Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage.

Higher stages of central auditory processing compensate for a loss of cochlear nerve synapses by increasing the gain on remaining afferent inputs, thereby restoring firing rate codes for rudimentary sound features. The benefits of this compensatory plasticity are limited, as the recovery of precise temporal coding is comparatively modest. We reasoned that persistent temporal coding deficits could be ameliorated through modulation of voltage-gated potassium (Kv) channels that regulate temporal firing patterns. Here, we characterize AUT00063, a pharmacological compound that modulates Kv3.1, a high-threshold channel expressed in fast-spiking neurons throughout the central auditory pathway. Patch clamp recordings from auditory brainstem neurons and in silico modeling revealed that application of AUT00063 reduced action potential timing variability and improved temporal coding precision. Systemic injections of AUT00063 in vivo improved auditory synchronization and supported more accurate decoding of temporal sound features in the inferior colliculus and auditory cortex in adult mice with a near-complete loss of auditory nerve afferent synapses in the contralateral ear. These findings suggest modulating Kv3.1 in central neurons could be a promising therapeutic approach to mitigate temporal processing deficits that commonly accompany aging, tinnitus, ototoxic drug exposure or noise damage.

Paroxismia vestibular: reporte de un caso / Vestibular paroxysmia: case report

Presentamos el caso de un paciente joven quien presenta 4 a 5 crisis diarias de vértigo espontáneo de segundos de duración, todos o casi todos los días desde hace 9 meses. Estas crisis no tienen gatillo posicional, y hay completa ausencia de sintomatologia entre crisis. Como discutimos en el artículo, este cuadro coíncide con los recientemente publicados criterios para una paroxismia vestibular, entidad supuestamente secundaria a la compresión neurovascular del nervio vestibular. El paciente respondió de forma inmediata y completa a carbamazepina a dosis bajas, el tratamiento de elección en la paroxismia vestibular.

We present the case of a young patient, with a 9-month long history of 4 to 5 daily spells of spontaneous vertigo, each lasting only seconds. There is no positional trigger, and there is a complete lack of symptoms between attacks. As is discussed in the article, this matches the recently published criteria for Vestibular Paroxysmia, an entity allegedly secondary to neurovascular compression of the vestibular nerve. The patient responded immediately and completely to carbamazepine at low dosage, the preferred treatment for vestibular paroxysmia.

Antioxidants reduce neurodegeneration and accumulation of pathologic Tau proteins in the auditory system after blast exposure.

Cochlear neurodegeneration commonly accompanies hair cell loss resulting from aging, ototoxicity, or exposures to intense noise or blast overpressures. However, the precise pathophysiological mechanisms that drive this degenerative response have not been fully elucidated. Our laboratory previously demonstrated that non-transgenic rats exposed to blast overpressures exhibited marked somatic accumulation of neurotoxic variants of the microtubule-associated protein, Tau, in the hippocampus. In the present study, we extended these analyses to examine neurodegeneration and pathologic Tau accumulation in the auditory system in response to blast exposure and evaluated the potential therapeutic efficacy of antioxidants on short-circuiting this pathological process. Blast injury induced ribbon synapse loss and retrograde neurodegeneration in the cochlea in untreated animals. An accompanying perikaryal accumulation of neurofilament light chain and pathologic Tau oligomers were observed in neurons from both the peripheral and central auditory system, spanning from the spiral ganglion to the auditory cortex. Due to its coincident accumulation pattern and well-documented neurotoxicity, our results suggest that the accumulation of pathologic Tau oligomers may actively contribute to blast-induced cochlear neurodegeneration. Therapeutic intervention with a combinatorial regimen of 2,4-disulfonyl α-phenyl tertiary butyl nitrone (HPN-07) and N-acetylcysteine (NAC) significantly reduced both pathologic Tau accumulation and indications of ongoing neurodegeneration in the cochlea and the auditory cortex. These results demonstrate that a combination of HPN-07 and NAC administrated shortly after a blast exposure can serve as a potential therapeutic strategy for preserving auditory function among military personnel or civilians with blast-induced traumatic brain injuries.

Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas.

Neurofibromatosis type 2 (NF2) is a genetic disorder with bilateral vestibular schwannomas (VS) as the most frequent manifestation. Merlin, the NF2 tumor suppressor, was identified as a negative regulator of mammalian target of rapamycin complex 1. Pre-clinical data in mice showed that mTORC1 inhibition delayed growth of NF2-schwannomas. We conducted a prospective single-institution open-label phase II study to evaluate the effects of everolimus in ten NF2 patients with progressive VS. Drug activity was monitored every 3 months. Everolimus was administered orally for 12 months and, if the decrease in tumor volume was >20 % from baseline, treatment was continued for 12 additional months. Other patients stopped when completed 12 months of everolimus but were allowed to resume treatment when VS volume was >20 % during 1 year follow-up. Nine patients were evaluable. Safety was evaluated using CTCAE 3.0 criteria. After 12 months of everolimus, no reduction in volume ≥20 % was observed. Four patients had progressive disease, and five patients had stable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment. In these patients, tumor growth resumed within 3-6 months after treatment discontinuation. Everolimus was then reintroduced and VS decreased by a median 6.8 % at 24 months. Time to tumor progression increased threefold from 4.2 months before treatment to > 12 months. Hearing was stable under treatment. The safety of everolimus was manageable. Although the primary endpoint was not reached, further studies are required to confirm the potential for stabilization of everolimus.

Test battery of cranial nerves VII and VIII for assessing herpes zoster oticus.

OBJECTIVE: This study adopted a test battery of cranial nerves (CNs) VII and VIII comprising a facial nerve function test, audiometry, a caloric test, and ocular and cervical vestibular-evoked myogenic potential (oVEMP and cVEMP, respectively) tests to assess the function of CNs VII and VIII comprehensively so as to predict facial nerve recovery in patients with herpes zoster oticus (HZO). STUDY DESIGN: Case series with chart review. SETTING: University hospital. METHODS: A total of 20 patients with HZO underwent a test battery of CNs VII and VIII. Registering the unaffected nerve bundles in the internal auditory canal was based on the number of normal results in the test battery of CNs VII and VIII. Fair facial nerve recovery is defined as the improvement of facial paresis to facial nerve grades I to II/VI. RESULTS: In 20 patients with HZO, 6, 7, 3, and 4 patients had 0, 1, 2, and 3 unaffected nerve bundles, respectively. A significantly positive correlation was identified between the number of unaffected nerve bundles and fair facial nerve recovery. Similarly, a statistically significant predictor of fair facial nerve recovery was noted for unaffected nerve bundles (odds ratio, 15.42) but not for grading of the facial nerve (odds ratio, 0.49). CONCLUSION: Grading of the facial nerve alone fails to predict the outcome of facial paresis in patients with HZO mainly because it overlooks the involvement of CN VIII. Alternatively, a combined test battery of CNs VII and VIII may serve as a strong predictor for facial nerve recovery.

[Cochleovestibular disorders: approaches to diagnostics and treatment].

The aim of this work was to evaluate the efficacy of introduction of milgamma and milgamma compositum in the treatment of 52 patients with cochleovestibular disorders of different etiology. Thirteen patients enrolled in the study received standard therapy and 39 others were given its combination with milgamma preparations. Combined therapy with milgamma and milgamma compositum ensured faster vestibular compensation including posturographic characteristics than the standard treatment (within 3-4 weeks compared with 5 weeks in controls). The results of the study give reason to recommend milgamma and milgamma compositum as neurotropic medicines in addition to standard therapy for the management of the patients presenting with cochleovestibular disorders for the acceleration of the vestibular compensation.

Fluctuating corticosteroid-responsive auditory neuropathy/dyssynchrony is suggestive of central nervous system pathology.

