Umbilical Cord Mesenchymal Stromal Cell-Derived Exosomes Rescue the Loss of Outer Hair Cells and Repair Cochlear Damage in Cisplatin-Injected Mice.

Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 µg/µL) injection at the same time point; and (ii) UCMSC exosome (1.2 µg/µL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.

Cochleotoxicity monitoring protocol.

INTRODUCTION: Cochlear damage is frequent in long-term aminoglycosides therapy or chemotherapeutic treatments with platinum-based agents. Despite its prevalence, it is currently underestimated and underdiagnosed. A monitoring protocol is vital to the early detection of cochleotoxicity and its implementation is widely encouraged in every hospital unit. Our aim was to elaborate a cochleotoxicity monitoring protocol for patients treated with platinum compounds or aminoglycosides antibiotics. METHODS: PubMed® database was searched using terms relevant to drug cochleotoxicity in order to identify the most adequate protocol. Several articles and guidelines influenced our decision. RESULTS: There is no consensus on a universal monitoring protocol. Its formulation and application rely heavily on available resources and personnel. High-frequency audiometry and otoacoustic emissions play an important role on early detection of cochleotoxicity caused by aminoglycoside antibiotics and platinum compounds. CONCLUSION: A cochleotoxicity monitoring protocol consisting on an initial evaluation, treatment follow-up and post-treatment evaluation is proposed.

Autologous intratympanic blood patch for presumed perilymphatic fistulas.

OBJECTIVE: To assess an alternative to bed rest and surgery for suspected perilymphatic fistulas using intratympanic blood injections. METHOD: A review was conducted of patients' history, physical and audiometric data, before and after treatment by intratympanic blood injections performed from 2009 to 2015. RESULTS: Twelve ears were identified, with trauma associated with air travel, water sports or nose blowing. Ten of these cases had hearing loss, six had vestibular symptoms. Four cases had audiological and vestibular symptoms, two had vestibular symptoms only, and six had audiological symptoms only. Time-to-treat varied from 1 day to 30 days. Magnetic resonance imaging scans were obtained for five cases. Ten cases received steroids. Six out of seven cases showed improvement of hearing loss. Five cases showed positive fistula test results, four with documented resolution. Seven cases had full resolution of all symptoms, four had near-full resolution and one had no improvement. CONCLUSION: Intratympanic blood injections offer an effective alternative to conservative or surgical therapy. Advantages include sooner time-to-treat, lower financial costs and decreased psychosocial burdens. It allows a more flexible and liberal use of a potential definite treatment for perilymphatic fistula.

Electrococleografía extratimpánica en una población normal. Estudio descriptivo / Extra-tympanic electrocochleography in a normal population. A descriptive study

Introducción y objetivos: La electrococleografía extratimpánica es un registro elecrofisiológico que refleja la actividad eléctrica acontecida en la cóclea tras un estímulo sonoro. Se obtiene mediante la aplicación del estímulo en el conducto auditivo externo y el registro de la actividad eléctrica mediante electrodos de superficie. Dada la escasa literatura existente acerca de la exploración electrococleográfica normal en nuestro medio, este estudio busca regularizar los valores obtenidos mediante esta exploración en sujetos sin enfermedad otoneurológica y explicar detalladamente el proceso mediante el cual se obtiene el registro. Métodos: Exploración mediante electrococleografía extratimpánica de 60 oídos sin enfermedad otoneurológica y análisis estadístico de los resultados obtenidos. De ellos, 30 oídos fueron explorados a 90dB mientras que otros 30 oídos fueron estimulados a 80dB. Resultados: Se muestran los valores medios de amplitud y latencia del potencial de sumación y del potencial de acción, así como las latencias medias de la onda I y la onda II. Asimismo, se presenta el cálculo del cociente potencial de sumación/potencial de acción. Obtenidos estos resultados se comparan en función de la intensidad del estímulo, del sexo del paciente, del oído estudiado y del grupo etario. Conclusiones: Este estudio recopila datos sobre la electrococleografía en una población normal. Los valores obtenidos están en el rango de los valores normales de otros países, expuestos en la literatura internacional. Estos datos pueden ser muy útiles como referencia a la hora de valorar exploraciones en pacientes con dolencias que afectan la estructura o la función coclear (AU)

