IMPORTANCESensitive outcome measures for disease progression are needed for treatment trials in geographic atrophy (GA) secondary to age-related macular degeneration (AMD).OBJECTIVE To quantify photoreceptor degeneration outside regions of GA in eyes with nonexudative AMD, to evaluate its association with future GA progression, and to characterize its spatio-temporal progression. Monocenter cohort study (Directional Spread in Geographic Atrophy [NCT02051998]) and analysis of data from a normative data study at a tertiary referral center. One hundred fifty-eight eyes of 89 patients with a mean (SD) age of 77.7 (7.1) years, median area of GA of 8.87 mm 2 (IQR, 4.09-15.60), and median follow-up of 1.1 years (IQR, 0.52-1.7 years), as well as 93 normal eyes from 93 participants. DESIGN, SETTING, AND PARTICIPANTSEXPOSURES Longitudinal spectral-domain optical coherence tomography (SD-OCT) volume scans (121 B-scans across 30°× 25°) were segmented with a deep-learning pipeline and standardized in a pointwise manner with age-adjusted normal data (z scores). Outer nuclear layer (ONL), photoreceptor inner segment (IS), and outer segment (OS) thickness were quantified along evenly spaced contour lines surrounding GA lesions. Linear mixed models were applied to assess the association between photoreceptor-related imaging features and GA progression rates and characterize the pattern of photoreceptor degeneration over time.MAIN OUTCOMES AND MEASURES Association of ONL thinning with follow-up time (after adjusting for age, retinal topography [z score], and distance to the GA boundary). RESULTSThe study included 158 eyes of 89 patients (51 women and 38 men) with a mean (SD) age of 77.7 (7.1) years. The fully automated B-scan segmentation was accurate (dice coefficient, 0.82; 95% CI, 0.80-0.85; compared with manual markings) and revealed a marked interpatient variability in photoreceptor degeneration. The ellipsoid zone (EZ) loss-to-GA boundary distance and OS thickness were prognostic for future progression rates. Outer nuclear layer and IS thinning over time was significant even when adjusting for age and proximity to the GA boundary (estimates of −0.16 μm/y; 95% CI, −0.30 to −0.02; and −0.17 μm/y; 95% CI, −0.26 to −0.09).CONCLUSIONS AND RELEVANCE Distinct and progressive alterations of photoreceptor laminae (exceeding GA spatially) were detectable and quantifiable. The degree of photoreceptor degeneration outside of regions of retinal pigment epithelium atrophy varied markedly between eyes and was associated with future GA progression. Macula-wide photoreceptor laminae thinning represents a potential candidate end point to monitor treatment effects beyond mere GA lesion size progression.

These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for geographic atrophy progression. However, a substantial part of the remaining variation in geographic atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

Mesopic and dark-adapted two-color perimetry may now be performed with fundus tracking facilitating sensitivity testing in patients with instable fixation. Patient-tailored perimetry grids were developed to allow for refined testing of the junctional zone in geographic atrophy. The results indicate that in proximity to the GA boundary, rod-dysfunction exceeds conedysfunction.

Hypertensive crisis causes end-organ damage through small-vessel damage as described histologically. Noninvasive optical coherence tomography angiography (OCTA) makes it possible to image retinal and choroidal capillaries on a microscopic level in vivo. We quantified eye vessel perfusion changes in hypertensive crisis using OCTA. Methods: Patients with hypertensive crisis (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg) and age-matched healthy controls were included in the study. OCTA en face 3 × 3-mm images of the superficial and deep retinal layers and the choriocapillaris were acquired. Outcome parameters included vessel density (VD) and vessel skeleton density (VSD) of the superficial and deep retinal layers, as well as flow voids of the choriocapillaris. Results: Twenty-eight eyes of 17 patients and 31 age-matched control eyes of 18 healthy subjects were included. VD and VSD of the deep retinal layer were significantly reduced in hypertensive crisis (P ≤ 0.004). Choriocapillaris signal intensity was more heterogeneous in patients, and flow voids exhibited confluence with a larger average area and a lower absolute count (P ≤ 0.045). These changes were independent of time since onset of hypertensive crisis and of the presence and extent of retinopathy. Deep retinal changes were associated with renal end-organ failure (P = 0.045). Conclusions: Hypertensive crisis is associated with a significant reduction in retinal and choroidal capillary perfusion based on OCTA findings. These alterations are independent of retinopathy and related to end-organ damage. Translational Relevance: OCTA might help distinguish hypertensive urgency from hypertensive emergency earlier than currently possible.

