Faculty Bibliography

PURPOSE: To comprehensively investigate spectral domain optical coherence tomography features associated with Type 3 neovascularization and determine the prevalence of each feature and to develop an updated staging system for Type 3 neovascularization based on spectral domain optical coherence tomography findings. METHODS: The authors retrospectively analyzed 34 eyes with new-onset Type 3 neovascularization. Spectral domain optical coherence tomography images at onset of Type 3 neovascularization, immediately after the first injection, and at the final quiescent visit were analyzed for the presence of specific optical coherence tomography features. In addition, when available, optical coherence tomography images from the visit before onset were studied. RESULTS: Among 18 eyes with preonset optical coherence tomography, 77.8% had preexisting intraretinal hyperreflective foci (precursor lesion). In the same group of eyes, 44.4% and 27.8% exhibited outer plexiform layer disruption and outer plexiform layer downward deflection, respectively. At the onset of detectable Type 3 neovascularization, all 34 eyes demonstrated a hyperreflective focus with cystoid macular edema and 85.3% exhibited disruption of the retinal pigment epithelium. Serous pigment epithelial detachment and subretinal fluid were present in 67.6% and 23.5% of eyes at onset, respectively. The rate of cystoid macular edema decreased from 100% to 17.6% after a single injection. At the final quiescent visit, focal atrophy at the site of Type 3 lesions, as evidenced by outer retinal and retinal pigment epithelium disruption developed in 88.2% and 52.9% of eyes, respectively. CONCLUSION: An updated staging system of Type 3 lesions was developed based on spectral domain optical coherence tomography findings. A precursor stage consists of a punctate hyperreflective focus in the outer retina. The subtle detection of associated outer plexiform layer disruption and downward deflection may indicate that this precursor lesion is more likely to progress to an active Type 3 neovascular lesion. Stage 1 consists of a larger intraretinal hyperreflective lesion associated with cystoid macular edema but without outer retinal disruption. Stage 2 is notable for outer retinal disruption that occurs with retinal pigment epithelium disruption in most of the cases. Stage 3 is defined by an intraretinal hyperreflective lesion that extends through the retinal pigment epithelium to vascularize a drusenoid pigment epithelial detachment creating a serous component of the pigment epithelial detachment.

PURPOSE: To enable future studies of retinal pigment epithelium (RPE) fate in the macular atrophy occurring in eyes with neovascular age-related macular degeneration (nvAMD), the authors determined how RPE morphology changes across the transition from health to atrophy in donor eyes with nvAMD. METHOD: In RPE-Bruch membrane flat mounts of 5 nvAMD eyes, the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histologic sections of 27 nvAMD eyes, RPE phenotypes were assessed at +/-500 mum and +/-100 mum from the descent of the external limiting membrane (ELM) toward the Bruch membrane. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE + BLamD were determined. Shapes of the ELM descent were recorded. RESULTS: Approaching the ELM descent, the percentage of different RPE phenotypes and the thickness of RPE, BLamD, and RPE + BLamD each stayed roughly constant. Compared with a separately described cohort of eyes with geographic atrophy, eyes with nvAMD were more likely to have RPE dysmorphia that did not worsen toward the atrophy border, thinner BLamD overall (3.25 +/- 3.46 mum vs. 7.99 +/- 7.49 mum for geographic atrophy), and a higher proportion of oblique ELM descents (47.9 vs. 31.9%). CONCLUSION: The distribution of RPE phenotypes at the transition to macular atrophy in eyes with nvAMD differs from that in primary geographic atrophy, likely reflecting greater photoreceptor loss and the effects of exudation in nvAMD. This distribution, the shape of ELM descents, and thickness profiles may be useful metrics in clinical studies of macular atrophy using optical coherence tomography and fundus autofluorescence.

