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Purpose To evaluate morphologic and microvascular differences between eyes with and without subretinal fibrosis (SF) caused by neovascular age-related macular degeneration (nAMD). Methods Patients with nAMD with a minimum history of 12 months of anti-VEGF treatment were prospectively included in this cross-sectional study. Patients were imaged using standard imaging, swept-source optical coherence tomography angiography for quantitative microvascular analysis and polarization-sensitive OCT as an ancillary method for automated SF segmentation. The presence of reticular pseudodrusen, hyperreflective foci (HRF), and outer retinal tubulation (ORT) were also evaluated. Results Sixty eyes of 60 participants (37 female) with nAMD and a mean 3.1 (±2.7)-year history of anti-VEGF treatment were included, 20 (33%) of which were diagnosed with SF. Eyes with SF had a higher prevalence of ORT (P < 0.001) and a lower prevalence of HRF (P = 0.004) than eyes without SF. Fifty eyes were analyzed quantitatively for microvascular biomarkers. Eyes with SF had a larger greatest vascular caliber (P = 0.001) and greatest linear diameter (P = 0.042), a larger microvascular neovascularization (MNV) area (P = 0.026), larger vessel area (P = 0.037), higher number of vessel junctions (P = 0.025), longer total vessel length (P = 0.027), higher number of vessel endpoints (P = 0.007), and higher endpoint density (P = 0.047). Conclusions This multimodal imaging approach demonstrated in vivo microvascular and morphological differences in eyes with and without SF. Eyes with SF tend to have larger MNV lesions with thicker vessels and are often associated with the presence of ORT. Translational Relevance This study points out imaging biomarkers in patients with SF, which may help identifying high-risk patients.

Purpose Cardiovascular disease and foremost coronary heart disease (CHD) are the worldwide leading causes of death. The aim of this study was to use non-invasive, multimodel retinal imaging to define microvascular features in patients with and without coronary angiography (CA)-confirmed CHD. Methods In this prospective, cross-sectional pilot study we included adult patients who presented to a tertiary referral center for elective CA due to suspected CHD. All patients underwent widefield fundus photography for retinopathy grading. Optical coherence tomography angiography was used to measure vessel density (VD) of the individual capillary plexuses in 6 × 6-mm macular volume scans. Adaptive optics imaging was performed to assess the first-order arteriolar lumen diameter (LD), total diameter (TD), wall-to-lumen ratio (WLR), and wall cross-section area, as well as to qualitatively describe vessel morphology. Results Of the included 45 patients (13 females; 65 ± 10 years old), 27 were confirmed with CHD in elective CA. The most prevalent retinal vascular pathologies were arteriovenous nickings, focal arterial narrowings, and microaneurysms. VD in the superficial capillary plexus, deep capillary plexus, and choriocapillaris was lower in CHD patients, although the odds ratios were not significantly different from 1 (P = 0.06-0.92). Median arterial LD, TD, and WLR values were 98.3 µm (interquartile range [IQR] = 13.0), 122.9 µm (IQR = 17.6), and 0.26 µm (IQR = 0.07), respectively, with a trend toward a higher WLR in CHD patients. Conclusions In a cardiovascular risk population, high-resolution quantitative and qualitative microvascular phenotyping in the retina may provide valuable subclinical indicators for coronary artery impairment, although larger clinical trials are needed. Translational relevance Subclinical retinal microvascular changes may serve as non-invasive, cost-effective biomarkers for risk stratification of patients with CHD.

