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PURPOSEValidated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/ PRAME classifier.MATERIALS AND METHODSThis study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS).RESULTS15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/ PRAME (-), 80.6% (95% CI, 73.9 to 87.9) for class 1/ PRAME (+), 58.3% (95% CI, 51.1 to 66.4) for class 2/ PRAME (-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/ PRAME (+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter.CONCLUSIONIn the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/ PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Purpose: To review sustained-release intraocular platforms used to treat diseases of the retina and choroid. Methods: A literature review of the current applications of biomaterials for sustained-release therapy in retinal and choroidal diseases was performed. Results: Retinal and choroidal diseases, such as neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), and uveitis, are commonly treated using intravitreal (IVT) therapies that require frequent IVT injections. Multiple sustained-release options for IVT therapy have been approved by the US Food and Drug Administration for the treatment of inflammatory eye diseases, including noninfectious uveitis, infectious diseases, and exudative retinal diseases (eg, retinal venous occlusive disease and DME) using drugs such as fluocinolone acetonide, ganciclovir, and dexamethasone. The platforms for these drugs are biodegradable or nonbiodegradable. They use biomaterials such as polymers and hydrogels and are typically implanted surgically or injected into the vitreous, where they release the drug gradually over months or years. Building on these technologies, novel platforms are being studied that are intended to treat conditions including nAMD, DR, DME, and uveitis. These platforms are being tested for their safety, efficacy, and ability to reduce the injection and visit burden. Conclusions: Multiple sustained-release ocular drug-delivery platforms are currently commercially available, and many new sustained-release IVT platforms are being investigated. The hope is that meaningfully reducing the injection burden by extending intervals between treatments while maintaining optimal efficacy will improve long-term outcomes., Competing Interests: Dr. Wykoff: Consulting—4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Annexon, Apellis, Arrowhead, Ascidian, Bayer, Bausch+ Lomb, Boehringer Ingelheim, Cholgene, Clearside, Curacle, Eyebiotech, EyePoint, Foresite, Frontera, Genentech, Gyroscope, Iveric Bio, Janssen, Kato, Kiora, Kodiak, Kriya, Merck, Nanoscope, Neurotech, NGM, Notal Vision, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, ONL, Opthea, Oxular, Palatin, PerceiveBio, Perfuse, Ray, RecensMedical, Regeneron, RegenxBio, Resonance, Roche, Sanofi, SciNeuro, Stealth, Surrozen, Suzhou Raymon, THEA, TissueGen, Valo. Grants—4DMT, Adverum, AffaMed, Alexion, Alimera, Alkahest, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Curacle, EyePoint, Gemini, Genentech, GlaxoSmithKline, Gyroscope, Ionis, iRenix, Iveric Bio, Janssen, Kodiak, LMRI, McMaster University, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, OliX, Ophthotech, Opthea, Oxurion, Oxular, Oyster Point, PerceiveBio, Regeneron, RegenxBio, Rezolute, Roche, SamChunDang Pharm, Sandoz, Shanghai Henlius, UNITY, Verily, Xbrane. Stock options (not owner)—ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, Vitranu. Dr. Kuppermann: Consulting—Allegro Ophthalmics, Allergan/AbbVie, Aviceda Therapeutics, Bausch+Lomb, Boehringer Ingelheim, Clearside, EyeBio, Eyedaptic, EyePoint, Genentech Inc, Glaukos Corporation, InflammX Therapeutics, Iveric Bio, jCyte, Molecular Partners, Neurotech, Novartis Pharmaceuticals, Ocular Therapeutix, Regeneron Pharmaceuticals Inc, ReVana Therapeutics, Ripple Therapeutics, Roche Pharmaceuticals, Stealth, Theravance Biopharma. Research support—Allergan, Apellis, Clearside, Genentech Inc, Ionis, Iveric Bio, Novartis Pharmaceuticals, Regeneron Pharmaceuticals Inc, RegenxBio. Speaker fees—Allergan, Genentech, Roche. Dr. Kuppermann acknowledges an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute. Dr. Regillo: Consulting—4DMT, Adverum, Allergan, Annexon, Apellis, Aviceda, Bausch and Lomb, Clearside, Cognition, Eyepoint, Genentech, Iveric, Janssen, Kodiak, Lineage, Merck, NGM, Novartis, Ocugen, Ocuterra, Occuphire, Opthea, Ray, RegenxBio, Stealth, Thea, Zeiss. Research grant support—Adverum, Allergan, Annexon, Apellis, Astellas, EyePoint, Genentech, Gyroscope, Iveric, Janssen, Kodiak, Lineage, NGM, Notal, Novartis, Ocugen, Ocuterra, Opthea, Regeneron, RegenxBio. Dr. Chang: Consulting—Genentech, RegenxBio, Iveric Bio. Research support—Regeneron, Allergan, Novartis, NGM, Opthea, Eyebio, OcuTerra, Alexion, Mylan. Dr. Hariprasad: Consulting/speaker fees—Alimera Sciences, Allergan, EyePoint, Regeneron, Biogen, Apellis, Iveric Bio. Drs. Duker, Altaf, and Saïm are employees of EyePoint Pharmaceuticals., (© The Author(s) 2024.)