OBJECTIVE: To highlight diagnostic and management features of auditory neuropathy/auditory dyssynchrony (AN/DS) due to central demyelinating disorder. PATIENTS: A child with AN/DS due to central nervous system pathologic findings. INTERVENTIONS: Audiometry, auditory brainstem response (ABR) test, otoacoustic emission test, magnetic resonance imaging (MRI) with gadolinium contrast, intravenous corticosteroid treatment, antiviral treatment, stereotactic biopsy, and cyclophosphamide immunomodulation. MAIN OUTCOME MEASURES: Pure-tone audiometry, speech discrimination testing, ABR, and MRI. RESULTS: A 12-year-old girl presented with acute sensorineural hearing loss, abnormal ABR, and normal otoacoustic emissions consistent with AN/DS. The hearing loss demonstrated fluctuation and corticosteroid responsiveness. Magnetic resonance imaging and stereotactic biopsy revealed brainstem demyelination consistent with multiple sclerosis. Definitive treatment consisted of cyclophosphamide immunomodulation. CONCLUSION: Although recent focus on pathophysiology of AN/DS has shifted from auditory nerve abnormalities to dyssynchrony within the cochlea, cases associated with fluctuating sensorineural hearing loss and responsiveness to corticosteroid therapy should raise the suspicion of central nervous system pathologic findings. Therefore, it is crucial to obtain brain MRI with contrast enhancement in all patients with AN/DS. This is critical in patients undergoing cochlear implantation because MRI may be contraindicated postoperatively.

[Cogan's syndrome revealed by haemorrhagic glairous diarrhoea]. / Syndrome de Cogan révélé par une diarrhée glairo-sanglante.

INTRODUCTION: Cogan's syndrome is defined by the combination of non syphilitic interstitial keratitis and inner ear dysfunction, similar to Meniere's disease. OBSERVATION: Cogan's syndrome was revealed by haemorrhagic glaireous diarrhoea in a 21 year-old woman whose medical history included Hirschsprung's disease. Cerebral MRI revealed viral-like bilateral neuritis of the eighth cranial nerve, never described in the literature before. The auditory and visual disorders regressed after treatment with corticosteroids. CONCLUSION: The early diagnosis of Cogan's syndrome permits the cure of the visual and auditory and notably inner ear symptoms with corticosteroid therapy.

Nimodipine ameliorates trauma-induced cochlear neuronal death.

Excessive entry of Ca2+ into injured cochlear neurons activates various Ca(2+)-activated enzymes and subsequent spiral ganglion cell death. Therefore, preventing intracellular calcium overload by using Ca2+ channel antagonists may become an important countermeasure to spiral ganglion cell death. We experimentally investigated whether an L-type Ca2+ channel blocker (nimodipine) can rescue traumatized cochlear neurons from degeneration. A group of rats (n = 6) was pre-operatively treated with nimodipine for one week and compression injury was applied to the cerebellopontine angle portion of the cochlear nerve in a highly quantitative fashion. The rats from the compression with nimodipine treatment groups were post-operatively treated with nimodipine for 10 days and killed for histological examination. The histological analysis of the temporal bones revealed that the spiral ganglion cells in the basal turn of the cochlea where the magnitude of traumatic impact had been the least in our experimental condition were rescued in a statistically significant fashion in the compression with nimodipine treatment group. The results of the present study indicate that nimodipine may become an intra- and post-operative important adjunct to raise the rate of hearing preservation in vestibular schwannoma excision or other cerebellopontine angle surgical interventions.

[Therapeutic trial with corticosteroid for auditory neuropathy].

OBJECTIVE: To explore the feasibility of corticosteroid for the treatment of auditory neuropathy. METHODS: Six patients with auditory neuropathy, diagnosed in the first affiliated hospital of Nanjing medical university between July 1998 and December 2001, were treated with corticosteroid therapy for one month (30-40 mg of prednisone daily for the first fifteen days, and 20 mg daily for following fifteen days). Prednisone was tapered gradually if a positive response to therapy was obtained. Hearing improvement was defined as 15 dB or more threshold drops in at least two of the standard audiometric frequencies in the same ear during the trial period. RESULTS: After one month's steroid treatment, significant hearing improvement was evident in two patients with raised speech discrimination scores from 48% to 95% and from 72% to 100%, respectively. In these two cases, prednisone was used continually up to 14 and 16 weeks, respectively, and the patients still had excellent pure tone hearing abilities and speech discriminations during follow-up of three years and four months, respectively. In other four patients, positive response for corticosteroid was not found within the period of one-month trail. CONCLUSION: Immunological damages of hearing system might play part role in the pathophysiological mechanisms of auditory neuropathy, and corticosteroids are potentially useful drugs for these cases.

