Chromatic Pupillometry Methods for Assessing Photoreceptor Health in Retinal and Optic Nerve Diseases

Abstract

The pupillary light reflex is mediated by melanopsin-containing intrinsically-photosensitive retinal ganglion cells (ipRGCs), which also receive input from rods and cones. Melanopsin-dependent pupillary light responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower to activate and de-activate compared with rod/cone-mediated responses. Given that rod/cone photoreceptors and melanopsin differ in their response properties, light stimuli can be designed to stimulate preferentially each of the different photoreceptor types, providing a read-out of their function. This has given rise to chromatic pupillometry methods that aim to assess the health of outer retinal photoreceptors and ipRGCs by measuring pupillary responses to blue or red light stimuli. Here, we review different types of chromatic pupillometry protocols that have been tested in patients with retinal or optic nerve disease, including approaches that use short-duration light exposures or continuous exposure to light. Across different protocols, patients with outer retinal disease (e.g., retinitis pigmentosa or Leber congenital amaurosis) show reduced or absent pupillary responses to dim blue-light stimuli used to assess rod function, and reduced responses to moderately-bright red-light stimuli used to assess cone function. By comparison, patients with optic nerve disease (e.g., glaucoma or ischemic optic neuropathy, but not mitochondrial disease) show impaired pupillary responses during continuous exposure to bright blue-light stimuli, and a reduced post-illumination pupillary response after light offset, used to assess melanopsin function. These proof-of-concept studies demonstrate that chromatic pupillometry methods can be used to assess damage to rod/cone photoreceptors and ipRGCs. In future studies, it will be important to determine whether chromatic pupillometry methods can be used for screening and early detection of retinal and optic nerve diseases. Such methods may also prove useful for objectively evaluating the degree of recovery to ipRGC function in blind patients who undergo gene therapy or other treatments to restore vision.

Living in Biological Darkness: Objective Sleepiness and the Pupillary Light Responses Are Affected by Different Metameric Lighting Conditions during Daytime

“…Analyzing these relative changes minimized the influence of preexisting pupil sizes and the impact of dark-adapted responses. Another limitation of our study is that with the current pupil measurement protocol, we are not able to completely isolate the different photoreceptor contributions to the physiological pupil responses, as was recently shown by others (McAdams et al, 2018; Rukmini et al, 2019). However, a methodological comparison revealed comparable results for the PIPR and this different method, called silent substitution (Estevez and Spekreijse, 1982; Spitschan and Woelders, 2018; Tsujimura et al, 2010).…”

“…A study by Gamlin et al showed that by blocking rods and cones in nonhuman primates, the sustained pupil response was largest after light exposure, with a peak wavelength at the maximal sensitivity of ipRGCs, following the sensitivity curve of melanopsin with a peak at 482 nm (Gamlin et al, 2007). Several attempts were made to physiologically isolate the photoreceptor contributions, especially the contribution from ipRGCs (for a review, see Rukmini et al, 2019). An action spectrum of the pupil response revealed peak sensitivity also around 480 nm in rod and coneless mice (Lucas et al, 2001) and in humans (Bouma, 1962; Gamlin et al, 2007), further indicating the melanopsin-driven impact on the pupil response to short-wavelength light stimuli.…”

Light-Induced Pupillary Responses in Alzheimer's Disease

“…But the senescence of the lens does not selectively reduce the mRGCs responses to intense blue light and is well-preserved, in spite of its decreased lens transmittance in aging and cataract (51). Different retinal and optic nerve conditions can affect PLR and using chromatic pupillometry it is possible to localize the loss of photoreceptoral function i.e., inner or outer retina (107). Primary open angle glaucoma is associated with decreased PLR in response to exposure to both red and blue light with decreased PIPR for blue light (28, 70), while retinal dystrophies affecting rods and cones lead to decreased PLR responses to red and low intensity blue light with an increased PIPR to bright blue light stimulus (108, 109).…”

Prediction accuracy of L- and M-cone based human pupil light models

“…Moreover, recent studies show that in mesopic and scotopic adaption the rods are involved in the phasic and sustained pupil light response 27,57,63,75,76 . At higher retinal illumination levels the melanopsin activated ipRGCs are dominating this contribution 2,74 .The time until the pupil diameter has reached its' steady state depends on the used spectrum composition 73,[77][78][79] . McDougal and Gamlin 30 showed, by fitting a custom receptor weighting function, that cones contribute little to the pupil light response after 30 s. The derived function for determining the receptor contribution did not consider the pupil light reflex's opponent channels.…”