Human Melanopic Pupillary Responses Isolated from Outer Retinal Photoreceptor Input in LCA Patients with Severe Vision Loss

Abstract

Purpose : Pupillary light reflex (PLR) refers to pupil size changes in response to retinal illumination. PLR is thought to be driven by rods and cones of the outer retina, and by melanopsin-expressing intrinsically-photosensitive retinal ganglion cells of the inner retina. In order to isolate the melanopic component of the human PLR, we considered patients with severe vision loss due to Leber congenital amaurosis (LCA) caused by gene mutations acting on the outer retina.

Methods : Direct PLR was recorded in the dark with achromatic full-field stimuli (2.5 log scot-cd.m-2; ~13 log quanta.cm-2.s-1) in dark-adapted eyes. Videos were analyzed frame-by-frame. Patients with autosomal recessive LCA with known mutations and severe loss of visual acuity (light perception, LP, or no light perception, NLP) were evaluated first with 100 ms stimuli. A subset of patients (n=19; mean age=18.4 y) showing no PLR to the 100 ms stimulus was further examined with 5 s stimuli. Full-field stimulus testing (FST) was used to quantify light perception.

Results : 12 of 19 patients with no PLR to the 100 ms stimulus showed a detectable contraction with the 5 s stimulus; 7 were non-responders. There was no difference in acuity between the two groups and there was an overlap of FST thresholds. Baseline pupil diameters were not significantly different (mean±SD; responders: 6.02±1.50 mm; non-responders: 4.54±1.80 mm) and anterior segments were mostly clear in both groups. In responders, PLR was much slower and smaller than normals. Specifically, the latency of the PLR in LCA was 3.07±1.19 s at 0.3 mm criterion amplitude whereas normal latency was 0.19±0.02 s. Peak contraction in LCA was 1.24±0.92 mm at 6.48±2.30 s, considerably different than normal amplitude of 4.15±0.42 mm at 2.97±0.41 s. Importantly, PLR in LCA responders was also much slower than normal PLR evoked with near threshold (~7 log unit dimmer) stimuli, ruling out input from remnant rods and cones with sensitivity loss driving the response.

Conclusions : The slow PLR evoked with bright and long stimuli in many LCA patients with severe and congenital vision loss likely represents the activity of the melanopic circuit isolated from rod and cone input. Knowledge of the properties of the human melanopic activity allows better interpretation of PLR as an objective outcome measure in clinical trials targeting outer retinal photoreceptors.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.