Vestibular dysfunction in patients with sporadic vestibular schwannomas and NF2-related schwannomatosis. - Vestibular schwannomas (VS), benign tumors that develop from Schwann cells of the vestibular nerve, are usually sporadic (sVS) but are also highly characteristic of neurofibromatosis type 2-related schwannomatosis (NF2), where they typically are bilateral (NF2/VS). VS tumors present with progressive vestibular symptoms, but the pathophysiology underlying vestibular dysfunction in VS patients remains uncertain, and the relationship between pre-intervention vestibular metrics with post-intervention (e.g., surgery, chemotherapy, radiation therapy) outcomes is not understood. We propose an observational study that examines vestibular pathophysiology in sVS and NF2/VS patients and the vestibular implications of standard interventions by analyzing vestibular function within a conceptual framework based on understanding the changes in afferent vestibular signal and noise. Signal (afferent firing encoding vestibular parameters) is reflected behaviorally by response accuracy (response amplitude relative to the ideal amplitude), while noise (random afferent firing), quantified as the signal-to-noise ratio, is reflected by response precision (inverse of response variability). We will also examine the relationship between vestibular dysfunction, clinical vestibular disability, and non- vestibular (molecular biologic, MRI/anatomic) parameters. Using this approach, we will analyze the following aims and sub-aims. SA 1 examines vestibular pathophysiology by measuring (SA 1A) dysfunction of vestibular-mediated behaviors. We hypothesize that response accuracy and precision will be degraded in sVS but only response precision will be degraded in NF2/VS. SA 1B relates vestibular dysfunction to clinical vestibular disability (e.g., dizziness, ataxia, quality of life) and we hypothesize that in both sVS and NF2/VS, vestibular imprecision will be the main correlate of clinical disability. SA 1C examines the relationship between vestibular dysfunction and non-vestibular (serum and tumor tissue molecular biologic, MRI/anatomic) parameters, and we hypothesize that molecular biologic measures will relate to vestibular function in both VS groups in a manner that recapitulates auditory-molecular biologic relationships, and that relationships between MRI and vestibular function will show both disease-specific patterns in sVS and NF2/VS. SA 2 examines the relationship between pre-intervention vestibular (and other) metrics and post-intervention outcomes, after patients undergo intervention proscribed by their treating physicians. SA 2A examines surgical outcomes, and we hypothesize that poor precision (e.g., high afferent noise) pre-operatively will associated with the best surgical outcomes. SA 2B examines radiation therapy (RT) outcomes. RT can damage or kill axons and myelin, so we hypothesize that good pre-RT precision (low noise) will be associated with worse chronic post- RT vestibular outcomes. SA 2C examines chemotherapy (bevacizumab) outcomes and we hypothesize that worse vestibular precision will be associated with better vestibular outcomes after chemotherapy.
