Outcome measure for the treatment of cone photoreceptor diseases: orientation to a scene with cone-only contrast

Abstract

Background: Inherited retinal degenerations (IRDs) preferentially affecting cone photoreceptor function are being considered for treatment trials aiming to improve day vision. The purpose of the current work was to develop cone-specific visual orientation outcomes that can differentiate day vision improvement in the presence of retained night vision.

Methods: A lighted wall (1.4 m wide, 2 m high) resembling a beaded curtain was formed with 900 individually addressable red, blue and green LED triplets placed in 15 vertical strips hanging 0.1 m apart. Under computer control, different combination of colors and intensities were used to produce the appearance of a door on the wall. Scotopically-matched trials were designed to be perceptible to the cone-, but not rod-, photoreceptor based visual systems. Unmatched control trials were interleaved at each luminance level to determine the existence of any vision available for orientation. Testing started with dark-adapted eyes and a scene luminance attenuated 8 log units from the maximum attainable, and continued with progressively increasing levels of luminance. Testing was performed with a three-alternative forced choice method in healthy subjects and patients with Leber congenital amaurosis (LCA) caused by mutations in GUCY2D, the gene that encodes retinal guanylate cyclase-1.

Results: Normal subjects could perform the orientation task using cone vision at 5 log attenuation and brighter luminance levels. Most GUCY2D-LCA patients failed to perform the orientation task with scotopically-matched test trials at any luminance level even though they were able to perform correctly with unmatched control trials. These results were consistent with a lack of cone system vision and use of the rod system under ambient conditions normally associated with cone system activity. Two GUCY2D-LCA patients demonstrated remnant cone vision but at a luminance level 2 log brighter than normal.

Conclusions: The newly developed device can probe the existence or emergence of cone-based vision in patients for an orientation task involving the identification of a door on the wall under free-viewing conditions. This key advance represents progress toward developing an appropriate outcome measure for a clinical trial to treat currently incurable eye diseases severely affecting cone vision despite retained rod vision.

Fig. 1

Presentation of scotopically matched scenes on an LED-lit wall. (a) Left, LED-lit wall and door device used for the three-alternative forced-choice design. A mix of light intensities for the “door” (three stripes at right, center or left) and “wall” (elsewhere) is calculated to be visible to cone-based vision but unable to be differentiated with rod-based scotopic vision. Right, spectral content of the LED lights compared to the spectral sensitivities of the rod (scotopic, V’_ʎ) and cone (photopic, V_ʎ) vision. All curves are normalized to unity at maximum. The relative intensities of the three lights are set such that they have the same effectiveness for rods (lower left) but substantially different effectiveness when perceived by cones (lower right). These differences permit differentiation of door and wall, and enhance visual orientation performance. (b) Rod vision is expected to perceive the scene as uniform stripes with no features (upper panels), and cone vision is expected to perceive the “door” as green stripes on a blue background (lower panels). (c) Appearance of unmatched control trials that should be visible to either rod or cone systems. (d) Departures of more than approximately 1.5 dB (0.15 log) from the scotopically matched mix of lights result in successful door-wall differentiation in normal subjects. (e) Representative examples of scotopically-matched test trials interleaved with unmatched control trials. For a three-alternative forced-choice setup, a subject with rod vision but no cone vision would be expected to get 33 % correct for matched-stimuli on average, whereas a subject using cone vision would be expected to get 100 % correct. Unmatched control presentations with door dimmer (1) or brighter (2) than wall are used to determine whether the subject has any vision (rod or cone or both) under the testing conditions

Fig. 2

Identification of cone vision as a function of scene luminance. (a) Percent correct identification of the location of photopically-mismatched but scotopically-matched trials using a three-alternative forced-choice method in normals as a function of scene luminance. Near normal scotopic threshold (7–8 log attenuation), subjects cannot differentiate between door and wall any better than chance. Upon increase in scene luminance, colors become visible and door identification accuracy reaches 100 %. The sigmoidal curve is a logistic function fitted to the data, with parameters θ = −5.01 log (threshold) and σ = 0.28 log (spread). (b) Five GUCY2D-LCA patients that fail to perform the visual orientation task with scotopically-matched trials across the full 8 log unit dynamic range of scene luminances (symbols). Four of the patients successfully orient with unmatched control trials (upper gray bars) over a range of scene luminances suggesting their use of scotopic vision. (c) Two GUCY2D-LCA patients who can correctly perform visual orientation task with scotopically-matched and unmatched trials but require greater scene luminance than normal. Fitted function and parameters as in (A) except for the shifted threshold parameter, which resulted in θ = −3.3 log. Both green/blue and green/red data are shown