PURPOSE: To localize the various levels of abnormalities in multiple evanescent white dot syndrome by comparing "en face" optical coherence tomography (OCT) and OCT angiography with various conventional imaging modalities. METHODS: In this retrospective case series, multimodal imaging was performed in 9 retinal centers on 36 patients with multiple evanescent white dot syndrome and included widefield fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography, and B-scan and "en face" C-scan enhanced depth imaging and spectral domain OCT. Optical coherence tomography angiography was also performed at the level of the superficial and deep retinal capillary plexus and choroid. RESULTS: Multiple evanescent white dot syndrome lesions were more numerous and more easily detectable with FA and FAF. Two types of lesions were identified with FAF, FA, and indocyanine green angiography: larger widely scattered "spots" (approximately 200 mu in diameter) that were hyperfluorescent with FA, hyperautofluorescent with FAF, and hyporeflective in indocyanine green angiography, representing abnormalities primarily at the retinal pigment epithelium/photoreceptor junction; and punctate "dots" (less than 100 mu in diameter) that were hyperfluorescent with FA, hyperautofluorescent, or isoautofluorescent with FAF, and hypofluorescent with indocyanine green angiography and that localized to the outer nuclear layer. These lesions colocalized with "en face" OCT. The larger confluent "spots" were hyporeflective and colocalized to the level of the ellipsoid zone, whereas smaller hyperreflective "dots" colocalized to the outer nuclear layer. The location of the "dots" in the outer nuclear layer was further confirmed by structural spectral domain optical coherence tomography which showed coalescence of the dots into hyperreflective lines extending from the external limiting membrane to the outer plexiform layer in certain cases. Optical coherence tomography angiography analysis of the retinal microvasculature and choriocapillaris and choroid were entirely unremarkable in 100% of our patients. CONCLUSION: By combining multimodal imaging, the authors propose that multiple evanescent white dot syndrome is primarily the result of inflammation at the outer photoreceptor level leading to a "photoreceptoritis" and causing loss of the inner and outer segments. Its evanescent nature suggests that the photoreceptor cell bodies remain intact ensuring complete recovery of the photoreceptor inner and outer segments in most cases, compatible with the clinical course of spontaneous resolution of white spots and dots.

Purpose: To evaluate the effects of retinal and choroidal thickness on near-infrared reflectance (NIR) scanning laser ophthalmoscopy in eyes with geographic atrophy (GA) secondary to non-neovascular age-related macular degeneration (AMD). Methods: This was a cross-sectional review of the clinical records and multimodal imaging data of eyes diagnosed with GA secondary to non-neovascular AMD. Imaging modalities included color fundus photography, fundus autofluorescence, NIR, and structural spectral-domain optical coherence tomography (SD-OCT). On SD-OCT images, the foveal retina thickness and the subfoveal choroidal thickness were measured by two independent readers. Near-infrared reflectance intensity within areas of GA was subjectively graded as hyperreflective, isoreflective, or hyporeflective and objectively estimated by using ImageJ to calculate the mean gray scale value within each GA area. A linear regression analysis was performed to model the relationship between mean NIR gray scale value and retinal and choroidal thickness. Results: One hundred four eyes of 104 patients with a mean age of 81.3 years (SD: +/-8.3) were included. The area of GA was hyperreflective on NIR in 88 eyes (85%), isoreflective in 13 eyes (12%), and hyporeflective in 3 eyes (3%). The mean foveal retinal thickness was 101.5 mum (SD: +/-54) showing no significant relationship with mean NIR (P = 0.464); and the mean subfoveal choroidal thickness was 172.6 mum (SD: +/-114.7) showing a statistically significant relationship with mean NIR intensity in the linear regression analysis (r = 0.590; r2 = 0.348; P < 0.00001). Conclusions: Variations in choroidal thickness appear to influence NIR intensity in areas of GA and have the potential to affect image interpretation. The recognition of this relationship may provide useful information regarding choroidal thickness.

PURPOSE: Subretinal drusenoid deposits (SDD) are the main structural lesion of reticular macular disease (RMD), a phenotype of age-related macular degeneration (AMD). We aim to demonstrate spatiotemporal relationships between SDD and choroidal thickness (CTh) alterations in RMD+ and RMD- eyes. METHODS: Thirty-three eyes (26 subjects) with early AMD/no SDD (RMD-) and 18 eyes (16 subjects) with early AMD/SDD (RMD+) underwent enhanced depth imaging spectral domain optical coherence tomography (SD-OCT) for CTh measurements at 11 points per scan, in 5 horizontal B scans, creating a grid of 55 points/eye. The 55 points were treated as a cluster, controlling within-subject correlation. Marginal generalized estimating equation modeling was used to estimate the association between CTh and RMD status. All eyes were divided by their median age (82 years) for stratified analyses. RESULTS: CTh was not significantly reduced in RMD+ eyes compared with RMD- eyes (mean difference [MD] -16.84 mum, P = 0.24). Among younger subjects, mean CTh was significantly reduced in RMD+ versus RMD- eyes (MD -53.72 mum, P = 0.01). Conversely, among older subjects, there was no significant difference in CTh between RMD+ and RMD-. CONCLUSIONS: In RMD, the association of SDD and CTh alterations varies with age but not by macular region. Among younger subjects (<82 years old), CTh was significantly thinner in RMD+ versus RMD- eyes.