spectrum of the foveal configuration and foveal avascular zone in patients with Alport syndrome. Invest Ophthalmol Vis Sci. 2020;61(2):5. https://doi.org/10.1167/iovs.61.2.5 PURPOSE.To investigate characteristics of the foveal pit and the foveal avascular zone (FAZ) in patients with Alport syndrome (AS), a rare monogenetic disease due to mutations in genes encoding for collagen type IV. METHODS.Twenty-eight eyes of nine patients with AS, and five autosomal-recessive carriers and 15 eyes from 15 age-similar healthy control subjects were examined using optical coherence tomography (OCT) and OCT-angiography (OCT-A). Foveal configuration and FAZ measures including the FAZ area, circularity, and vessel density in the central 1°and 3°were correlated. RESULTS.Foveal hypoplasia was found in 10 eyes from seven patients with either genotype. In contrast, a staircase foveopathy was found in seven eyes of four X-linked AS patients. The average FAZ area did not differ significantly between AS patients and control subjects (mean ± SD 0.24 ± 0.24 mm 2 vs. 0.21 ± 0.09 mm 2 ; P = 0.64). Five eyes showed absence or severe anomalies of the FAZ with crossing macular capillaries that was linked to the degree of foveal hypoplasia on OCT images leading to a significant inverse correlation of FAZ area and foveal thickness (r = −0.88; P < 0.001). In contrary, female patients with X-linked mutations exhibited a significantly greater FAZ area (0.48 ± 0.30 mm 2 vs. 0.21 ± 0.09 mm 2 ; P = 0.007), in line with OCT findings of a staircase foveopathy. CONCLUSIONS.The foveal phenotypic spectrum in AS ranges from foveal hypoplasia and absence of a FAZ to staircase foveopathy with an enlarged FAZ. Because the development of the FAZ and foveal pit are closely related, these findings suggest an important role for collagen type IV in foveal development and maturation.

To examine longitudinal changes of retinal thickness and retinal sensitivity in patients with intermediate age-related macular degeneration (iAMD) and predominantly reticular pseudodrusen (RPD). METHODS. At baseline 30 eyes of 25 iAMD patients underwent optical coherence tomography imaging, mesopic and scotopic fundus-controlled perimetry (FCP) with follow-up examinations at month 12 (20 eyes), 24 (12 eyes), and 36 (11 eyes). Thicknesses of different retinal layers and results of FCP testing (n = 56 stimuli) were spatially and longitudinally analyzed using linear mixed-effects models. RESULTS. At baseline, the thickness of the partial outer retinal layer (pORL, 70.21 vs. 77.47 μm) and both mesopic (16.60 vs. 18.72 dB) and scotopic (12.14 vs. 18.67 dB) retinal sensitivity were decreased in areas with RPD compared with unremarkable areas (P < 0.001). Over three years, mean change of pORL was −0.66 normative standard deviation (SD; i.e., z-score, P < 0.001) for regions with existing RPD, −0.40 SD (P < 0.001) for regions with new occurring RPD, and −0.17 SD (P = 0.041) in unremarkable regions. Decrease of scotopic and mesopic sensitivity over three years was more pronounced in areas with existing (−3.51 and −7.76 dB) and new occurring RPD (−2.06 and −5.97 dB). Structure-function analysis revealed that 1 SD decrease of pORL thickness was associated with a sensitivity reduction of 3.47 dB in scotopic and 0.79 dB in mesopic testing. CONCLUSIONS. This study demonstrates progressive outer retinal degeneration and impairment of photoreceptor function in eyes with iAMD and RPD over three years. Preservation of outer retinal thickness and reduction of RPD formation may constitute meaningful surrogate endpoints in interventional trials on eyes with AMD and RPD aiming to slow outer retinal degeneration.

This study underscores the prognostic value of demographic, functional, genetic, and lesion geometry parameters in ABCA4-related retinopathy. Trial design including inclusion criteria based on these factors may provide economic benefits by selection of appropriate participants.

IMPORTANCE Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. OBJECTIVE To elucidate the contribution of common genetic variants to geographic atrophy lesion growth. DESIGN, SETTING, AND PARTICIPANTS This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). MAIN OUTCOMES The correlation between square root-transformed geographic atrophy growth rate and 7 596 219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times. MAIN OUTCOMES AND MEASURES Slopes per allele, 95% CIs, and P values of genetic variants correlated with geographic atrophy lesion growth. RESULTS A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066]; P = 4.09 × 10 −8) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95% CI, 0.068-0.143]; P = 4.07 × 10 −7) as the most likely progression-associated genes. CONCLUSIONS AND RELEVANCE These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.