Cone Photoreceptor Irregularity on Adaptive Optics Scanning Laser Ophthalmoscopy Correlates With Severity of Diabetic Retinopathy and Macular Edema

Abstract

Purpose: To determine whether cone density, spacing, or regularity in eyes with and without diabetes (DM) as assessed by high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) correlates with presence of diabetes, diabetic retinopathy (DR) severity, or presence of diabetic macular edema (DME).

Methods: Participants with type 1 or 2 DM and healthy controls underwent AOSLO imaging of four macular regions. Cone assessment was performed by independent graders for cone density, packing factor (PF), nearest neighbor distance (NND), and Voronoi tile area (VTA). Regularity indices (mean/SD) of NND (RI-NND) and VTA (RI-VTA) were calculated.

Results: Fifty-three eyes (53 subjects) were assessed. Mean ± SD age was 44 ± 12 years; 81% had DM (duration: 22 ± 13 years; glycated hemoglobin [HbA1c]: 8.0 ± 1.7%; DM type 1: 72%). No significant relationship was found between DM, HbA1c, or DR severity and cone density or spacing parameters. However, decreased regularity of cone arrangement in the macular quadrants was correlated with presence of DM (RI-NND: P = 0.04; RI-VTA: P = 0.04), increasing DR severity (RI-NND: P = 0.04), and presence of DME (RI-VTA: P = 0.04). Eyes with DME were associated with decreased density (P = 0.04), PF (P = 0.03), and RI-VTA (0.04).

Conclusions: Although absolute cone density and spacing don't appear to change substantially in DM, decreased regularity of the cone arrangement is consistently associated with the presence of DM, increasing DR severity, and DME. Future AOSLO evaluation of cone regularity is warranted to determine whether these changes are correlated with, or predict, anatomic or functional deficits in patients with DM.

Figure 1

Overlay of a wide-field infrared image with macular AOSLO images. The white rectangles indicate the location of the four regions of interest for AOSLO imaging: superior-nasal (SN), superior-temporal (ST), inferior-temporal (IT), and inferior-nasal (IN). The asterisk indicates the center of the fovea. Scale bar: 200 μm.

Figure 2

Bland-Altman plot of cone density (cones/mm²) results of the graders. The horizontal line represents the mean difference between the graders' results. The upper/lower horizontal dashed lines represent 1.96× the standard deviation of the difference.

Figure 3

Examples of AOSLO cone reflection images (A, C, E) and corresponding Voronoi tile simulations (B, D, F). Upper row (nondiabetic control): Notice the densely packed cones (A) and the regular arrangement (B) represented by uniform shading of the Voronoi tiles. Middle (severe nonproliferative diabetic retinopathy [NPDR]) and bottom row (proliferative DR): Notice the reduced cone density (C, E) and reduced arrangement regularity represented by less uniformity of the shading of the corresponding Voronoi tiles (D, F). Vessels and Voronoi tiles at the edges of the image and vessel areas were excluded from the analysis (see also Methods section and Supplementary Fig. S2).

Figure 4

Examples of AOSLO cone reflection images (A, C) and corresponding Voronoi tile simulations (B, D). Upper row (moderate nonproliferative diabetic retinopathy [NPDR], no diabetic macular edema [DME] present): Notice the clearly visible cones (A). Lower row (moderate NPDR, DME present): The cone mosaic is less distinct and blurred by the presence of local edema (C). Regularity is markedly reduced indicated by irregularly shaped Voronoi tiles with nonuniform shading (D). Vessels and Voronoi tiles at the edges of the image and vessel areas were excluded from the analysis (see also Methods section and Supplementary Fig. S2).

Figure 5

Box plots of the association of age (A), presence of diabetes (B), severity of diabetic retinopathy (C), and presence of diabetic macular edema (D) with the regularity indices of nearest neighbor distance and Voronoi tile area in macular quadrants. Regularity index (RI) calculated as mean/SD. RI-NND, regularity index of nearest neighbor distance; RI-VTA, regularity index of Voronoi tile area; DM, diabetes; DR, diabetic retinopathy; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. Circle: mean; horizontal lines: median; asterisk: upper/lower outlier.