Fred F. Telischi

Objective: Safety and efficacy of pediatric auditory brainstem implants (ABI) are well established. Commonly reported complications include cerebrospinal fluid (CSF) leak and pseudomeningocele. Infection is rare but potentially serious due to intracranial location of the device. Data on pediatric ABI infections remain limited. We report a case of pediatric ABI infection and perform a scoping review of the literature. Databases reviewed: PubMed, Web of Science, Scopus, and the Cochrane Library. Methods: The patient’s medical record was reviewed for clinical course and outcomes. A scoping review was conducted to summarize findings of studies reporting pediatric ABI-related infections. Results: A 12-year-old female with NF2 -related schwannomatosis and bilateral vestibular schwannomas underwent urgent right tumor resection with ABI placement. She represented on postoperative day 13 with meningitis and collection surrounding the device. Surgical exploration revealed purulence involving the ABI pocket and paddle. Device preservation was achieved with washout, fat graft replacement, vancomycin powder application, and prolonged antibiotic therapy. For the scoping review, 961 studies were screened and 9 included, identifying 12 pediatric ABI infections. Five were managed with antibiotics alone, 3 required additional CSF diversion, and 4 necessitated surgical intervention. Conclusion: Pediatric ABI infections are uncommon but potentially life-threatening, necessitating prompt recognition and aggressive management. Our scoping review revealed that pediatric ABI infections have been managed with antibiotics with or without surgical intervention, and infection-related ABI explantation in pediatric patients has not been reported. In our case, device preservation was achieved with washout, fat graft replacement, and intravenous and intrathecal antibiotics.

Hypothesis: Electrical stimulation of the external ear mediates cardiovascular changes in anesthetized rats. Background: Auricular vagus nerve stimulation (aVNS) has been proposed as a noninvasive treatment for cardiovascular disease. Stimulation is typically achieved via electrodes placed on the external ear, but the exact mechanisms by which aVNS induces cardiovascular changes remains unclear. In particular, the relative contributions of sympathetic and parasympathetic pathways have not been well elucidated. In this study, we use a rodent model to determine the hemodynamic effects of stimulating two auricular regions and assess the autonomic pathways mediating these responses. Methods: Bipolar transcutaneous electrical stimulation was applied to the external ear of adult Sprague-Dawley rats. Cardiovascular parameters including mean arterial pressure (MAP), photoplethysmography (PPG), and cardiac electrical activity were recorded. Cervical vagotomies and hexamethonium sympathetic blockade were performed to assess the parasympathetic and sympathetic contributions to evoked cardiovascular responses. Results: Electrical stimulation at the concha resulted in significant changes in MAP and PPG. MAP changes were larger with stimulation in the concha compared with the anterior pinna. MAP responses increased in a dose-dependent manner with increasing current amplitude. Bilateral vagotomy resulted in persistent but decreased evoked cardiovascular responses. Complete autonomic blockade using intravenous hexamethonium resulted in the absence of any evoked cardiovascular responses with aVNS. Conclusion: Cardiovascular changes from aVNS are mediated by modulation of both parasympathetic and sympathetic activity.

Hypothesis: A novel adeno-associated virus (AAV) can be used to label the sensory nerves of the external ear in mice. Background: Stimulation of the auricular branch of the vagus nerve (ABVN) has been proposed as a noninvasive approach to vagus nerve stimulation. Here, we use a recently introduced AAV with enhanced tropism for peripheral sensory neurons (AAV-PHP.S) to label the somatosensory nerves of the external ear, including the ABVN. Methods: AAV-PHP.S capsids with a Cre-dependent fluorescent reporter cargo were injected retro-orbitally into 9 adult transgenic mice. Sensory ganglia for cranial nerves V, VII, IX, X, along with cervical dorsal root ganglia (DRG) and the external ear, were harvested. Immunohistochemistry was used to visualize expression of the reporter, tdTomato, in ganglion neurons and in sensory afferent nerve fibers in the external ear. Results: Eight of the 9 injected animals showed expression in all the relevant ganglia (CN V, VII, IX, X, and DRG). Expression was quantified in the jugular ganglion of the vagus nerve (which houses the cell bodies of the ABVN); 15.8%±1.3% of the neurons in this ganglion were successfully transduced with a fluorescent reporter (tdTomato). In 8 of the 9 animals, we also detected reporter expression in sensory nerve fibers in the external ear. We quantified the expression of the reporter in the external ear and found that the majority of nerve fiber area (66%±18%) strongly expressed tdTomato. Conclusion: AAV-PHP.S can be used to transduce the sensory nerves of the external ear in mice, including the ABVN.

Background/Objectives: NF2-related schwannomatosis (NF2-SWN) is a genetic tumor predisposition syndrome of the nervous system caused by pathogenic variants in NF2 encoding the merlin tumor suppressor. Truncating variants in NF2 cause severe phenotypes with higher tumor burden, early mortality, and a lifetime need for multiple surgeries due to lack of medications that control schwannoma growth. Methods: We developed a functional precision medicine (FPM)-inspired workflow to identify drug sensitivities in cells isolated from a pediatric severe NF2-SWN patient’s spinal and peripheral schwannomas. Transcriptomic profiling, high-content drug sensitivity assays, tissue and isolated cell immunostaining, flow cytometry, and capillary-based immunoblotting were used to study the available tissues. Results: Aberrant merlin-dependent pathway expression was conserved between the spinal schwannoma and its cultured primary cells. Drug sensitivity screens in 2- and 3-dimensional formats revealed cytotoxic effects of fimepinostat in primary cells; dasatinib with brigatinib was the most effective cytostatic combination. Ineffective therapies attempted in the patient were also ineffective ex vivo. Conclusions: These data support the idea of using the FPM workflow to improve and individualize the standard of care for severe NF2-SWN patients using surgical samples.

There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression.

Objective: The primary objective of this study is to review the evidence for aspirin use to prevent the growth of vestibular schwannomas (VS) and to propose a prospective trial to determine the progression‐free survival of VS patients after up to 42 months of treatment with aspirin. Secondary study objectives are to determine the effect of aspirin on VS growth, hearing function, serum biomarker levels, and the quality of life, as well as to determine the tolerability of aspirin treatment and whether serum biomarker and salicylate levels predict the response to aspirin.Study Design: Literature review.Setting: Six academic and private medical centers.Methods: Review of recent English literature regarding prophylactic aspirin use for VS.Results: The retrospective reviews on the utility of aspirin to prevent VS growth are inconclusive. Eighty‐four patients have been enrolled in a prospective double‐blinded, placebo‐controlled trial thus far to determine the effect of aspirin on VS.Conclusions: Completion of a robust study design is necessary. The current aspirin dose has been well tolerated, with minimal adverse events to date.Level of Evidence: Review of retrospective studies: Level 4; Proposed randomized, placebo‐controlled, double‐blinded clinical trial: Level 2.

Western Blot Raw Images and Quantification

Supplemental Table 2. Selectivity Score of Top Three Drug Combinations for Merlin-deficient Over Isogenic Normal Human Schwann Cells.

Supplemental Figure 1. HS01 western blots for dasatinib target and necroptosis markers.