Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice.

Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17ß-estradiol (E2), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)- and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL.

Lateral Modified Brandt-Daroff Exercises: A Novel Home Treatment Technique for Horizontal Canal BPPV.

OBJECTIVES: Brandt-Daroff exercises (BDEs) are commonly used as an at-home treatment for posterior canalithiasis, but their efficacy in the treatment of benign paroxysmal positional vertigo (BPPV) of the horizontal canal (HC-BPPV) has not been previously studied. Using biomechanical model simulation, we investigated modifications that may optimize BDE use for HC-BPPV treatment. MATERIALS AND METHODS: The BPPV Viewer, a three-dimensional model of the human labyrinth, was used to analyze BDE for HC-BPPV treatment. While moving the model through sequential BDE positions, the expected position of otoliths was demonstrated. Treatment steps were adjusted to maximize otolith movement around the canal circumference without compromising otolith repositioning into the semicircular duct's anterior arm. All adjustments were integrated into lateral modified BDEs (LMBDEs) presented here. RESULTS: By implementing several modifications, BDE can effectively treat HC-BPPV. Model simulation indicates tilting the head 20° upward in the lateral position, instead of 45° specified by the original technique, which significantly increases displacement of otoliths originating from the horizontal duct's anterior and intermediate segments. LMBDE can be performed as a direct two-step sequence without pausing in the upright position before switching sides. If the affected ear is known, positioning the head 45° below horizontal on the unaffected side as a third treatment step can promote actual canal evacuation. These treatment enhancements increase circumferential otolith movement around the canal and may promote horizontal canal evacuation. CONCLUSION: LMBDEs are a modification of BDE that may increase their effectiveness for use in patients with HC-BPPV. This safe treatment adjunct between office visits may promote long-term symptom reduction.

Short CRP for Anterior Canalithiasis: A New Maneuver Based on Simulation With a Biomechanical Model.

Introduction/Objective: Anterior canalithiasis is an uncommon and challenging diagnosis. This is due in part to the difficulty of defining the affected side, the extreme positioning required to carry out described therapeutic maneuvers, and the infrequent use of specific maneuvers. Our objective is to present a new treatment alternative for anterior canalithiasis which is based on the well-known canalith repositioning procedure (CRP) described by Epley and which is used routinely in the treatment of both posterior and anterior canalithiasis. Analysis of the standard CRP for anterior canalithiasis with a biomechanical model validates that this new maneuver is an enhanced treatment option for anterior canalithiasis. We call the new maneuver the "short CRP." Methods: A previously published 3D biomechanical model of the human labyrinths for the study of BPPV was used to analyze the conventional CRP in the treatment of anterior canalithiasis. The expected position of free otoliths near the anterior ampulla of the anterior semicircular duct was followed while recreating the sequential positions of the CRP. Although the standard CRP was possibly effective, certain enhancements were evident that could increase successful repositioning. These enhancements were incorporated into the modification of the CRP presented here as the "short CRP" for anterior canalithiasis. Results: The traditional CRP used for posterior canalithiasis can also be used for anterior canalithiasis. Although in the traditional CRP the head hangs 30° below horizontal, our simulation shows that a 40° head-hang below horizontal is an enhancement and may ensure progression of anterior otolith debris. Elimination of Position 4 of the classic CRP, in which the face is turned 45° toward the floor, was also seen as an enhancement as this position is predicted to cause retrograde movement of otoliths back into the anterior canal if the patient tucks the chin in position 4 or when sitting up. Conclusion: A modification of the CRP called the "short CRP" can be used to treat anterior canalithiasis. Model analysis predicts possible increased efficacy over the standard CRP. Model analysis of existing BPPV treatments is a valuable exercise for examination and can lead to realistic enhancements in patient care.

The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice.

BACKGROUND: Noise-induced hearing loss (NIHL) is the most prevalent form of acquired hearing loss and affects about 40 million US adults. Among the suggested therapeutics tested in rodents, suberoylanilide hydroxamic acid (SAHA) has been shown to be otoprotective from NIHL; however, these results were limited to male mice. METHODS: Here we tested the effect of SAHA on the hearing of 10-week-old B6CBAF1/J mice of both sexes, which were exposed to 2 h of octave-band noise (101 dB SPL centered at 11.3 kHz). Hearing was assessed by measuring auditory brainstem responses (ABR) at 8, 16, 24, and 32 kHz, 1 week before, as well as at 24 h and 15-21 days following exposure (baseline, compound threshold shift (CTS) and permanent threshold shift (PTS), respectively), followed by histologic analyses. RESULTS: We found significant differences in the CTS and PTS of the control (vehicle injected) mice to noise, where females had a significantly smaller CTS at 16 and 24 kHz (p < 0.0001) and PTS at 16, 24, and 32 kHz (16 and 24 kHz p < 0.001, 32 kHz p < 0.01). This sexual dimorphic effect could not be explained by a differential loss of sensory cells or synapses but was reflected in the amplitude and amplitude progression of wave I of the ABR, which correlates with outer hair cell (OHC) function. Finally, the frequency of the protective effect of SAHA differed significantly between males (PTS, 24 kHz, p = 0.002) and females (PTS, 16 kHz, p = 0.003), and the magnitude of the protection was smaller in females than in males. Importantly, the magnitude of the protection by SAHA was smaller than the effect of sex as a biological factor in the vehicle-injected mice. CONCLUSIONS: These results indicate that female mice are significantly protected from NIHL in comparison to males and that therapeutics for NIHL may have a different effect in males and females. The data highlight the importance of analyzing NIHL experiments from males and females, separately. Finally, these data also raise the possibility of effectors in the estrogen signaling pathway as novel therapeutics for NIHL.

Upfront boost Gamma Knife "leading-edge" radiosurgery to FLAIR MRI-defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy.

OBJECTIVE Glioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery [LERS]) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes. METHODS Between December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed. The LE was defined as a region outside the contrast-enhancing tumor nidus, defined by FLAIR MRI. The median age of patients was 59 years (range 22-87 years). Patients underwent LERS a median of 18 days from original diagnosis. The median target volume of 48.5 cm3 (range 2.5-220.0 cm3) of LE tissue was targeted using a median dose of 8 Gy (range 6-14 Gy) at the 50% isodose line. RESULTS The median overall survival was 23 months (mean 43 months) from diagnosis. The 2-, 3-, 5-, 7-, and 10-year actual overall survival rates after LERS were 39%, 26%, 16%, 10%, and 4%, respectively. Nine percent of patients developed treatment-related imaging-documented changes due to LERS. Nineteen percent of patients were hospitalized for management of edema, 22% for resection of a tumor cyst or new tumor bulk, and 2% for shunting to treat hydrocephalus throughout the course of their disease. Of the patients still alive, Karnofsky Performance Scale scores remained stable in 90% of patients and decreased by 1-3 grades in 10% due to symptomatic treatment-related imaging changes. CONCLUSIONS LERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM.