Deep Phenotyping of Hearing Instability Disorders: Cohort Establishment, Biomarker Identification, Development of Novel Phenotyping Measures, and Discovery of Therapeutic Targets

Study Description: Disorders of hearing instability remain poorly characterized, phenotyped and ineffectively treated, and may result in sudden changes in hearing. These disorders include, but are not limited to, sudden sensorineural hearing loss (SSNHL) as well as hearing fluctuation, including, but not limited to, autoimmune inner ear disease (AIED), Meniere s disease (MD) and enlarged vestibular aqueduct syndrome (EVAS). While this group of disorders is likely to be clinically and etiologically heterogeneous, a common feature is fluctuation of hearing thresholds and speech understanding as measured by word recognition scores (WRS). This protocol seeks to ascertain a cohort of patients with hearing fluctuation to correlate these main phenotypic features with other phenomic data including audiometric indicators of endolymphatic hydrops as well as radiologic and immunologic biomarkers of inflammation over time. The overall hypothesis is that phenomic data will enable stratification of the phenotype of patients with hearing instability disorders. Healthy volunteers will be recruited to establish the normative range of endolymph and perilymph on contrast-enhanced delayed FLAIR MRI to allow for quantitative computational analysis of contrastenhanced delayed FLAIR MRI images. Objectives: Primary objective: To develop a cohort of patients with hearing instability (HI). Secondary objectives: 1. To correlate evidence of HI with changes in phase-shift distortion product otoacoustic emissions (DPOAEs). 2. To compare phase-shift DPOAEs to existing measures of auditory function including word recognition score (WRS), standard DPOAEs, and electrocochleography (ECochG) over time. 3. To compare phase-shift DPOAEs to vestibular measures including cervical and ocular vestibular evoked myogenic potentials (VEMPs) over time. 4. To correlate auditory and vestibular indicators of hearing instability and endolymphatic hydrops (EH) on MRI with quantitative differences in immunologic markers of inflammation over time. 5. Establish the normative range of endolymph and perilymph volume on contrast-enhanced delayed FLAIR MRI to allow for quantitative computational analysis of contrast-enhanced delayed FLAIR MRI images Exploratory objective: 1. To stratify patients with hearing instability (HI) by differences in cytokine levels, which will inform the identification of clinical subtypes of HI and potentially identify therapeutic targets for future treatment with targeted agents. 2. To perform transcriptional and immunoprofiling of PBMCs at time points associated with hearing fluctuation from phenotyped patient cohorts. Endpoints: Primary Endpoint: Identification of phenomic features associated with HI. Secondary Endpoint: (1) Identification of a variety of phenomic features of patients with HI that allow assignment to clinical subdivisions. Exploratory Endpoints 1. Identification of potential targets for therapeutics based on longitudinal immune/transcriptional profiling of patients with hearing instability. 2. Identification of subtype-specific immune cell distributions 3. Identification of immune profiles as well as immune cell transcriptional profiles related to hearing fluctuation