Purpose: To assess the long-term safety and clinical outcomes of a ganciclovir intravitreal implant in patients with cytomegalovirus (CMV) retinitis. Methods: A retrospective study was performed of patients with CMV retinitis treated with a ganciclovir intravitreal implant. Results: The study included 13 patients (16 eyes) previously treated with a ganciclovir intravitreal implant. The mean time since the last implant placement was 21.3 years and the mean total duration of follow-up, 22.7 years. Visual acuity (VA) ranged from 20/25 to light perception, with 56% of eyes maintaining a VA of 20/60 or better at the most recent follow-up examination. Common ocular complications included epiretinal membrane (38%), macular fibrosis/scarring (25%), retinal detachment (RD) (25%), implant dislocation (25%), and immune reactivation uveitis (19%). Intraocular surgery was required in 10 eyes (63%), with the most frequent being cataract extraction (31%), pars plana vitrectomy (PPV) for implant removal (19%), and PPV for RD (13%). Conclusions: Results show the long-term safety of the ganciclovir intravitreal implant despite its residual inactive inert shell. Complication rates are consistent with those expected from infectious sequelae., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Duker is an employee of EyePoint Pharmaceuticals., (© The Author(s) 2024.)

Background: This study aimed to develop a deep learning (DL) algorithm that enhances the quality of a single-frame enface OCTA scan to make it comparable to 4-frame averaged scan without the need for the repeated acquisitions required for averaging., Methods: Each of the healthy eyes and eyes from diabetic subjects that were prospectively enrolled in this cross-sectional study underwent four repeated 6 × 6 mm macular scans (PLEX Elite 9000 SS-OCT), and the repeated scans of each eye were co-registered to produce 4-frame averages. This prospective dataset of original (single-frame) enface scans and their corresponding averaged scans was divided into a training dataset and a validation dataset. In the training dataset, a DL algorithm (named pseudoaveraging) was trained using original scans as input and 4-frame averages as target. In the validation dataset, the pseudoaveraging algorithm was applied to single-frame scans to produce pseudoaveraged scans, and the single-frame and its corresponding averaged and pseudoaveraged scans were all qualitatively compared. In a separate retrospectively collected dataset of single-frame scans from eyes of diabetic subjects, the DL algorithm was applied, and the produced pseudoaveraged scan was qualitatively compared against its corresponding original., Results: This study included 39 eyes that comprised the prospective dataset (split into 5 eyes for training and 34 eyes for validating the DL algorithm), and 105 eyes that comprised the retrospective test dataset. Of the total 144 study eyes, 58% had any level of diabetic retinopathy (with and without diabetic macular edema), and the rest were from healthy eyes or eyes of diabetic subjects but without diabetic retinopathy and without macular edema. Grading results in the validation dataset showed that the pseudoaveraged enface scan ranked best in overall scan quality, background noise reduction, and visibility of microaneurysms (p < 0.05). Averaged scan ranked best for motion artifact reduction (p < 0.05). Grading results in the test dataset showed that pseudoaveraging resulted in enhanced small vessels, reduction of background noise, and motion artifact in 100%, 82%, and 98% of scans, respectively. Rates of false-positive/-negative perfusion were zero., Conclusion: Pseudoaveraging is a feasible DL approach to more efficiently improve enface OCTA scan quality without introducing notable image artifacts., (© 2023. Brazilian Retina and Vitreous Society.)