Introduction and objectives: Extra-tympanic electrocochleography is an electrophysiological register obtained after stimulating the cochlea with an audible stimulus. This stimulus is applied using an earphone over the external auditory canal, while the electrical activity is registered by surface electrodes. There are few studies that analyse normal electrocochleography in our environment. Thus, the main objective of our study was to regularize the values obtained with electrocochleography in ears without any otoneurological diseases. We explain in detail the process of obtaining the register. Methods: Sixty healthy ears were studied by extratympanic electrocochleography. Statistical results were analysed. While 30 ears were studied with a stimulus at 90dB, another 30 ears were studied with a stimulus at 80dB. Results: Summating potential and action potential latencies and amplitudes were measured. Summating potential/action potential ratios were calculated. Wave I and wave II latencies were also determined. These results were analysed in function of stimulus intensity, patient gender, patient age group and ear side studied. Conclusions: This study collected extra-tympanic electrocochleography data in a normal population and the results were in the range of other international studies obtained in other countries. These data can be used as a reference to evaluate illnesses that affect cochlear structure or functions (AU)

Cochlear fistula in a noncholesteatomatous ear.

Bony destruction of the labyrinth is usually associated with long-standing cholesteatomatous otitis media. The promontory is not a common site for bone resorption because (1) it is not an area that is involved in accumulation of cholesteatoma perimatrix substances, (2) it is the densest bone of the human body, and (3) pressure necrosis from overlying tissue is uncommon. We report a case of cochlear erosion associated with noncholesteatomatous middle ear disease. As far as we know, this is only the second such case reported in the literature. We also review decision-making factors and techniques for the safe management of this condition.

Atoh1 induces auditory hair cell recovery in mice after ototoxic injury.

OBJECTIVES/HYPOTHESIS: To evaluate the ability of the Ad28.gfap.atoh1 to promote hair cell regeneration and hearing recovery in cochlea injured with kanamycin and furosemide. STUDY DESIGN: In vivo model of hair cell ablation and subsequent treatment with Atoh1. METHODS: The hair cells of C57BL/6 mice were ablated with systemic administration of kanamycin and furosemide. The left ears were treated with Ad28.gfap.atoh1. The right ears were not treated. Preablation audiograms and distortion product otoacoustic emissions (DPOAEs) were compared to 1- or 2-month postablation studies. Harvested cochleae were examined for histologic evidence of hair cell regeneration and spiral ganglion cell survival. RESULTS: Delivery of Ad28.gfap.atoh1 results in development of auditory hair cells. There was no recovery of DPOAEs at 1 or 2 months post-treatment. Two months after delivery of Ad28.gfap.atoh1, the left ear exhibited a moderate recovery of hearing at 4 and 8 kHz (P < .01). There was no significant difference at 16 or 32 kHz. One month after treatment, myosin VII-positive immunohistochemical staining can be seen in both the inner and outer hair cells of the treated ear. In the untreated ear, minimal myosin VII-positive debris is seen, with no indication of normal hair cells. Two months after ablation, there is evidence of hair cell recovery on the treated side, whereas the untreated cochlea demonstrates a flattened epithelium. Untreated ears showed decreased spiral ganglion cell density at the basal turn compared to treated ears. CONCLUSIONS: Ad28.gfap.atoh1 promotes hair cell regeneration in cochlea ablated with kanamycin and furosemide resulting in moderate hearing recovery.

Cochlear gene therapy.

PURPOSE OF REVIEW: This review highlights recent advances in cochlear gene therapy over the past several years. Cochlear gene therapy has undergone tremendous advances over the past decade. Beginning with some groundbreaking work in 2005 documenting hair cell regeneration using virally mediated delivery of the mouse atonal 1 gene, gene therapy is now being explored as a possible treatment for a variety of causes of hearing loss. RECENT FINDINGS: Recent advances in cochlear gene therapy include improved methods of gene delivery with a better delineation of viral vectors that are suitable for this purpose, additional improvements in hair cell regeneration, and directed research toward autoimmune hearing loss, ototoxicity, spiral ganglion survival, and genetic forms of hearing loss. SUMMARY: If successful, cochlear gene therapy will dramatically alter our ability to treat a variety of forms of acquired and genetic hearing loss.

Vestibular migraine: perspectives of otology versus neurology.

