Dark Adaptation and Its Role in Age-Related Macular Degeneration

Abstract

Dark adaptation (DA) refers to the slow recovery of visual sensitivity in darkness following exposure to intense or prolonged illumination, which bleaches a significant amount of the rhodopsin. This natural process also offers an opportunity to understand cellular function in the outer retina and evaluate for presence of disease. How our eyes adapt to darkness can be a key indicator of retinal health, which can be altered in the presence of certain diseases, such as age-related macular degeneration (AMD). A specific focus on clinical aspects of DA measurement and its significance to furthering our understanding of AMD has revealed essential findings underlying the pathobiology of the disease. The process of dark adaptation involves phototransduction taking place mainly between the photoreceptor outer segments and the retinal pigment epithelial (RPE) layer. DA occurs over a large range of luminance and is modulated by both cone and rod photoreceptors. In the photopic ranges, rods are saturated and cone cells adapt to the high luminance levels. However, under scotopic ranges, cones are unable to respond to the dim luminance and rods modulate the responses to lower levels of light as they can respond to even a single photon. Since the cone visual cycle is also based on the Muller cells, measuring the impairment in rod-based dark adaptation is thought to be particularly relevant to diseases such as AMD, which involves both photoreceptors and RPE. Dark adaptation parameters are metrics derived from curve-fitting dark adaptation sensitivities over time and can represent specific cellular function. Parameters such as the cone-rod break (CRB) and rod intercept time (RIT) are particularly sensitive to changes in the outer retina. There is some structural and functional continuum between normal aging and the AMD pathology. Many studies have shown an increase of the rod intercept time (RIT), i.e., delays in rod-mediated DA in AMD patients with increasing disease severity determined by increased drusen grade, pigment changes and the presence of subretinal drusenoid deposits (SDD) and association with certain morphological features in the peripheral retina. Specifications of spatial testing location, repeatability of the testing, ease and availability of the testing device in clinical settings, and test duration in elderly population are also important. We provide a detailed overview in light of all these factors.

Keywords: age-related macular degeneration (AMD); cone-rod break (CRB); dark adaptation (DA); longitudinal monitoring; phototransduction; rod-intercept time (RIT); spatial gradient; subretinal drusenoid deposits (SDD).

Figure 1

The retinoid cycle. Reproduced with permission from Lamb et al. 2004 [3]. represents important steps, enzymes and chaperon proteins comprising the retinoid cycle. (1) Photoactivation; The 11-cis retinal isomerized to the all-trans-retinal [(=Rh*) represents activated rhodopsin after absorption of photon] (4) reduction of aldehyde, (7) transport of all trans retinol across photoreceptor plasma membrane and the interphotoreceptor matrix (IPM) to RPE cell chaperoned by Inter-photoreceptor retinol binding protein (IRBP); (9) Isomerization from the all-trans to the 11-cis form, (10) oxidation of 11-cis retinol to 11-cis retinal and its delivery to opsin in the photoreceptor outer segments across the IPM.

Figure 2

The Dark Adaptation curve reproduced with permission from Uddin et al. [38] This shows a representative dark adaptation curve along with key derived parameters. The gray region with the green and red triangles illustrates the measurement of scotopic thresholds at 505 nm and 625 nm respectively before delivery of bleach. Following exposure to a bleaching light, retinal sensitivity reaches an initial plateau mediated by cones (CT). Once rods become more sensitive to cones (Cone-rod break), retinal sensitivity continues to improve at a fixed rate (R dec/min) before reaching final asymptotic rod threshold (Tf). Rod intercept time (RIT), the time taken to detect a stimulus of −3.1 log phot cd/m² has been widely used to assess DA in AMD.

Figure 3

Impaired DA in different AMD stages. Reproduced with permission from Flamendorf et al. [98], an example for impaired DA in different AMD stages. (A). Representative dark adaptation raw data for individual participants with no large drusen (group 0), large drusen in the study eye only (group 1), large drusen in both eyes (group 2), advanced disease in the nonstudy eye (group 3), and reticular pseudodrusen (RPD). The rod intercept time is the time required for the patient’s visual sensitivity to recover to a stimulus intensity 3 log units dimmer than the initial threshold (arrows). (B). Graph showing averaged raw data for each group. The group curves were derived by averaging the fitted values over a grid of points (2-s intervals) from time 0 to 40 min based on a 3-component piecewise linear fit to the raw data (excluding fixation errors).

Figure 4

Dark adaptation in different AMD disease stages and on various retinal locations in the inferior retina in the vertical meridian. Reproduced with permission from Flynn et al. [54]. The left figure shows mean rod intercept time (RIT) for different eccentricities, showing that alterations are more pronounced in the 4°, 6° and 8° compared to the more eccentric 12° locations. (Post hoc comparisons to group 0 by eccentricity: ** p < 0.0001) The right figure compares different disease stages at certain retinal locations exhibiting markedly increased RIT values in presence of SDD. (Post hoc comparisons of RIT at 4°, 6° and 8° relative to 12° by group; * p < 0.0015, ** p < 0.0001).