Abstract: PURPOSE: The pupil light response (PLR) is driven by rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). In this study, we aimed to isolate ipRGC-driven pupil responses using chromatic pupillometry in blind patients with retinitis pigmentosa (RP) with severely damaged photoreceptor cells, characterize the kinetic characteristics of the pupil response, and determine the state of ipRGC function in different RP severities.
METHODS: A total of 100 eyes from 67 RP blinds were included. The best corrected visual acuity was less than 0.05 or the visual field radius was less than 10 degrees, which met the legal blindness standard. Patients were divided into groups according to severity of visual impairment: no light perception (NLP, 9 eyes), light perception (LP, 19 eyes), faint form perception (FFP, 34 eyes), or form perception (FP, 38 eyes). 18 healthy volunteers (18 eyes) were recruited as the control group. Pupil responses to rod-weighted (487 nm, -1 log cd/m², 1 s), cone-weighted (630 nm, 2 log cd/m², 1 s), and ipRGC-weighted (487 nm, 2 log cd/m², 1 s) stimuli were recorded. The following indicators were calculated and analyzed after normalizing pupil measurements: the postillumination pupil response (PIPR), maximal contraction velocity (MCV), contraction duration, and maximum dilation velocity (MDV).
RESULTS: We found a slow, sustained PLR response to the ipRGC-weighted stimulus in most patients with NLP (8/9), but these patients had no detectable rod- or cone-driven PLR. The PIPR amplitude of the NLP group (0.230 ± 0.128) was not significantly different from that of the control group (0.156 ± 0.084). The MCV of ipRGC-driven PLR was 0.269 ± 0.150 / s, the contraction duration was 2.562 ± 0.902 s, and the rapid expansion was absent, which was significantly different from those of the rod and cone responses. Comparing the ipRGC-driven PLR in different stages of RP blinds, the PIPR amplitude of the four RP blind groups was not lower than that of the control group, and the PIPR amplitude of the LP group was even significantly increased. As the disease progressed, The MCV and MDV of RP blinds gradually decreased, the contraction time was prolonged, and the kinetic index gradually approached the level of ipRGC-driven PLR.
CONCLUSIONS: In this study, ipRGC-driven pupil response was isolated for the first time in RP blinds without light perception, and its reaction kinetic characteristics of slow contraction, continuous contraction, and no rapid expansion stage were demonstrated. We proved that ipRGC-driven pupil response gradually became the main component of PLR in RP blinds by chromatic pupillometry, which provided a new technique for the evaluation of residual visual cell function in end-stage RP blinds. It provides a convenient and objective diagnostic tool for studying the visual reconstruction of RP-blind people using emerging optogenetic therapy.

Key words: advanced retinitis pigmentosa, chromatic pupillometry, intrinsically photosensitive retinal ganglion cells, postillumination pupil response, pupil kinetics