Purpose The purpose of this study was to assess density and morphology of cone photoreceptors (PRs) and corresponding retinal sensitivity in ischemic compared to nonischemic retinal capillary areas of diabetic eyes using adaptive optics optical coherence tomography (AO-OCT) and microperimetry (MP). Methods In this cross-sectional, observational study five eyes of four patients (2 eyes with proliferative diabetic retinopathy (DR) and 3 eyes moderate nonproliferative DR) were included. PR morphology and density was manually assessed in AO-OCT en face images both at the axial position of the inner-segment outer segment (IS/OS) and cone outer segment tips (COSTs). Retinal sensitivity was determined by fundus-controlled microperimetry in corresponding areas (MP-3, Nidek). Results In AO-OCT, areas affected by capillary nonperfusion showed severe alterations of cone PR morphology at IS/OS and COST compared to areas with intact capillary perfusion (84% and 87% vs. 9% and 8% of area affected for IS/OS and COST, respectively). Mean reduction of PR signal density in affected areas compared to those with intact superficial capillary plexus (SCP) and deep capillary plexus (DCP) perfusion of similar eccentricity was –38% at the level of IS/OS (P = 0.01) and –39% at the level of COST (P = 0.01). Mean retinal sensitivity was 10.8 ± 5.4 in areas affected by DCP nonperfusion and 28.2 ± 1.5 outside these areas (P < 0.001). Conclusions Cone PR morphology and signal density are severely altered in areas of capillary nonperfusion. These structural changes are accompanied by a severe reduction of retinal sensitivity, indicating the importance of preventing impaired capillary circulation in patients with DR.

Purpose To refine estimates of macular soft drusen abundance in eyes with age-related macular degeneration (AMD) and evaluate hypotheses about drusen biogenesis, we investigated topographic distribution and growth rates of drusen by optical coherence tomography (OCT). We compared results to retinal features with similar topographies (cone density and macular pigment) in healthy eyes. Methods In a prospective study, distribution and growth rates of soft drusen in eyes with AMD were identified by human observers in OCT volumes and analyzed with computer-assistance. Published histologic data for macular cone densities (n = 12 eyes) and in vivo macular pigment optical density (MPOD) measurements in older adults with unremarkable maculae (n = 31; 62 paired eyes, averaged) were revisited. All values were normalized to Early Treatment Diabetic Retinopathy Study (ETDRS) subfield areas. Results Sixty-two eyes of 44 patients were imaged for periods up to 78 months. Soft drusen volume per unit volume at baseline is 24.6-fold and 2.3-fold higher in the central ETDRS subfield than in outer and inner rings, respectively, and grows most prominently there. Corresponding ratios (central versus inner and central versus outer) for cone density in donor eyes is 13.3-fold and 5.1-fold and for MPOD, 24.6 and 23.9-fold, and 3.6 and 3.6-fold. Conclusions Normalized soft drusen volume in AMD eyes as assessed by OCT is ≥ 20-fold higher in central ETDRS subfields than in outer rings, paralleling MPOD distribution in healthy eyes. Data on drusen volume support this metric for AMD risk assessment and clinical trial outcome measure. Alignment of different data modalities support the ETDRS grid for standardizing retinal topography in mechanistic studies of drusen biogenesis.

Purpose To investigate the impact of subretinal drusenoid deposits (SDD) and photoreceptor integrity on global and local geographic atrophy (GA) progression. Methods Eighty-three eyes of 49 patients, aged 50 years and older with GA secondary to age-related macular degeneration (AMD), were prospectively included in this study. Participants underwent spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging at baseline and after 12 months. The junctional zone and presence of SDD were delineated on SD-OCT and FAF images. Linear mixed models were calculated to investigate the association between GA progression and the junctional zone area, baseline GA area, age, global and local presence of SDD and unifocal versus multifocal lesions. Results The area of the junctional zone was significantly associated with the progression of GA, both globally and locally (all P < 0.001). SDD were associated with faster growth in the overall model (P = 0.039), as well as in the superior-temporal (P = 0.005) and temporal (P = 0.002) sections. Faster progression was associated with GA baseline area (P < 0.001). No difference was found between unifocal and multifocal lesions (P > 0.05). Age did not have an effect on GA progression (P > 0.05). Conclusions Photoreceptor integrity and SDD are useful for predicting global and local growth in GA. Investigation of the junctional zone is merited because this area is destined to become atrophic. Photoreceptor loss visible on SD-OCT might lead to new structural outcome measurements visible before irreversible loss of retinal pigment epithelium occurs.