Macrophage invasion into injured cochlear nerve and its modification by methylprednisolone.

Post-traumatic invasion of macrophages into the cochlear nerve of the rat and measurement of how their invasion was modified by the administration of methylprednisolone were investigated for the first time by using a reproducible and quantifiable experimental model of cochlear nerve injury. Two weeks after precise cochlear nerve compression, a massive invasion of ED1 immunostained macrophages was observed at the compressed portion of the cochlear nerve, and this invasion of macrophages was markedly reduced in the rats to which methylprednisolone had been administered during the pre- and post-compression period. Concomitantly, the residual number of spiral ganglion cells was found to be greater in the compression+methylprednisolone group than in the control compression group. The tissue loss observed in the lesion epicenter was also significantly less in the compression+methylprednisolone group than in the control compression group. The results of our present study demonstrated the effectiveness of methylprednisolone treatment to ameliorate trauma induced cochlear nerve degeneration in the acute phase. However, these results may reflect the sum effects of methylprednisolone on macrophages, including both its beneficial effect by inhibiting the negative aspects of macrophages through attenuating macrophage recruitment to the lesion site, and at the same time an undesirable effect by sacrificing the positive aspects of macrophage function. Moreover, one reservation should be added that the protective effects of steroid to injured cochlear nerve may have operated via a pathway not related to macrophage function. Besides macrophages, various cells and factors participate in the process of CNS injury, and their effects may potentially work either positively or negatively with respect to CNS protection and regeneration at each particular time during the on-going process of CNS injury. Therefore, future investigation in CNS injury should be directed toward understanding such complex mechanisms involved in this process.

Efficacy of intracochlear administration of betamethasone on peripheral vestibular disorder in the guinea pig.

We evaluated the effect of steroid hormone on vestibular function in a guinea pig of peripheral vestibular disorder. The right lateral semicircular canal was surgically damaged, and after surgery, animals were treated with 0.1 mg/ml of betamethasone in saline, 1 mg/ml of betamethasone in saline, or saline only, which was administrated directly into the scala tympani by osmotic pump. Rotation tests were performed, and the post-rotatory nystagmus (PRN) ratio (PRN number after counterclockwise rotation/PRN number after clockwise rotation) was calculated. The PRN ratio was recovered to normal at 5 days after treatment in the betamethasone administrated groups, but it did not recover to normal until 14 days after treatment in the saline administrated group. Results indicate that in the vestibular periphery steroid hormones may play an important role in recover of vestibular function.

Recovery of the vestibular function after vestibular neuronitis.

We performed steroid therapy on 34 cases with vestibular neuronitis and compared them with 77 patients not subjected to this therapy to examine the role of recovery of their vestibular function. Since no relation was noted between use of steroid and changes in subjective symptom of dizziness, the use of steroid is likely to facilitate the disappearance of spontaneous nystagmus in the early recovery stage. Canal paralysis recovered significantly by steroid and in cases of slight and moderate paralysis at the onset, recovery was more significant. Steroid therapy is argued to be effective for the recovery of vestibular function in cases of vestibular neuronitis.

Reversibilidade do envolvimento do VIII par craniano na sarcoidose / Reversibility of involvement of the VIII cranian in sarcoidosis

O espectro do envolvimento sistêmico da sarcoidose é bastante amplo, conferindo à doença um grande polimorfismo clínico. Dentro desta diversidade destacam-se algumas formas peculiares de apresentaçäo. Descreve-se uma forma neuro-ocular onde o acometimento do VIII par associa-se à lesäo de outros pares cranianos. Pöe-se em evidência o caráter reversível da disacusia neurossensorial, comparando-se a evoluçäo com casos da literatura