ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retina

Abstract

Purpose: To study the parapapillary retinal region in patients with ABCA4-associated retinal degenerations.

Methods: Patients with Stargardt disease or cone-rod dystrophy and disease-causing variants in the ABCA4 gene were included. Fixation location was determined under fundus visualization, and central cone-mediated vision was measured. Intensity and texture abnormalities of autofluorescence (AF) images were quantified. Parapapillary retina of an eye donor with ungenotyped Stargardt disease was examined microscopically.

Results: AF images ranged from normal, to spatially homogenous abnormal increase of intensity, to a spatially heterogenous speckled pattern, to variably sized patches of low intensity. A parapapillary ring of normal-appearing AF was visible at all disease stages. Quantitative analysis of the intensity and texture properties of AF images showed the preserved region to be an annulus, at least 0.6 mm wide, surrounding the optic nerve head. A similar region of relatively preserved photoreceptor nuclei was apparent in the donor retina. In patients with foveal fixation, there was better cone sensitivity at a parapapillary locus in the nasal retina than at the same eccentricity in the temporal retina. In patients with eccentric fixation, approximately 30% had a preferred retinal locus in the parapapillary retina.

Conclusions: Human retinal degenerations caused by ABCA4 mutations spare the structure of retina and RPE in a circular parapapillary region that commonly serves as the preferred fixation locus when central vision is lost. The retina between fovea and optic nerve head could serve as a convenient, accessible, and informative region for structural and functional studies to determine natural history or outcome of therapy in ABCA4-associated disease.

Figure 1

Standardized images of autofluorescence in a representative normal subject (A) and three patients (B-D) with ABCA4-associated retinal degeneration (ABCA4-RD). Excitation wavelength was 488 nm. Intensities are mapped to a pseudocolor scale shown; results of P42 were uniformly scaled (X 0.7) to fit the 256-level dynamic range. Black represents no image data and purple corresponds to the dark-level of the detector. All eyes are shown as equivalent right eyes.

Figure 2

Detailed analysis of autofluorescence abnormalities in a region around the optic nerve head (ONH) in four ABCA4-RD patients (A–D). The contrast of each grayscale image is uniformly stretched for better visibility of features. Standardized image data from temporal (T) and nasal (N) semi-annular retinal regions from the edge of the ONH to an eccentricity of 2.5 mm (white circles overlaid on images) have been analyzed and shown as pseudo-profiles of intensity and run-length. Black lines represent data from patients and gray regions show the normal range.

Figure 3

Quantification of the extent of parapapillary preservation in ABCA4-RD patients. (A) Pseudo-profiles in the group of patients (left panel) showing normal autofluorescence intensity in the vicinity of the parapapillary region versus the remaining patients (right panel) showing abnormal results. (B) Pseudo-profiles of mean run-length in the two groups of patients as in panel A. (C) Percent of patients in each group showing normal run-length results as a function of eccentricity from the center of the optic nerve. Vertical dashed lines delineate the extents of parapapillary preservation defined as the eccentricity at which 90% of the patients show normal run-length. (D) Histopathology in a donor eye with Stargardt disease showing the parapapillary region nasal to the optic nerve head. Two regions (black rectangles) are shown at higher magnification as insets. Arrowheads point to photoreceptor nuclei, which are more numerous in the parapapillary region.

Figure 4

Visual function consequences of the preservation of parapapillary retina in ABCA4 disease. (A) Psychophysical cone sensitivity profiles in ABCA4-RD patients with documented foveal fixation. Two horizontal axes represent the standard perimetric coordinate system centered on the fovea (F) and an alternate coordinate system centered on the optic nerve head (ONH). Hatched region represents the expected location of the ONH; gray region delimits the normal range of cone sensitivity. (B) Graphical representation of retinal fixation loci in one eye of all patients (numbers designate individual patients) with central scotomas and extra-foveal fixation. Data are shown as right-eye equivalent on a schematic showing ONH (circle) and major retinal blood vessels (curved lines). Fixation locus of P30 was in the far supero-nasal retina in the direction pointed to by the arrow. (C) Autofluorescence images of both eyes of P32 with bilateral central atrophy of the RPE. Fixation loci determined individually in each eye are shown (white stars with black outline). The contrast of each grayscale image is uniformly stretched for better visibility of features.

Figure 5

Estimation of local intensity heterogeneity by calculating mean run-length image. (A) A representative autofluorescence (AF) intensity image showing regions of high local heterogeneity and regions of relative homogeneity. The contrast of the grayscale images are uniformly stretched for better visibility of features. (B) Magnification of a 10×10 pixel region of the image in panel A. (C) Intensity values corresponding to each pixel of the magnified grayscale image shown in panel B. The extents of run-lengths in eight principal directions are demarcated (lines) around a chosen pixel of interest (circle); the mean run-length is 1.99 pixels, which corresponds to 0.035 mm on the retina. (D) Gray scale representation of the mean run-length values calculated at each pixel for the image shown in panel A. Regions of local intensity heterogeneity have short run-lengths and darker pixels, regions of local intensity homogeneity have longer run-lengths and lighter pixels.

Figure 6

Demonstration of the semi-polar integral transformation used to perform data reduction on images. (A) A representative autofluorescence intensity image of the parapapillary region is divided into temporal and nasal halves. Radius (r) and angle (θ) axes of polar coordinates are shown with respect to the center of the optic nerve head (ONH). (B) A two-level mask image showing image pixels (black) corresponding to ONH and retinal blood vessels, which are to be excluded from further calculations. (C, D) Application of a rectangular to polar transformation to the intensity and mask images shown in panels A and B. Representative regions (black lines) and locations (white squares) demonstrating the correspondence between rectangular and polar coordinate representations are shown in panels A and C. (E) The result of integrating the semi-polar transformed images along the angle coordinate. Locations corresponding to black pixels of the mask image are not included in the integral.