PURPOSE: To determine if the area of the foveal avascular zone (FAZ) is correlated with visual acuity (VA) in diabetic retinopathy (DR) and retinal vein occlusion (RVO). DESIGN: Cross-sectional study. PARTICIPANTS: Ninety-five eyes of 66 subjects with DR (65 eyes), branch retinal vein occlusion (19 eyes), and central retinal vein occlusion (11 eyes). METHODS: Structural optical coherence tomography (OCT; Spectralis, Heidelberg Engineering) and OCT angiography (OCTA; Avanti, Optovue RTVue XR) data from a single visit were analyzed. FAZ area, point thickness of central fovea, central 1-mm subfield thickness, the occurrence of intraretinal cysts, ellipsoid zone disruption, and disorganization of retinal inner layers (DRIL) length were measured. VA was also recorded. Correlations between FAZ area and VA were explored using regression models. Main outcome measure was VA. RESULTS: Mean age was 62.9+/-13.2 years. There was no difference in demographic and OCT-derived anatomic measurements between branch retinal vein occlusion and central retinal vein occlusion groups (all P >/= 0.058); therefore, data from the 2 groups were pooled together to a single RVO group for further statistical comparisons. Univariate and multiple regression analysis showed that the area of the FAZ was significantly correlated with VA in DR and RVO (all P /= 0.210). Remaining variables evaluated in this study were not predictive of VA (all P >/= 0.225). CONCLUSIONS: The area of the FAZ is significantly correlated with VA in DR and RVO and this relationship is modulated by patient age. Further study about FAZ area and VA correlations during the natural course of retinal vascular diseases and following treatment is warranted.

Purpose: Drusenoid pigment epithelial detachments (PEDs) are a defined path to atrophy in age-related macular degeneration (AMD). We analyzed the relationships between retinal pigment epithelium (RPE) and drusen volume changes during the PED lifecycle, using spectral-domain optical coherence tomography (SD-OCT). Methods: Twenty-one cases of drusenoid PED tracked using SD-OCT through periods of growth and collapse were evaluated. Volumetric calculations and piece-wise linear regression analysis were used to determine the breakpoint between growth and collapse. Spectral-domain OCT scans were independently evaluated for the appearance of intraretinal hyperreflective foci, acquired vitelliform lesions (AVLs), and disruptions to the RPE+basal lamina band. Timing of these events with respect to the breakpoint was statistically evaluated. Morphometric characteristics of drusenoid PEDs were correlated with rate of PED collapse and final visual acuity. Results: Mean age of subjects was 75.3 years and mean period of follow up was 4.1 years (median 4.5 years; range, 0.6-6.6 years). The lifecycle of drusenoid PEDs was asymmetric, in that the rate of collapse (0.199 mm3/month) is significantly faster (P < 0.001) than the rate of growth (0.022 mm3/month). Appearance of intraretinal hyperreflective foci and AVLs preceded the breakpoint (both P < 0.001). The timing of disruptions to the RPE+basal lamina band did not differ from the breakpoint (P = 0.510). Maximal height, volume, and diameter of drusenoid PEDs were inversely correlated with final visual acuity (all P < 0.001) and positively correlated with the rate of PED collapse (all P < 0.001). Conclusions: Spectral-domain OCT signatures, plausibly attributable to anteriorly migrated RPE and disintegration of the RPE layer, precede or occur simultaneously with changes in volume of drusenoid PED during the lifecycle of this lesion.

Purpose: We used fractal dimensional analysis to analyze retinal vascular disease burden in eyes with diabetic retinopathy using spectral-domain optical coherence tomography angiography (OCTA). Methods: A retrospective study was performed of 13 eyes with diabetic retinopathy without diabetic macular edema and 56 control eyes. Optical coherence tomography angiography images were acquired using the RTVue XR Avanti. Automated segmentation was obtained through the superficial and deep capillary plexuses for each eye. Grayscale OCTA images were standardized and binarized using ImageJ. Fractal box-counting analyses were performed using Fractalyse. Fractal dimensions (FD) as well as software-generated vascular density analyses of the superficial and deep capillary plexuses were compared between diabetic and control eyes using 2-tailed t-tests and 1-way multivariate ANOVA (MANOVA) analyses. Results: The superficial and deep plexuses from diabetic and control eyes were analyzed. The average FD for diabetic eyes was significantly lower than control eyes for the superficial (P = 4.513 x 10-3) and deep (P = 2.653 x 10-3) capillary plexuses. In diabetic eyes, the vascular density also was significantly reduced in the superficial (P = 8.068 x 10-5) and deep (P = 3.120 x 10-6) capillary plexuses. One-way MANOVA showed a significant difference between diabetic and control eyes. Conclusions: The OCTA FD is significantly reduced in the superficial and deep capillary plexuses in eyes with diabetic retinopathy. Applying fractal analysis to OCTA imaging holds the potential to establish quantitative parameters for microvascular pathology.