OBJECTIVE: To compare the attitudes and opinions of otologists and neurologists regarding the cause, diagnosis, and management of vestibular migraine. STUDY DESIGN: Survey questionnaire. METHODS: An 18-question survey designed to elicit opinions about the cause, diagnosis, pathophysiology, and management of migraine and dizziness was mailed to the entire memberships of the American Neurotology Society (ANS) and the International Headache Society (IHS). Survey participant responses were recorded for physician practice characteristics and for opinions on various clinical features of vestibular migraine. RESULTS: Of the 917 surveys mailed, 146 were completed by ANS members and 110 by IHS members. The frequency of respondents listing symptom origin as central to a diagnosis of migraine was 43% for ANS members versus 62% of IHS members. Only 31% of ANS respondents thought that a sensory trigger was a major etiologic factor. Of the IHS respondents, 60% thought a triggering event was mediated by the Vth nerve and 28% by the VIIIth nerve. Opinions varied on the character of dizziness and cochlear symptoms associated with migraine. Compared with 26% of IHS members, 55% of ANS members were more likely to view hearing loss as a migraine symptom. IHS members expressed a greater tendency to use triptans and anticonvulsants when compared with ANS members. CONCLUSION: The results suggested that ANS and IHS members have different perspectives on the clinical presentation, pathophysiology, and management of vestibular migraine. These differences can result in patient confusion and inadvertently have an adverse effect on patient care, thereby potentially affecting patient outcomes.

Oxidative stress in the cochlea: an update.

This paper will focus on understanding the role and action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the molecular and biochemical pathways responsible for the regulation of the survival of hair cells and spiral ganglion neurons in the auditory portion of the inner ear. The pivotal role of ROS/RNS in ototoxicity makes them potentially valuable candidates for effective otoprotective strategies. In this review, we describe the major characteristics of ROS/RNS and the different oxidative processes observed during ototoxic cascades. At each step, we discuss their potential as therapeutic targets because an increasing number of compounds that modulate ROS/RNS processing or targets are being identified.

[Hirudotherapy in the treatment of peripheral cochleovestibular disorders of vascular origin].

Basic therapy of peripheral cochleovestibular disorders of vascular origin consists of the rational combination of medicamentous and non-medicamentous treatments that collectively ensure positive clinical results. The use of hirudotherapy for the management of peripheral cochleovestibular disorders resulted in the substantial decrease of ear noise and the maintenance of the tendency toward further improvement of cochlear and vestibular functions.

Preliminary results of auditory brainstem implantation in prelingually deaf children with inner ear malformations including severe stenosis of the cochlear aperture and aplasia of the cochlear nerve.

OBJECTIVE: The aim of our study is to present the results of 11 children where auditory brainstem implantation (ABI) was successfully performed to restore hearing. STUDY DESIGN: Case presentation. This study was conducted at the departments of Otolaryngology and Neurosurgery at Hacettepe University Ankara, Turkey. PATIENTS: Between July 2006 and April 2008, 11 prelingual (30-56 mo) deaf children with several cochlear malformations had ABI. INTERVENTION: All patients were programmed and were enrolled in auditory verbal therapy sessions and family counseling programs at Hacettepe Auditory Verbal Center. The evaluation was performed at preimplant and again 1, 3, 6, 9, and 12 months post-switch on. MAIN OUTCOME MEASURES: The main test components composing this test battery were Ling 6 Sound Detection-Identification Test, Word Identification Test in Turkish, Meaningful Auditory Integration Scale, and Meaningful Use of Speech Scale. RESULTS: Successful brainstem implantations were performed in all patients with retrosigmoid approach. Six children gained basic audiologic functions and were able to recognize and discriminate sounds, and many could identify environmental sounds such as a doorbell and telephone ring by the third month of ABI. Improvement in mean performance on Meaningful Auditory Integration Scale is apparent for all ABI children. Improvement in Meaningful Use of Speech Scale scores in 2 patients, demonstrating that the child using its own voice for speech performance, was observed between the baseline and 12th month. First, 5 children were able to identify Ling's 6 sound by the end of 2 to 6 months, and 2 of them also started to identify words due to their pattern differences and multisyllabic word identification by 6 to 9 months. Two children with Attention Deficit Hyperactivity Disorder have made slower progress than the other children with ABIs. CONCLUSION: Our preliminary results show that there is adequate contribution of brainstem implants in the development of auditory-verbal skills. Additional handicaps slow the progress of the prelingually deaf children.