Purpose: To describe retinal pigment epithelium (RPE) aperture preceding the collapse of retinal pigment epithelium detachments (RPED) in eyes with neovascular and non-neovascular age-related macular degeneration (AMD)., Methods: Medical records from five patients with RPE aperture associated with vascular and avascular RPED were reviewed between 2010 and 2021 at the New England Eye Center at Tufts Medical Center. Main outcome measures were analysis of RPE aperture characteristics and temporal course of RPED collapse., Results: RPE apertures were identified in six eyes from five women (mean age of 72.6 years). Two eyes had neovasacular AMD and four eyes had non-neovascular AMD. The RPE aperture initially appeared as a discontinuity at the apex of the RPED without rippling or retraction. Each aperture was associated with hypertransmission of OCT signal into the choroid as well as hyperreflective foci. The mean time between the appearance of the RPE aperture to near complete collapse of the RPED was 9 months. Following RPED collapse, one eye developed choroidal neovascularization, three eyes progressed to geographic atrophy, one eye had recurrence of the RPED, and one eye remained unchanged., Conclusion: RPE aperture is a characteristic OCT finding that can be observed in avascular or vascularized RPED secondary to AMD. RPE apertures precede RPED collapse, which are most likely to occur within nine months of RPE aperture detection.

While ocular complications of systemic medications are uncommon, it is important to recognize that vision-threatening toxicities can occur. This review details the vision-threatening adverse effects of a select group of commonly prescribed systemic medications and describes the recommended screening guidelines for those that are particularly high risk.

Background and Objective: The purpose of this article is to demonstrate the optical coherence tomography angiography (OCTA) Analysis Toolkit (OAT), a custom-designed software package, as a repeatable and reproducible tool for computing OCTA metrics across different devices., Materials and Methods: Fourteen participants were imaged using three devices. Foveal avascular zone, vessel index, vessel length index, and vessel diameter index were calculated using the OAT. Repeatability and reproducibility were assessed using the coefficient of variation and interclass correlation coefficient (ICC)., Results: Analysis of identical images demonstrated perfect levels of repeatability for all metrics (coefficient of variation 0%), which was a consequence of the software being deterministic (ie, producing the same outputs for the same inputs). Foveal avascular zone ICC values were in the excellent-to-good range (I CC > 0.6) for all devices. All values for vessel index (VI), vessel length index, and vessel diameter index fell in the good-to-fair (I CC > 0.4) or excellent-to-good range, except for vessel index analysis in the Cirrus device (I CC = 0.34)., Conclusions: The OAT appears to be a reliable tool that may enable comparison between OCTA data sets acquired on different imaging instruments, thereby facilitating a more consistent approach to OCTA analysis. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:114-122.] .

Background: The CLOSE study group proposes an updated surgical classification for large macular holes based on a systematic review of new treatments. Recently, many new techniques have been introduced to treat large full-thickness macular holes (FTMH); although the indications are not clear. An updated surgical classification is needed to help surgical decision-making., Methods: We gathered published series by the CLOSE Study Group members and from literature search until June 2021. Techniques included: internal limiting membrane peeling (ILM peeling), ILM flaps, macular hydrodissection (macular hydro), human amniotic membrane graft (hAM), and autologous retinal transplantation (ART). Within each technique, chi-square test assessed association between the minimal linear diameter (MLD) (in µm) and closure rate; the postoperative best-corrected visual acuity (BCVA) gains were compared among groups., Results: Data extraction included 31 published articles: total of 1135 eyes. Eyes were divided into the following groups: ILM peel (n: 683), ILM Flap (n: 233), macular hydrodissection (n: 64), hAM (n: 59), and ART (n: 96). The initial BCVA and size were heterogenous between the groups. ILM peel showed the best results in large FTMH ≤ 535 µm (closure rate 96.8%); adjusted mean BCVA: 0.49 (LogMAR) with a statistical difference among groups. Large FTMH between 535 and 799 µm: ILM flap technique showed better results (closure rate 99.0%); adjusted mean BCVA: 0.67(LogMAR); also with a statistical difference. For large FTMH ≥ 800 µm more invasive techniques are required. Use of hAM, macular hydrodissection and ART showed higher closure rates for this category (100%, 83.3% and 90.5% respectively), and adjusted mean BCVA varied from 0.76 to 0.89. Although there was no statistical difference between those techniques for this group due to the smaller number of cases., Conclusions: The CLOSE study group demonstrated the potential usefulness of a new surgical classification for large FTMHs and propose OCT biomarkers for use in clinical practice and future research. This new classification demonstrated that Large (400-550 µm) and X-Large (550-800 µm) holes can be treated highly successfully with ILM peel and ILM flap techniques, respectively. Further studies are necessary for the larger FTMHs (XX-Large and Giant), using the CLOSE classification, in order to determine which technique is better suited for each hole size and characteristics., (© 2023. The Author(s).)

