Mesopic and dark-adapted two-color fundus-controlled perimetry in patients with cuticular, reticular, and soft drusen

Abstract

Purpose: To examine the feasibility and utility of dark-adapted two-color fundus-controlled perimetry (FCP) in patients with cuticular, reticular, and soft drusen, and to compare FCP data to microstructural spectral-domain optical coherence tomography (SD-OCT) data.

Methods: Forty-four eyes (24 eyes of 24 patients with drusen, age 69.4 ± 12.6 years; 20 normal eyes of 16 subjects, 61.7 ± 12.4 years) underwent duplicate mesopic, dark-adapted cyan and dark-adapted red FCP within 14° of the central retina (total of 12 936 threshold tests) using the Scotopic Macular Integrity Assessment (S-MAIA, CenterVue, Padova, Italy) device. FCP data were registered to SD-OCT data to obtain outer nuclear layer, inner and outer photoreceptor segment, and retinal pigment epithelium drusen complex (RPEDC) thickness data spatially corresponding to the stimulus location and area (0.43°). Structure-function correlations were assessed using mixed-effects models.

Results: Mean deviation values for eyes with cuticular, soft, and reticular drusen were similar for mesopic (-2.1, -3.4, and -3.6 dB) and dark-adapted red (-1.4, -2.6, and -3.3 dB) FCP. For the dark-adapted cyan FCP (0.1, -1.9, and -5.0 dB) and for the cyan-red sensitivity difference (+1.0, +0.5, and -2.4 dB), the mean deviation values differed significantly in dependence of the predominant drusen type (one-way ANOVA; p < 0.05). RPEDC thickness was associated with reduction of mesopic sensitivity (-0.34 dB/10 µm RPEDC thickening; p < 0.001), dark-adapted cyan sensitivity (-0.11 dB/10 µm RPEDC thickening; p = 0.003), and dark-adapted red sensitivity (-0.26 dB/10 µm RPEDC thickening; p < 0.001).

Conclusions: In contrast to mesopic FCP, dark-adapted two-color FCP allowed for meaningful differential testing of rod and cone function in patients with drusen indicating predominant cone dysfunction in eyes with cuticular drusen and predominant rod dysfunction in eyes with reticular drusen. RPEDC thickness was the strongest predictor of the evaluated SD-OCT biomarkers for point-wise sensitivity.

Fig. 1

The columns show a representative example eye for each drusen type (from left to right) with color fundus photography (first row), fundus autofluorescence imaging (second row), and the horizontal spectral-domain optical coherence tomography B-scan centered to the fovea (third row). The overlay in the color fundus photographs displays the results of the first dark-adapted cyan test. The last row depicts the corresponding cumulative defect (Bebie) curves for each type of testing. The normative data with 95% confidence intervals are shown in the background. The data of the patient are plotted in the foreground. Patient 6 (P6) exhibited multiple, yellowish, small, round, “hard” drusen with distinct borders and was classified as predominant cuticular drusen. The cumulative defect curves indicated that the mesopic and dark-adapted red deficit exceeded the dark-adapted cyan deficit. Patient 24 (P24) exhibited multiple confluent “soft” drusen and was thus classified as predominant soft drusen. The cumulative defect curves indicated defect for all three types of testing. Patient 13 (P13) exhibited small dot- and ribbon-shaped lesion and was classified as predominant reticular drusen. The cumulative defect curves exhibited parallel shift for mesopic and dark-adapted red testing along the y-axis (indicating global defect or media opacity) and most prominently global and diffuse defect for dark-adapted cyan testing

Fig. 2

The spectral-domain optical coherence tomography (SD-OCT) data were segmented semi-automatically (internal limiting membrane [ILM], outer plexiform layer and outer nuclear layer boundary [OPL/ONL], external limiting membrane [ELM], interdigitation zone [IZ], and Bruch’s membrane [BM]). The retinal pigment epithelium drusen complex (RPEDC) ranged from BM to the IZ (red overlay). The inner and outer segments (IS + OS) ranged from the IZ to the ELM (green overlay). The ONL ranged from the ELM to the OPL/ONL boundary (blue overlay). Hereby, the Henle fiber layer was counted toward the outer nuclear layer as shown in a. The inner retina encompassed all layers from the OPL/ONL boundary to the ILM (purple overlay). The full retina was defined as thickness from BM to the ILM (turquoise overlay). The fundus-controlled perimetry grid consisted of 49 test points over 14° of the central retina as shown in b (central test point plus 12 test points at an eccentricity of 1°, 3°, 5°, and 7°). The FCP data were registered to an SD-OCT en-face image using nonlinear affine transformation according to vessel bifurcations. Thus, the FCP data were also aligned to the thickness maps of the corresponding layers (b). Thickness data corresponding to the precise stimulus location and area (Goldmann III, 0.43°) was then extracted from the SD-OCT data for each layer (c)

Fig. 3

The plot shows the mean deviation (MD, dots indicate the average MD and error bars the SD of the MD) as compared to normative data of the three functional tests and the cyan–red difference for each predominant drusen type and according to the degree of eccentricity. Eyes with cuticular drusen and soft drusen exhibited high MD for mesopic and dark-adapted red testing at 0–1° with little MD for cyan testing. This resulted in positive values for the MD of the cyan–red sensitivity difference indicating cone dysfunction at 0–1°. At 5° and 7°, eyes with cuticular drusen exhibited overall little MD. Eyes with soft drusen exhibited at 3°, 5°, and 7° equal amounts of MD for dark-adapted cyan and red testing indicating a similar degree of rod and cone dysfunction. Eyes with reticular drusen exhibited at 3°, 5°, and 7° predominantly MD for dark-adapted cyan testing resulting in negative MD values for the cyan–red sensitivity difference, indicating predominant rod dysfunction

Fig. 4

Scatter plots for the mesopic (first row), dark-dapated cyan (second row), and dark-adapted red (third row) in dependence of the predominant drusen type (first column), full retinal thickness (second column), outer nuclear layer thickness (third column), and retinal pigment epithelium drusen complex thickness (fourth column). Since many data points obscured each other, the points were made semitransparent. Further, the points of the first column (predominant drusen type) were spread along the x-axis to reduce overplotting. All data were plotted in terms of number of normative standard deviation from the normative mean (i.e., z-score). The largest differences in sensitivity in dependence of drusen type were observable for dark-adapted cyan testing. Yet, the steepest slopes in dependence of point-wise SD-OCT biomarkers were observable for mesopic and dark-adapted red testing