Longitudinal Results With Intratympanic Dexamethasone in the Treatment of Ménière’s Disease

To assess patient satisfaction with vertigo control using intratympanic (IT) dexamethasone (12 mg/mL) for medically refractory unilateral Meniere's disease. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral neurotology clinic. PATIENTS: One hundred twenty-nine subjects diagnosed with unilateral Meniere's disease still having vertigo despite medical therapy. INTERVENTION: IT dexamethasone injections as needed to control vertigo attacks. MAIN OUTCOME MEASURE: A Kaplan-Meier time-to-event method was used to determine the rate of "survival," meaning sufficient satisfaction with vertigo control that the subject did not wish to have subsequent ablative treatment. "Failure" was defined as poor control and the choice to proceed to ablative treatment. RESULTS: Acceptable vertigo control ("survival") was achieved in 117 (91%) of 129 subjects. Vertigo control required only one dexamethasone injection in 48 (37%), 2 injections in 26 (20%), 3 injections in 18 (14%), and 4 injections in 10 (8%). More than 4 injections were needed in 15 subjects (21%). Of 12 failures (9%), 9 occurred within 6 months of the first IT dexamethasone injection. Follow-up data for 2 years were available for 96 subjects. Of these, 87 (91%) had vertigo control with IT dexamethasone, of whom 61 (70)% required no further injections after 2 years, 23 (26%) continued to receive IT dexamethasone injections, and 3 (3%) chose IT gentamicin treatment. CONCLUSION: IT dexamethasone injection therapy on an as-needed outpatient basis can provide vertigo control that is satisfactory in patients with Meniere's disease. The Kaplan-Meier method addresses the need for an outcome measure suited to repeated treatments and variable lengths of follow-up. However, due to the retrospective nature of this study, the presence of bias caused by loss of subjects from follow-up cannot be ruled out

Retinoic acid degradation shapes zonal development of vestibular organs and sensitivity to transient linear accelerations

Each vestibular sensory epithelium in the inner ear is divided morphologically and physio- logically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)- mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions

Preventing episodic migraine with caloric vestibular stimulation: a randomized controlled trial

Objective: To evaluate the safety and efficacy of a novel solid-state, caloric vestibular stimulation (CVS) device to provide adjuvant therapy for the prevention of episodic migraine in adult migraineurs. Background: Migraine causes significant disability in ~12% of the world population. No current migraine preventive treatment provides full clinical relief, and many exhibit high rates of discontinuation due to adverse events. Thus, new therapeutic options are needed. CVS may be an effective and safe adjuvant-therapy for the prevention of episodic migraine. Methods: In a multicenter, parallel-arm, block-randomized, placebo-controlled clinical trial (clinicaltrials.gov: NCT01899040), subjects completed a 3-month treatment with the TNMTM device for CVS (refer to Figure 2 for patient enrollment and allocation). The primary endpoint was the change in monthly migraine days from baseline to the third treatment month. Secondary endpoints were 50% responder rates, change in prescription analgesic usage and difference in total subjective headache-related pain scores. Device safety assessments included evaluation of any impact on mood, cognition or balance. Results: Per-protocol, active-arm subjects showed immediate and steady declines in migraine frequency over the treatment period. After three months of treatment, active-arm subjects exhibited significantly fewer migraine days (-3.8 ± 0.5 from a baseline burden of 7.7 ± 0.5 migraine days). These improvements were significantly greater than those observed in control subjects (-1.1 ± 0.6 from a baseline burden = 6.9 ± 0.7 migraine days) and represented a therapeutic gain of -2.7 migraine days, CI = -0.9 to -4.7, p = 0.012. Active arm subjects also reported greater reductions in acute medication usage and monthly pain scores compared to controls. No adverse effects on mood, cognition or balance were reported. Subjects completed the trial with an average rate of 90% treatment adherence. No serious or unexpected adverse events were recorded. The rate of expected adverse events was similar across the active and the placebo groups, and evaluation confirmed that subject blinding remained intact. Conclusion: The TNM device for CVS appears to provide a clinically efficacious and highly tolerable adjuvant therapy for the prevention of episodic migraine