Purpose To visualize and characterize photoreceptor (PR) layers on a subcellular level in healthy and pathologically aged eyes using adaptive-optics optical coherence tomography technology (AO-OCT). Methods AO-OCT scanning was performed within a 2° × 2° field of view, focused on the PR layer at different retinal regions in healthy aged eyes (n = 32 eyes/16 subjects; 62- to 85-years old), eyes with early to intermediate AMD (n = 16 eyes/8 subjects, 65- to 83-years old), and eyes with advanced nonneovascular AMD (n = 16 eyes/8 subjects, 61- to 84-years old). Areas of interest were determined by AO-fundus camera, which is part of the AO-OCT system and spectral-domain (SD)-OCT. PR integrity was evaluated in AO-OCT en face and cross-sectional images at the level of inner/outer segment junction (IS/OS) and cone/PR end tips (COST/ETPR). Results AO-OCT in healthy eyes showed clearly distinguishable and regular IS/OS and COST patterns and an inverse relation between cone density and eccentricity. In early to intermediate AMD, PR in between drusen showed more irregular patterns (P < 0.001) and slightly lower PR density (P ≤ 0.002). Drusen caused attenuated and distorted signals and a loss of PR mosaic. In advanced AMD, IS/OS and COST patterns were affected to different degrees between surrounding area, junctional zone, and atrophic area (P < 0.001), ranging from reduced PR densities to total signal loss. Conclusions AO-OCT imaging allows the three-dimensional visualization of different PR layers in patients with AMD and age-matched healthy subjects. Thereby, AO-OCT provides a unique insight into PR morphology and shows potential to fill the gap between conventional OCT and histologic examination of the retina.

Purpose To identify the spatial distribution of exudative features of choroidal neovascularization in neovascular age-related macular degeneration (nAMD) based on the localization of intraretinal cystoid fluid (IRC), subretinal fluid (SRF), and pigment-epithelial detachment (PED). Methods This retrospective cross-sectional study included spectral-domain optical coherence tomography volume scans (6 × 6 mm) of 1341 patients with treatment-naive nAMD. IRC, SRF, and PED were detected on a per-voxel basis using fully automated segmentation algorithms. Two subsets of 37 volumes each were manually segmented to validate the automated results. The spatial correspondence of components was quantified by computing proportions of IRC-, SRF-, or PED-presenting A-scans simultaneously affected by the respective other pathomorphologic components on a per-patient basis. The median across the population is reported. Odds ratios between pairs of lesions were calculated and tested for significance pixel wise. Results Automated image segmentation was successful in 1182 optical coherence tomography volumes, yielding more than 61 million A-scans for analysis. Overall, 81% of eyes showed IRC, 95% showed SRF, and 92% showed PED. IRC-presenting A-scans also showed SRF in a median 2.5%, PED in 32.9%. Of the SRF-presenting A-scans, 0.3% demonstrated IRC, 1.4% PED. Of the PED-presenting A-scans, 5.2% contained IRC, 2.0% SRF. Similar patterns were observed in the manually segmented subsets and via pixel-wise odds ratio analysis. Conclusions Automated analyses of large-scale datasets in a cross-sectional study of 1182 patients with active treatment-naive nAMD demonstrated low spatial correlation of SRF with IRC and PED in contrast to increased colocalization of IRC and PED. These morphological associations may contribute to our understanding of functional deficits in nAMD.

Purpose Alterations in retinal oxygen metabolism and retinal microcirculation are signs of impending diabetic retinopathy (DR). However, if specific retinal regions are primarily affected is so far unknown. The purpose of this study was to investigate if retinal oxygen saturation (SO2) and microvascular hemodynamic parameters follow a distinct regional pattern in patients with diabetes but no DR. Methods Patients with type II diabetes without clinically apparent DR were imaged as follows: SO2 in peripapillary vessels was assessed with dual-wavelength oximetry. Optical coherence tomography angiography (OCTA) scans were acquired with a prototype system using a swept-source laser with an effective 400 kHz A-scan rate and 16° field of view. Regional flow indices termed "flux" were calculated for the peripapillary microvasculature. Parafoveal capillary density was evaluated with the commercially available AngioVue OCTA. Results Twenty-nine eyes of 16 consecutive patients (59 ± 10 years, 6 females) were included in this study. SO2 differed significantly between quadrants (P < 0.001), with a decreasing pattern from the upper nasal through the lower nasal, the upper temporal and the lower temporal quadrant in arterioles and venules. In contrast, peripapillary flux followed an increasing trend from nasally to temporally. Peripapillary and parafoveal microvascular hemodynamic parameters demonstrated no significant regional variability as observed for retinal oxygenation. Conclusions Metabolic imaging identified regional differences in retinal SO2 without an associated topographic variance in microvascular hemodynamics in type II diabetes without DR. Future studies should focus on the mechanisms causing this heterogeneity in metabolic demand.