Cellular targeting for cochlear gene therapy.

Gene therapy has considerable potential for the treatment of disorders of the inner ear. Many forms of inherited hearing loss have now been linked to specific locations in the genome, and for many of these the genes and specific mutations involved have been identified. This information provides the basis for therapy based on genetic approaches. However, a major obstacle to gene therapy is the targeting of therapy to the cells and the times that are required. The inner ear is a very complex organ, involving dozens of cell types that must function in a coordinated manner to result in the formation of the ear, and in hearing. Mutations that result in hearing loss can affect virtually any of these cells. Moreover, the genes involved are active during particular times, some for only brief periods of time. In order to be effective, gene therapy must be delivered to the appropriate cells, and at the appropriate times. In many cases, it must also be restricted to these cells and times. This requires methods with which to target gene therapy in space and time. Cell-specific gene promoters offer the opportunity to direct gene therapy to a desired cell type. Moreover, conditional promoters allow gene expression to be turned off and on at desired times. Theoretically, these technologies offer a mechanism by which to deliver gene therapy to any cell, at any given time. This chapter will examine the potential for such targeting to deliver gene therapy to the inner ear in a precisely controlled manner.

Transmeatal low-level laser therapy for chronic tinnitus with cochlear dysfunction.

OBJECTIVES: To establish the efficacy of low-level laser therapy for tinnitus. METHODS: We performed a prospective, randomized double-blind study on 60 outpatients with tinnitus presenting sensorineural hearing loss in the affected ear. They were randomly divided into two groups, the first performing active laser therapy 20 min a day for 3 months with a 650-nm, 5-mW soft laser (group L), the second using a dummy device which duplicated all aspects of active laser therapy except for the activation of the laser beam (group C). One subject in both groups dropped out due to an increase in tinnitus loudness. Two more patients in each group ceased to comply with the protocol due to familiar problems. RESULTS: The Tinnitus Handicap Inventory (THI) was considered the main outcome measure; no statistical difference was detected between the 2 groups in the THI total score (p = 0.97), and its functional (p = 0.89), emotional (p = 0.89) and catastrophic (p = 0.89) subscales. Moreover, a visual analog scale for self-perceived loudness of the tinnitus showed no difference between the groups (p = 0.69). Regarding psychoacoustic parameters, the minimum masking level showed no difference (p = 0.42), while loudness expressed in sensation level exhibited lower values in group L (p = 0.0127). Group L subjects also presented a decreased rate of hyperacusis (p = 0.02). No changes were detected in the audiometric threshold in both groups. CONCLUSIONS: Soft laser therapy demonstrated no efficacy as a therapeutic measure for tinnitus.

Gene transfer into guinea pig cochlea using adeno-associated virus vectors.

BACKGROUND: Several genes are candidates for treating inner ear diseases. For clinical applications, minimally invasive approaches to the inner ear are desirable along with minimal side-effects. METHODS: Adeno-associated virus (AAV) was used as a vector into the guinea pig inner ear. Six AAV-cytomegalovirus hybrids (AAV-2/1, -2/2, -2/5, -2/7, -2/8 and -2/9) were infused into perilymph of the cochlea basal turn, an approach that could be used in cochlear implant surgery. At 7 days after injection, distribution of gene expression, hearing and morphology were evaluated. Adenoviral vector was also used to compare distributions of gene expression. Moreover, distribution of cell surface receptors of AAV in the cochlea was examined using immunohistochemistry. RESULTS: Using the perilymphatic approach, adenovirus could be transferred to mesothelial cells lining the perilymph, but not sensory cells. Conversely, all AAV serotypes displayed tissue tropism to inner hair cells, with AAV-2/2 showing particularly efficient transfer to sensory cells. This tissue tropism of AAV could not be explained by the distribution of AAV receptors. Hearing and morphology were largely unaffected. CONCLUSIONS: Our results indicate that AAV vector can be safely applied to the inner ear and AAV-2/2 offers a good tool for transferring transgenes into sensory cells of the inner ear efficiently without toxicity.

Applications of the marchbanks transcranial-cerebral sonography technique in neurootology: preliminary report.