Background and Objective: To examine the relationship between gene expression profile class and tumor thickness reduction as measured by ultrasonography in response to plaque brachytherapy using a single-center, retrospective cohort study., Methods: A total of 15 patients with choroidal melanoma who underwent biopsy for gene expression profiling and were treated with plaque brachytherapy from a single institution from 12/8/14 through 12/19/19 were retrospectively reviewed for clinical characteristics and rate of tumor regression. Ultrasonographic B-scan tumor height was recorded just prior to plaque placement and following plaque removal in the patient's chart to assess percent reduction in tumor thickness from baseline., Results: A total of 15 patients met inclusion criteria and were analyzed in this study. Minimum follow-up was 6 months after plaque removal. The percent regression in tumor thickness from baseline as measured by ultrasonography was greater for class 2 tumors than for class 1 tumors at 12-month follow up after treatment, and this difference was statistically significant (P = 0.012). There was no statistical significance in reduction at 3 months (P = 0.46) and 9 months (P = 0.10) after plaque brachytherapy. Although not statistically significant, class 2 tumors appeared to regress more rapidly than class 1 tumors in response to radiation., Conclusions: In this study, class 2 choroidal melanoma tumors show a more rapid anatomic response to treatment than class 1 tumors at 12 months post plaque brachytherapy., (© 2022. The Author(s).)

Purpose: To assess global, zonal, and local correlations between vessel density changes measured by optical coherence tomography angiography and retinal sensitivity measured by microperimetry across diabetic retinopathy severity., Methods: Diabetic patients and nondiabetic controls underwent optical coherence tomography angiography imaging and microperimetry testing. Pearson's correlation was used to assess associations between average sensitivity and skeletonized vessel density (SVD) or foveal avascular zone area centrally. Linear mixed effects modeling was used to assess relationships between local SVD measurements and their spatially corresponding retinal sensitivity measurements., Results: Thirty-nine eyes from 39 participants were imaged. In all slabs, there was a statistically significant positive correlation between retinal sensitivities and SVDs on both global and zonal scales. No statistically significant correlation was found between central retinal sensitivities and the foveal avascular zone areas. Assessment of 1,136 spatially paired retinal sensitivity and SVD measurements revealed a statistically significant local relationship; this seemed to be driven by eyes with proliferative diabetic retinopathy that had reduced retinal sensitivities., Conclusion: This study supports positive correlations between SVD and retinal sensitivity at global and zonal spatial scales in diabetic eyes. However, our analysis did not find evidence of statistically significant correlations between retinal sensitivity and SVD on a local scale until advanced diabetic retinopathy.