Purpose To determine the distribution of leakage on fluorescein angiography (FA) and explore the clinically protective role of astrocytes against damage to the inner blood retinal barrier (iBRB) in diabetic macular edema (DME). Methods A consecutive case series of 87 eyes of 87 patients with DME was included. We measured the leakage area in each field of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid on late-phase FA images. The normative thickness of the nerve fiber layer (NFL), in which the astrocytes are confined, was derived from a previous work using spectral-domain optical coherence tomography. We explored the difference in leakage areas in every two fields. Moreover, we investigated the correlation between the mean of the leakage area and the mean of thickness of the NFL in each ETDRS field. Results The leakage areas in the nasal, inferior, superior, and temporal fields were 2.34 mm2, 2.84 mm2, 3.03 mm2, and 3.96 mm2. The difference in leakage area between each two fields was significant in all cases (P < 0.05) except between the inferior and superior fields (P = 0.65). The temporal field was the only field that showed leakage in all 87 cases. The correlation between the leakage area and the thickness of the NFL in the ETDRS fields was negative and highly significant: r = -0.96 (95% confidence interval -0.99 to -0.02). Conclusion The distribution of leakage correlates inversely and statistically significantly with the thickness of the NFL, suggesting astrocytes in the NFL play a pivotal role in preventing damage to the iBRB and subsequent evolution of microaneurysms in DME. Moreover, fluid extravasation due to damage to the iBRB is expressed earlier in the temporal than in the other three fields.

Purpose The purpose of this study was to predict low and high anti-VEGF injection requirements during a pro re nata (PRN) treatment, based on sets of optical coherence tomography (OCT) images acquired during the initiation phase in neovascular AMD. Methods Two-year clinical trial data of subjects receiving PRN ranibizumab according to protocol specified criteria in the HARBOR study after three initial monthly injections were included. OCT images were analyzed at baseline, month 1, and month 2. Quantitative spatio-temporal features computed from automated segmentation of retinal layers and fluid-filled regions were used to describe the macular microstructure. In addition, best-corrected visual acuity and demographic characteristics were included. Patients were grouped into low and high treatment categories based on first and third quartile, respectively. Random forest classification was used to learn and predict treatment categories and was evaluated with cross-validation. Results Of 317 evaluable subjects, 71 patients presented low (≤5), 176 medium, and 70 high (≥16) injection requirements during the PRN maintenance phase from month 3 to month 23. Classification of low and high treatment requirement subgroups demonstrated an area under the receiver operating characteristic curve of 0.7 and 0.77, respectively. The most relevant feature for prediction was subretinal fluid volume in the central 3 mm, with the highest predictive values at month 2. Conclusions We proposed and evaluated a machine learning methodology to predict anti-VEGF treatment needs from OCT scans taken during treatment initiation. The results of this pilot study are an important step toward image-guided prediction of treatment intervals in the management of neovascular AMD.