Transcranial-cerebral sonography (TCCS) is a noninvasive technique that allows clinicians to detect nanoliter (billionths of a liter) displacements of the tympanic membrane. This technique was developed to assess cerebrospinal fluid (CSF) pressure in cases of shunted hydrocephalus; it takes advantage of the CSF connection to the inner ear through the cochlear aqueduct. The movements of the tympanic membrane that are observed in TCCS are those evoked by the acoustic stapedius reflex and those spontaneous movements generated by intracranial arterial, venous, and respiratory pulses transmitted through the inner ear to the stapes and thence to the tympanic membrane. Analysis of the amplitude and direction of these displacements has enabled neurosurgeons and neurologists to estimate CSF pressures accurately in patients evaluated by TCCS. TCCS allows for applications in neurootology, particularly in those patients who present with symptoms of pulsating tinnitus, dizziness and imbalance, or hearing loss. This preliminary report describes the test and its application in a series of patients whose diagnoses included pulsating tinnitus, idiopathic intracranial hypertension, Ménière's disease, perilymphatic fistula, perilymphatic hypertension, arterial stenosis, and Arnold-Chiari syndrome. We conclude that TCCS is a valuable addition to the armamentarium of neurootologists.

Hematopoietic stem cells prevent hair cell death after transient cochlear ischemia through paracrine effects.

Transplantation of hematopoietic stem cells (HSCs) is regarded to be a potential approach for promoting repair of damaged organs. Here, we investigated the influence of hematopoietic stem cells on progressive hair cell degeneration after transient cochlear ischemia in gerbils. Transient cochlear ischemia was produced by extracranial occlusion of the bilateral vertebral arteries just before their entry into the transverse foramen of the cervical vertebra. Intrascalar injection of HSCs prevented ischemia-induced hair cell degeneration and ameliorated hearing impairment. We also showed that the protein level of glial cell line-derived neurotrophic factor (GDNF) in the organ of Corti was upregulated after cochlear ischemia and that treatment with HSCs augmented this ischemia-induced upregulation of GDNF. A tracking study revealed that HSCs injected into the cochlea were retained in the perilymphatic space of the cochlea, although they neither transdifferentiated into cochlear cell types nor fused with the injured hair cells after ischemia, suggesting that HSCs had therapeutic potential possibly through paracrine effects. Thus, we propose HSCs as a potential new therapeutic strategy for hearing loss.

Células madre en el tratamiento de la sordera / Stem cells for the treatment of hearing loss

Uno de los mayores retos en el tratamiento de las enfermedades del oído interno es conseguir un tratamiento para la sordera causada por pérdida de células ciliadas cocleares o de neuronas del ganglio espiral. El reciente descubrimiento de células madre (CM) en el oído interno adulto que son capaces de diferenciarse en células ciliadas, así como el hallazgo que las células madre embrionarias pueden convertirse en células ciliadas, han levantado esperanzas para el desarrollo futuro de tratamientos basados en células madre

One of the greatest challenges in the treatment of inner ear disorders is to find a cure for the hearing loss caused by the loss of cochlear hair cells or spiral ganglion neurons. The recent discovery of stem cells in the adult inner ear that are capable of differentiating into hair cells, as well as the finding that embryonic stem cells can be converted into hair cells, raise hope for the future development of stem-cell-based treatments

Changes in programming over time in postmeningitis cochlear implant users.

OBJECTIVE: Although successful cochlear implantation of patients with deafness following meningitis is expected, long-term stability of electrical current requirements has not been systematically evaluated. This study evaluated changes in programming for patients deafened by bacterial meningitis and stability of auditory performance over time. STUDY DESIGN AND SETTING: In this retrospective descriptive study, cochlear implant (CI) stimulation mode and performance of 14 patients deafened by meningitis were compared with those of an age-matched control group of patients deafened by other causes. RESULTS: There were no significant differences in mean performance between the meningitis group and control group (P > 0.05). However, the postmeningitis group required progressively higher stimulation levels and higher programming modes over time as compared to the control group. CONCLUSIONS: Even with deafness accompanied by labyrinthine ossification attributed to meningitis, neural elements were present and could be stimulated. Because increasing levels of stimulation were required over time, postmeningitic children with CIs, and those with cochlear ossification in particular, may need frequent programming adjustments to maintain performance. SIGNIFICANCE: These patients need close follow-up of stimulation levels and programming modes postoperatively in order to perform optimally with CIs. EBM RATING: B-3.