Cone-weighted chromatic pupillometry as an outcome measure for clinical trials in Usher syndrome patients

Abstract

Purpose: Progressive dysfunction of photoreceptors, particularly cones, leads to severe visual impairment in Usher syndrome patients. Reliable cone functional estimates are of key importance for measuring safety and efficacy outcomes in clinical trials. The aim of this study was to evaluate the cone-weighted chromatic pupillometry potential to be used as a standard outcome measure in Usher syndrome patient clinical trials.

Methods: The prospective case series study enrolled 50 Usher syndrome patients. All patients underwent in-depth phenotypic examination and were found to carry at least one mutation. Monocular pupil diameter was recorded (Neurolight®, IDMed, Marseilles, France) in response to red (640 nm) light stimuli for varied intensity levels (ranging from 1000 cd/m² to 0.001cd/m²). Raw data were exported and analyzed off-line using MATLAB software. Data were fitted using the sigmoid Naka-Rushton function. Repeatability and reproducibility was evaluated. Mean response amplitudes were analyzed and compared to the clinical phenotype.

Results: The mean cone-weighted response amplitude was 75±20μm in Usher syndrome patients. Lower cone-weighted responses were related to the reduced b-wave amplitude in full field scotopic electroretinogram (ERG) (r=0,49;p<0.001) and decreased P1N1 peaks in mfERG (r=0.60;p<0.001). Cone-weighted responses were measurable in all cases, even with non-recordable scotopic ERG and mfERG. Higher cone-weighted responses were positively associated with preserved kinetic visual field area (r=0,63;p<0.001), although they were not correlated with best- corrected visual acuity. Higher cone-weighted response amplitudes were observed in cases with a preserved inner/outer segment in optical coherence tomography (r=0,54;p<0.001) and increased cone density in adaptive optics (r=0,56;p<0.001). Repeatability and reducibility were 98% and 95%, respectively.

Conclusions: Cone-weighted chromatic pupillometry responses are repeatable and reproducible, with a significant correlation potential for cone-related phenotype measures in Usher syndrome patients. Cone-weighted chromatic pupillometry could be used as a standard outcome measure to assess safety and efficacy in clinical trials, particularly in advanced Usher syndrome cases.