vestibular function in patients with usher syndrome

VESTIBULAR FUNCTION IN PATIENTS WITH USHER SYNDROME Joost Stultiens, Julianne Edwards, Guang Wei Zhou, Jacob Brodsky and Margaret Kenna Department of Otolaryngology and Communication Enhancement Boston  Children’s  Hospital,  Boston,  Massachusetts,  United  States  of  America

Background • Usher syndrome (USH) is a clinically heterogeneous condition characterized by sensorineural hearing loss (SNHL), progressive retinal degeneration, and vestibular dysfunction. • USH1 is commonly associated with absent vestibular function and USH3 can cause occasional vestibular dysfunction. Vestibular function in USH2 has been studied very little. • In 2005, Alagramam et al. detected functional deficits in the otolith organs within the vestibular system of mice using linear vestibular evoked potential testing, showing promise for further physiological examination of these inner ear structures and their connection to USH. • However, there has been minimal clinical research reported on vestibular function in children with genetically documented USH, even though the early and persistent balance dysfunction in these individuals adds considerably to their disability. • The heterogeneous nature of the USH genotypephenotype is increasingly apparent, suggesting that patients with any of the USH types may be at risk for vestibular dysfunction, not just those with USH type 1. • The presence of vestibular dysfunction in a child with SNHL, manifested by late walking or clumsiness, could suggest USH. • The goal of the present study is to characterize vestibular function in patients with Usher Syndrome.

Identified patients diagnosed with USH; confirmed by genetic testing

Diagram 1. Outline of Study Design

Symptomatic group

Asymptomatic group

Schedule for a clinical vestibular assessment Consent for inclusion of data in study

Offer enrollment via mailed recruitment letter Schedule for research appointment

Diagram 1. Outline of Study Design

Conduct vestibular testing on enrolled participants in Balance Lab

Compare vestibular test results to genetic, audiometric and ophthalmological information

Table 1. Vestibular Tests

Vestibular Test

Ages

Cervical Vestibular Evoked Myogenic Potential (VEMP) testing

All

Bayley Scales of Infant and Toddler Development Rotational Testing

1 month to 3.5 years 2 years and up

Visual-Vestibular Interaction Testing (VVI)

2 years and up

Methods • This is a prospective study of patients with 2 pathogenic Usher mutations (type 1, 2 or 3). • Patients were divided into a symptomatic and an asymptomatic group according to their vestibular symptoms and will be mailed a recruitment letter or offered enrollment in clinic (see Diagram 1 for Study Design) • The symptomatic group was defined as all patients with USH 1, 2 or 3, who have signs of vestibular dysfunction. • The asymptomatic group was defined as patients with USH1, 2 or 3 and no signs of vestibular dysfunction • Enrolled patients will undergo a series of vestibular testing depending on the patients’ age and level of cooperation (see Table 1). • Data on the patients’ genetic, audiometric and ophthalmologic results willl also be collected.

Initial Analysis

Diagram 1. Outline of Study Design

Videonystagmography (VNG) 2 years and up Electronystagmography (ENG) Testing

Computerized Dynamic Posturography (CDP) Testing

4 years and up

Video Head Impulse Testing (vHIT)

5 years and up

Subjective Visual Vertical (SVV) Testing

7 years and up

• Among patients with USH seen at BCH (n = 14), only two had previously had vestibular testing. • Many of our patients were described as late-walkers or clumsy. However, this information was only revealed after the diagnosis of USH was made, and had often been forgotten or underappreciated by the parents, therefore no formal evaluation of vestibular function was ever conducted. • Both patients who underwent vestibular testing had genetic testing prior to having their balanced tested. • These patients both walked late and had abnormal vestibular results. • Testing on these patients was done post cochlear implantation (CI) so it is difficult to determine the cause of vestibular abnormalities.

Discussion Measures Responses reflect dysfunction of the saccule and/or the inferior vestibular nerve Evaluates the patient’s gross motor skills Evaluates for peripheral vestibular dysfunction (involving the lateral semicircular canal). Indicates central vestibular impairment involving the brainstem or cerebellum Indicates central or peripheral vestibular dysfunction, as well as primary ocular motility disorders Evaluates for balance impairment, quantifies the degree of imbalance, and establishes what contributions are made to the patient’s imbalance from the visual, vestibular, and somatosensory systems Evaluates each of the 3 semicircular canal organs of the inner ear Measures utricle function and can detect central vestibular disease

• This study will involve collecting information on vestibular function in patients with all three types of Usher Syndrome, and correlating this data with genetic diagnosis, and hearing and vision loss phenotypes. • A standard set of vestibular tests will be used on each patient so that results can be compared across cases. • When possible, patients will be tested pre-CI to eliminate the uncertainty of cause of vestibular dysfunction.

Conclusions • Characterization of vestibular function in this population could facilitate earlier diagnosis of USH, as well as further define the relationship between specific genetic mutations and clinical findings of hearing and balance. • Furthermore, it may help to predict if children with USH would benefit from vestibular-specific therapies, such as vestibular rehabilitation which has shown efficacy in improving motor development and balance in children with SNHL.

Acknowledgement We would like to thank the Foundation “Forschung contra Blindheit – Intitiative Usher Syndrom e.V.” for financial support, which made the presentation of this research at this symposium possible.