Purpose To develop a data-driven interpretable predictive model of incoming drusen regression as a sign of disease activity and identify optical coherence tomography (OCT) biomarkers associated with its risk in intermediate age-related macular degeneration (AMD). Methods Patients with AMD were observed every 3 months, using Spectralis OCT imaging, for a minimum duration of 12 months and up to a period of 60 months. Segmentation of drusen and the overlying layers was obtained using a graph-theoretic method, and the hyperreflective foci were segmented using a voxel classification method. Automated image analysis steps were then applied to identify and characterize individual drusen at baseline, and their development was monitored at every follow-up visit. Finally, a machine learning method based on a sparse Cox proportional hazard regression was developed to estimate a risk score and predict the incoming regression of individual drusen. Results The predictive model was trained and evaluated on a longitudinal dataset of 61 eyes from 38 patients using cross-validation. The mean follow-up time was 37.8 ± 13.8 months. A total of 944 drusen were identified at baseline, out of which 249 (26%) regressed during follow-up. The prediction performance was evaluated as area under the curve (AUC) for different time periods. Prediction within the first 2 years achieved an AUC of 0.75. Conclusions The predictive model proposed in this study represents a promising step toward image-guided prediction of AMD progression. Machine learning is expected to accelerate and contribute to the development of new therapeutics that delay the progression of AMD.

Purpose To identify and quantify subretinal fibrosis in eyes with advanced neovascular age-related macular degeneration (nAMD) using polarization-sensitive optical coherence tomography (PS-OCT). Methods Eyes of patients with subretinal fibrosis secondary to nAMD were included in this case series. All patients underwent a complete ophthalmic examination to clearly identify advanced nAMD lesions with fibrosis. Examinations of PS-OCT were performed using a novel system with an integrated eye tracker. Areas of fibrosis in PS-OCT, automatically segmented using a custom-built algorithm, were compared with conventional imaging modalities including spectral-domain OCT, fluorescein angiography, and color fundus photography in their potential to visualize fibrosis in nAMD. Results Fifteen eyes of 15 consecutive patients were included. In polarization-sensitive OCT B-scans, a distinct "column-like" pattern was observed in averaged axis orientation images. En face analysis provided a precise mapping of the fibrotic scar component. Fibrous tissue was selectively identified by PS-OCT based on birefringence in all lesions, whereas in SD-OCT, subretinal hyperreflective material (SHRM) could not be further classified into scar tissue, fibrovascular material, or other AMD-specific material. Based on simultaneous polarization analyses in PS-OCT, the level of RPE alteration could be evaluated as well, showing thinning and loss of RPE associated with subretinal fibrosis. Conclusions Using PS-OCT, subretinal fibrosis can be identified as an intrinsically birefringent structure and can be segmented based solely on tissue-specific contrast. Polarization-sensitive OCT offers a unique method to identify clinically relevant components of SHRM (i.e., neovascular tissue versus fibrous tissue) and therefore allows for an optimized disease management and evaluation of therapeutic strategies.

PURPOSE To determine the subclinical RPE lesions detected by tissue selective polarization-sensitive optical coherence tomography (PS-OCT) in eyes with central serous chorioretinopathy (CSC) and to compare PS-OCT findings to current imaging standards. METHODS In this prospective observational case series, individuals with unilateral or bilateral active CSC were imaged using PS-OCT at baseline and after resolution of serous retinal detachment. Features seen on PS-OCT were compared with corresponding lesions as seen on conventional, intensity-based spectral-domain OCT (SD-OCT), fluorescein angiography, and indocyanine green angiography (ICGA). Features of RPE evaluated by PS-OCT were as follows: area and volume of pigment epithelium detachment (PED), presence of RPE aggregations, RPE skip lesions, RPE thickening, and RPE atrophy. RESULTS Twenty-five study eyes and 23 fellow eyes of 25 participants (2 women, 23 men; mean age ± standard deviation = 40.5 ± 7.4 years) were included and followed for 6.1 ± 3 months. Study eyes and fellow eyes with recurrent CSC showed more RPE abnormalities in PS-OCT than eyes with acute CSC, which correlated well with lesions in ICGA. Closure of the leakage site was observed only in eight (32%) eyes after resolution of subretinal fluid (SRF). All study eyes showed widespread RPE aggregates and 23 (92%) eyes showed RPE skip lesions after resolution of SRF. CONCLUSIONS Features of RPE indicative of previous episodes of CSC detected by PS-OCT correspond well to choroidal lesions in ICGA. In addition, noninvasive PS-OCT imaging enables detection of RPE microrips and aggregations invisible to clinical examination or SD-OCT, thus providing valuable information about disease processes in vivo.