Purpose: Describe the utility of anterior segment optical coherence tomography angiography (AS-OCTA) to assess ocular surface lesions., Methods: Retrospective, case-control study of 10 eyes of 9 patients with malignant lesions and 23 eyes of 22 patients with benign lesions. Lesions included 13 epithelial, 10 pigmented and 10 lymphoid lesions. Graders performed an average of 3 depth and diameter measurements of peri-lesional vessels entering each lesion on AS-OCTA. Statistical models to assess differences between groups accounted for bilateral eye inclusion and lesion thickness (on AS-OCT). Receiver operating characteristic (ROC) curve and area under the curve (AUC) were performed for each parameter., Results: In the benign and malignant groups, age was 49.5 ± 22.4 and 64.3 ± 10.6 years (p = 0.145) with 45% males and 55% males (p = 0.458), in their respective groups. AS-OCTA showed greater peri-lesional vessel depth and diameter in malignant lesions (315.2 ± 73.0 μm, p < 0.001 and 76.4 ± 18.2 μm, p < 0.001; respectively) compared to benign lesions (199.4 ± 34.1 μm and 44.0 ± 9.4 μm, respectively). Malignant lesions showed deep and dilated peri-lesional vessels, which may represent feeder vessels. Vessel depth showed AUC = 0.980, 90.9% sensitivity and 100.0% specificity with a 236.5 μm cutoff. Vessel diameter showed AUC = 0.960, 100.0% sensitivity and 88.9% specificity with a 53.9 μm cutoff., Conclusion: AS-OCTA shows greater peri-lesional vessel depth and diameter of malignant lesions compared to benign lesions. This imaging modality provides novel and non-invasive functional vascular parameters that can potentially aid the assessment of ocular surface lesions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To assess the full-thickness macular hole (FTMH) size using the choroidal hypertransmission signal on spectral-domain optical coherence tomography and to compare this method to the standard aperture measurement of the minimum aperture size at the level of the neurosensory retina., Design: Cross-sectional study of retrospective data., Methods: Eyes with FTMH imaged on spectral-domain optical coherence tomography were included. Two independent masked graders used the device's built-in caliper tool to measure the FTMH minimum aperture size at the level of the neurosensory retina and the size of the corresponding hypertransmission signal below the level of the retinal pigment epithelium/Bruch membrane complex. To assess the reproducibility of the hypertransmission measurement in tilted scans, two measurements were obtained and compared; the first was traced parallel to the retinal pigment epithelium (parallel hypertransmission), and the second was horizontal to the image frame (horizontal hypertransmission), both using Image J software., Results: A total of 31 eyes were enrolled. The mean FTMH minimum aperture size was smaller compared with both the choroidal parallel hypertransmission and horizontal hypertransmission measurements (mean ± SD: 335.7 ± 139.5 µm, 376.7 ± 150.6 µm, 375.1 ± 150.0 µm, respectively. P < 0.001 for both comparisons)., Conclusion: The proposed hypertransmission measurement is a feasible and reproducible alternative to assess FTMH size and could provide the basis for an automated FTMH measurement on cross-sectional spectral-domain optical coherence tomography scans, as presented in this study, or on the spectral-domain optical coherence tomography volumetric data set by using an en face projection.

Background: To evaluate the changes in the mean macular intercapillary area (ICA) from sequential enface optical coherence tomography angiography (OCTA) images following intravitreal anti-vascular endothelial growth factor (VEGF) therapy in initially treatment-naïve eyes with diabetic macular oedema (DME)., Methods: In this multicentre retrospective study, 6 × 6 and 3 × 3 mm customised, total retinal projection enface OCTA images were collected and processed for quantitative assessment of ICA by a customised MATLAB software. Measurements were done in concentric regions centred on the fovea-with the exclusion of foveal avascular zone (FAZ)-in 0.5 mm diameter increments as well as within the intervening rings., Results: In this study, 6 × 6 mm OCTA images from 46 eyes of 29 patients, and 3 × 3 mm OCTA images from 23 eyes of 15 patients were included. There was no significant change in mean ICA after treatment in either scan size or in any measurement regions (all p > 0.05). Multivariate analysis revealed that baseline BCVA was significantly correlated with the visual outcome (p = 0.039). Additionally, after correction for age, baseline central retinal thickness (CRT), baseline BCVA, and retinopathy severity, mean ICA in the 1.5 mm circle was found to be a significant predictor of post treatment CRT, (p = 0.006)., Conclusions: Absence of significant change in mean ICA after a minimum of three intravitreal