Effects of ocean acidification on the shells of four Mediterranean gastropod species near a CO 2 seep

Marine CO2seeps allow the study of the long-term effects of elevated pCO2(ocean acidification) on marine invertebrate biomineralization. We investigated the effects of ocean acidification on shell composition and structure in four ecologically important species of Mediterranean gastropods (two limpets, a top-shell snail, and a whelk). Individuals were sampled from three sites near a volcanic CO2seep off Vulcano Island, Italy. The three sites represented ambient (8.15 pH), moderate (8.03 pH) and low (7.73 pH) seawater mean pH. Shell mineralogy, microstructure, and mechanical strength were examined in all four species. We found that the calcite/aragonite ratio could vary and increased significantly with reduced pH in shells of one of the two limpet species. Moreover, each of the four gastropods displayed reductions in either inner shell toughness or elasticity at the Low pH site. These results suggest that near-future ocean acidification could alter shell biomineralization and structure in these common gastropods

Rhesus Cochlear and Vestibular Functions Are Preserved After Inner Ear Injection of Saline Volume Sufficient for Gene Therapy Delivery

Sensorineural losses of hearing and vestibular sensation due to hair cell dysfunction are among the most common disabilities. Recent preclinical research demonstrates that treatment of the inner ear with a variety of compounds, including gene therapy agents, may elicit regeneration and/or repair of hair cells in animals exposed to ototoxic medications or other insults to the inner ear. Delivery of gene therapy may also offer a means for treatment of hereditary hearing loss. However, injection of a fluid volume sufficient to deliver an adequate dose of a pharmacologic agent could, in theory, cause inner ear trauma that compromises functional outcome. The primary goal of the present study was to assess that risk in rhesus monkeys, which closely approximates humans with regard to middle and inner ear anatomy. Secondary goals were to identify the best delivery route into the primate ear from among two common surgical approaches (i.e., via an oval window stapedotomy and via the round window) and to determine the relative volumes of rhesus, rodent, and human labyrinths for extrapolation of results to other species. We measured hearing and vestibular functions before and 2, 4, and 8 weeks after unilateral injection of phosphate-buffered saline vehicle (PBSV) into the perilymphatic space of normal rhesus monkeys at volumes sufficient to deliver an atoh1 gene therapy vector. To isolate effects of injection, PBSV without vector was used. Assays included behavioral observation, auditory brainstem responses, distortion product otoacoustic emissions, and scleral coil measurement of vestibulo-ocular reflexes during whole-body rotation in darkness. Three groups (N = 3 each) were studied. Group A received a 10 μL transmastoid/trans-stapes injection via a laser stapedotomy. Group B received a 10 μL transmastoid/trans-round window injection. Group C received a 30 μL transmastoid/trans-round window injection. We also measured inner ear fluid space volume via 3D reconstruction of computed tomography (CT) images of adult C57BL6 mouse, rat, rhesus macaque, and human temporal bones (N = 3 each). Injection was well tolerated by all animals, with eight of nine exhibiting no signs of disequilibrium and one animal exhibiting transient disequilibrium that resolved spontaneously by 24 h after surgery. Physiologic results at the final, 8-week post-injection measurement showed that injection was well tolerated. Compared to its pretreatment values, no treated ear’s ABR threshold had worsened by more than 5 dB at any stimulus frequency; distortion product otoacoustic emissions remained detectable above the noise floor for every treated ear (mean, SD and maximum deviation from baseline: −1.3, 9.0, and −18 dB, respectively); and no animal exhibited a reduction of more than 3 % in vestibulo-ocular reflex gain during high-acceleration, whole-body, passive yaw rotations in darkness toward the treated side. All control ears and all operated ears with definite histologic evidence of injection through the intended site showed similar findings, with intact hair cells in all five inner ear sensory epithelia and intact auditory/vestibular neurons. The relative volumes of mouse, rat, rhesus, and human inner ears as measured by CT were (mean ± SD) 2.5 ± 0.1, 5.5 ± 0.4, 59.4 ± 4.7 and 191.1 ± 4.7 μL. These results indicate that injection of PBSV at volumes sufficient for gene therapy delivery can be accomplished without destruction of inner ear structures required for hearing and vestibular sensation