL and ML amplitudes were similar between groups, SL and ML latencies were delayed in the HTLV-1 groups compared to the control group (p<0.001). Using neurological examination as the gold standard, ROC curve showed an area under the curve of 0.83 (p<0.001) for SL and 0.86 (p<0.001) for ML to detect spinal cord injury. Sensibility and specificity were, respectively, 76% and 86% for SL and 79% and 85% for ML. Galvanic-VEMP disclosed alterations that were progressive in HTLV-1-neurological disease, ranging from SL delayed latency in HTLV-1-asymptomatic carriers, SL and ML delayed latency in possible HAM group, to absence of VEMP response in HAM group. CONCLUSIONS/SIGNIFICANCE: The worse the galvanic-VEMP response, the more severe the myelopathy. Galvanic-VEMP alteration followed a pattern of alteration and may be a prognostic marker of progression from HTLV-1-asymptomatic carrier to HAM.

Noninvasive in-ear monitoring of intracranial pressure during microgravity in parabolic flights.

Among possible causes of visual impairment or headache experienced by astronauts in microgravity or postflight and that hamper their performance, elevated intracranial pressure (ICP) has been invoked but never measured for lack of noninvasive methods. The goal of this work was to test two noninvasive methods of ICP monitoring using in-ear detectors of ICP-dependent auditory responses, acoustic and electric, in acute microgravity afforded by parabolic flights. The devices detecting these responses were handheld tablets routinely used in otolaryngology for hearing diagnosis, which were customized for ICP extraction and serviceable by unskilled operators. These methods had been previously validated against invasive ICP measurements in neurosurgery patients. The two methods concurred in their estimation of ICP changes with microgravity, i.e., 11.0 ± 7.7 mmHg for the acoustic method ( n = 7 subjects with valid results out of 30, auditory responses being masked by excessive in-flight noise in 23 subjects) and 11.3 ± 10.6 mmHg for the electric method ( n = 10 subjects with valid results out of 10 tested despite the in-flight noise). These results agree with recent publications using invasive access to cerebrospinal fluid in parabolic flights and suggest that acute microgravity has a moderate average effect on ICP, similar to body tilt from upright to supine, yet with some subjects undergoing large effects whereas others seem immune. The electric in-ear method would be suitable for ICP monitoring in circumstances and with subjects such that invasive measurements are excluded. NEW & NOTEWORTHY In-ear detectors of intracranial pressure-dependent auditory responses allow intracranial pressure to be monitored noninvasively during acute microgravity. The average pressure increase during 20-s long sessions in microgravity is 11 mmHg, comparable with an effect of body tilt. However, intersubject variability is large, with subjects who repeatedly experience from nothing to twice the average effect. A systematic in-flight use would allow the relationship between space adaptation syndrome and ICP to be established or dismissed.

Transient Abnormalities in Masking Tuning Curve in Early Progressive Hearing Loss Mouse Model.

Damage to cochlear outer hair cells (OHCs) usually affects frequency selectivity in proportion to hearing threshold increase. However, the current clinical heuristics that attributes poor hearing performance despite near-normal auditory sensitivity to auditory neuropathy or "hidden" synaptopathy overlooks possible underlying OHC impairment. Here, we document the part played by OHCs in influencing suprathreshold auditory performance in the presence of noise in a mouse model of progressive hair cell degeneration, the CD1 strain, at postnatal day 18-30 stages when high-frequency auditory thresholds remained near-normal. Nonetheless, total loss of high-frequency distortion product otoacoustic emissions pointed to nonfunctioning basal OHCs. This "discordant profile" came with a huge low-frequency shift of masking tuning curves that plot the level of interfering sound necessary to mask the response to a probe tone, against interfering frequency. Histology revealed intense OHC hair bundle abnormalities in the basal cochlea uncharacteristically associated with OHC survival and preserved coupling with the tectorial membrane. This pattern dismisses the superficial diagnosis of "hidden" neuropathy while underpinning a disorganization of cochlear frequency mapping with optimistic high-frequency auditory thresholds perhaps because responses to high frequencies are apically shifted. The audiometric advantage of frequency transposition is offset by enhanced masking by low-frequency sounds, a finding essential for guiding rehabilitation.

Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia.

OBJECTIVES: In patients with Friedreich ataxia (FRDA), mitochondrial failure leads to impaired cellular energetics. Since many FRDA patients have impaired hearing in noise, we investigated the objective consequences on standard auditory brainstem-evoked responses (ABRs). METHODS: In 37 FRDA patients, among whom 34 with abnormal standard ABRs, hearing sensitivity, speech-in-noise intelligibility and otoacoustic emissions were controlled. ABR recordings were split into four consecutive segments of the total time frame used for data collection, thus allowing the dynamics of ABR averaging to be observed. RESULTS: Most ears showed features of an auditory neuropathy spectrum disorder with flattened ABRs and impaired speech-in-noise intelligibility contrasting with near-normal hearing sensitivity and normal preneural responses. Yet split-ABRs revealed short-lived wave patterns in 26 out of 68 ears with flattened standard ABRs (38%). While averaging went on, the pattern of waves shifted so that interwave latencies increased by 35% on average. CONCLUSIONS: In FRDA, the assumption of stationarity used for extracting standard ABRs is invalid. The preservation of early split-ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure. SIGNIFICANCE: This model of metabolic sensory neuropathy warns against exposure of metabolically-impaired patients to sustained auditory stimulation.

Resistance of Gerbil Auditory Function to Reversible Decrease in Cochlear Blood Flow.

The objective was to design in gerbils a model of reversible decrease in cochlear blood flow (CBF) and analyze its influence on cochlear function. In Mongolian gerbils injected with ferromagnetic microbeads, a magnet placed near the porus acusticus allowed CBF to be manipulated. The cochlear microphonic potential (CM) from the basal cochlea was monitored by a round-window electrode. In 13 of the 20 successfully injected gerbils, stable CBF reduction was obtained for 11.5 min on average. The CM was affected only when CBF fell to less than 60% of its baseline, yet remained >40% of its initial level in about 2/3 of such cases. After CBF restoration, CM recovery was fast and usually complete. Reduced CM came with a 35- to 45-dB threshold elevation of neural responses determined by compound action potentials. This method allowing reversible changes of CBF confirms the robustness of cochlear function to decreased CBF. It can be used to study whether a hypovascularized cochlea is abnormally sensitive to stress.

Noninvasive detection of alarming intracranial pressure changes by auditory monitoring in early management of brain injury: a prospective invasive versus noninvasive study.

BACKGROUND: In brain-injured patients intracranial pressure (ICP) is monitored invasively by a ventricular or intraparenchymal transducer. The procedure requires specific expertise and exposes the patient to complications such as malposition, hemorrhage or infection. As inner-ear fluid compartments are connected to the cerebrospinal fluid space, ICP changes elicit subtle changes in the physiology of the inner ear. Notably, we previously demonstrated that the phase of cochlear microphonic potential (CM) generated by sound stimuli rotates with ICP. The aim of our study was to validate the monitoring of CM as a noninvasive method to follow ICP. METHODS: Non-invasive measure of CM-phase was compared to ICP recorded invasively in a prospective series of patients with acute brain injury managed in a neuro-intensive care unit. The study focused on patients with varying ICP and normal middle-ear function. RESULTS: In the 24 patients with less than 4 days of endotracheal ventilation and whose ICP fluctuated (50-hour data), we demonstrated close correlation between CM-phase rotation and ICP (average 1.26 degrees/mmHg). As a binary classifier, CM phase changes of 7-10 degrees signaled 7.5-mmHg ICP increases with a sensitivity of 83% and 19% fallout. CONCLUSION: Reference methods to measure ICP require the surgical placement of a pressure transducer. Noninvasive CM-based monitoring of ICP might be beneficial to early management of brain-injured patients with initially preserved consciousness and to the diagnosis of neurological conditions, whenever invasive monitoring cannot be performed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01685476 , registered on 30 August 2012.