Figure 1. Mean (SD) pupil response (calculated as pupil size at peak contraction divided by prestimulus baseline size) vs stimulus intensity (blue and red light) for 10 control subjects. Open circles indicate null response. Regression analysis through responses to dimmer light intensities (−4.0 to −1.0 log cd/m2) describes rod activity and determines response thresholds (arrows). The leftward shift of blue light responses indicates greater sensitivity of rods to blue light.
Figure 2. Pupil responses (calculated as pupil size at peak contraction divided by prestimulus baseline size) to red and blue light stimuli for 4 patients with Leber congenital amaurosis, including patient 1 (aged 30 years, female, RDH mutation, light perception, no visual field) (A), patient 2 (aged 44 years, female, TULP mutation, light perception, 3° central field) (B), patient 3 (aged 15 years, male, RPE65 mutation, visual acuity 20/400, 5°-10° central field) (C), and patient 4 (aged 29 years, female, RDH mutation, visual acuity 20/200, 1°-2° central field) (D). Compared with control subjects, patients with Leber congenital amaurosis have marked loss of rod and cone sensitivity (large rightward shift of pupil responses). Rod-mediated pupil responses are mostly absent (open circles). Responses to bright red stimuli are reduced but measurable, indicating residual cone activity.
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Kawasaki A, Munier FL, Leon L, Kardon RH. Pupillometric Quantification of Residual Rod and Cone Activity in Leber Congenital Amaurosis. Arch Ophthalmol. 2012;130(6):798–800. doi:10.1001/archophthalmol.2011.1756
Quantifying the pupil response to colored light stimuli is a noninvasive technique that objectively assesses rod, cone, and melanopsin activity.1-4 In this study, we used chromatic pupillometry to quantify residual rod and cone function in eyes with advanced outer retinal photoreceptor degeneration.
The study was conducted under the tenets of the Declaration of Helsinki with authorization from the local ethical committee for human research. Four patients with Leber congenital amaurosis (LCA) and 10 control subjects with healthy eyes were studied. The chromatic pupillometer consisted of a ColorDome Ganzfeld bowl (Diagnosys) linked to a dual-channel pupil recorder with a sampling rate of 30 Hz (Arrington Research).5 Testing was performed under conditions of dark adaptation. Pupil responses to a 1-second red light (640 ± 10 nm) and blue light (467 ± 17 nm), matched for photopic intensity over a 6–log unit range of intensities (−4.0 to 2.0 log cd/m2), were recorded continuously.
The pupil response (pupil size at peak contraction divided by prestimulus baseline size) was plotted against stimulus intensity, and a regression line was fitted through pupil responses to dim light stimuli (−4.0 to −1.0 log cd/m2). The line was extrapolated to intersect through y = 1, where the pupil size at peak contraction was the same as at baseline, indicating the light intensity at which no pupil response can be detected. This intensity was termed the rod-related pupil response threshold (Figure 1).
In healthy eyes, pupil responses to brighter light intensities derive from mixed rod-cone and melanopsin contributions. In patients whose rod activity is pupillometrically absent, pupil responses to red light (≥0.5 log cd/m2) are mediated predominantly by cones and a cone-related response threshold can be similarly estimated from regression analysis.
Inner retinal photoreception mediated by melanopsin was assessed by the difference in sustained pupil contraction between a bright (2.6 log cd/m2) blue and red light stimulus.4
Control subjects were aged 20 to 52 years, and patients with LCA were aged 15 to 44 years. Genetic analysis of patients revealed an RDH mutation in 2 patients, an RPE65 mutation in 1, and a TULP mutation in 1. Neither rod nor cone activity was detectable by electroretinography in any patient. Visual acuities ranged from 20/200 to light perception. Kinetic visual fields were unobtainable in 1 patient and severely constricted in the others.
In healthy eyes, rod-mediated pupil responses to dim light stimuli were easily recordable and showed a greater sensitivity to blue light compared with red light, consistent with the spectral sensitivity of rods. Patients with LCA had severely reduced or absent pupil responses to light intensities below −1.0 log cd/m2 (Figure 2). The rod-related pupil response threshold was quantifiable in only 1 patient (−3.1 log cd/m2), being almost 2 log units greater than the control mean (−4.9 log cd/m2). In contrast, pupil responses to brighter stimulus intensities were readily present in all patients and a cone-related response threshold was quantifiable (range, −2.3 to −0.8 log cd/m2). Melanopsin activity was not significantly different between patients with LCA and control subjects.
Pupil responses to dim stimulus lights under conditions of dark adaptation derive from isolated rod activation and permit determination of the rod-related pupil response threshold. In advanced stages of LCA, degenerating rods have lost their contribution to afferent retinal signaling so that residual cones and melanopsin are the mediators of the pupil light reflex. In such patients, cone function can be separated from melanopsin and quantified from pupil responses to bright red stimulus lights. Determination of the pupil response threshold from rods and cones has a greater dynamic range than standard electroretinography for quantifying low levels of outer retinal photoreceptor activity in patients with retinal degeneration.
Correspondence: Dr Kawasaki, Hôpital Ophtalmique Jules Gonin, Ave de France 15, Lausanne 1004, Switzerland (firstname.lastname@example.org).
Author Contributions: All of the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: Dr Kawasaki has received financial compensation from Bayer for consultation on a topic unrelated to this article.
Funding/Support: This work was supported by an unrestricted grant from Research to Prevent Blindness. Dr Kawasaki was supported in part by a grant from the Foundation for Research in Ophthalmology and Loterie Romande Swiss. Dr Munier was supported by grant 320030-127558 from the Swiss National Science Foundation. Dr Kardon is the recipient of funds from the Department of Veterans Affairs Rehabilitation Research and Development Division, Department of Defense and the Pomerantz Chair in Ophthalmology.