anti-VEGF injections, may indicate that, in the short term, anti-VEGF injections neither impair nor improve macular perfusion in DME. Baseline BCVA was found to be a robust predictor of functional outcome, while inner mean ICA was a significant predictor for macular thickness outcomes., (© 2021 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: To evaluate the use of swept-source optical coherence tomography angiography to detect distinct vascular features in small choroidal melanomas and choroidal nevi., Methods: Patients with a choroidal nevus or a treatment-naïve choroidal melanoma were imaged with color fundus photography, ultrasound, and swept-source optical coherence tomography angiography (12 × 12 mm). High-risk features including overlying fluid, orange pigment, shaggy photoreceptors, acoustic hollowness, depth >2 mm, and basal diameter >5 mm were assessed. Optical coherence tomography angiography vascular markers included: choroidal vessel visualization, choroidal vessel depth, and choriocapillaris flow signal, assessed qualitatively by comparison with surrounding, unaffected choriocapillaris., Results: Twenty-nine lesions were included in this study, seven flat choroidal nevi, 17 elevated choroidal nevi, and 5 choroidal melanomas. Distinct vascular patterns were noted between flat nevi, elevated nevi, and small choroidal melanomas. Choroidal melanomas displayed two types of vasculature: "nevus-like" vasculature with straight parallel vessels and complex vasculature with vascular loops and crosslinking. Visualized choroidal vessels were significantly deeper in melanomas (110 µm) than elevated (84 µm) or flat nevi (70 µm). In a size-matched subanalysis of 5 elevated choroidal nevi and 5 choroidal melanomas, choroidal melanomas had increased mean choroidal vessel depth (P = 0.015), deepest choroidal vessel visualized (P = 0.034), and presence of a deep choroidal vessel >155 µm (P = 0.048)., Conclusion: Swept-source optical coherence tomography angiography may detect distinct vascular features in choroidal nevi and small choroidal melanomas., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Purpose: To evaluate the usefulness of a high-magnification module (HMM) lens to visualize retinal photoreceptors, retinal nerve fiber layer (RNFL), and superficial retinal vasculature in physiologic and pathologic retinal conditions., Design: Observational descriptive study., Participants: Thirty-two participants with normal and pathologic retina examination results., Methods: Normal and pathologic maculae were imaged in vivo using still and video HMM lens modes, with fixation and contrast adjustments to enhance visualization. The HMM images were classified qualitatively based on structures identified as either good (photoreceptors seen), average (photoreceptor mosaic cannot be visualized clearly, retinal vessels and other retinal changes can be seen), or poor (no identifiable structures). Selected eyes were imaged with fundus photography, OCT, OCT angiography, indocyanine green angiography, and fluorescein angiography for comparison with the pathologic maculae., Main Outcomes Measures: Description of HMM module-obtained macula images., Results: From 32 eyes imaged (16 normal and 16 pathologic retinas), 12 of 16 normal and 11 of 16 pathologic retinas demonstrated at least average image quality, in which retinal vasculature and landmarks could be visualized. The mosaic pattern of hexagonal shapes representing photoreceptors could not be resolved in most pathologic retinas. For the retinas in which the photoreceptor mosaics were visualized (12 of 16 normal and 2 of 16 pathologic retinas), parafoveal mosaic patterns appeared denser with better image quality for all participants compared with foveal photoreceptors. Difficulty in resolving the photoreceptors in the umbo, fovea, and perifovea was encountered, similar to what has been reported with adaptive optics devices. The RNFL was seen as arcuate hyperreflective bundles. Flow was observed in the macular microvasculature. Poorly resolved photoreceptors and scattered hyperreflective foci were correlated with changes in the retinal pigment epithelium in eyes with age-related macular degeneration or central serous chorioretinopathy. Macular striae were seen in eyes with epiretinal membrane., Conclusions: In most eyes, regardless of whether retinal pathologic features were present, it was challenging to obtain average quality (or better) images. In the few participants with good-quality imaging, the parafoveal photoreceptor mosaic, vascular flow, and various features of pathologic eyes could be visualized., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Age-related macular degeneration (AMD) affects a significant percentage of the elderly population and end-stage disease classified by either geographic atrophy (GA) or neovascular AMD (nvAMD) is one of the leading causes of vision loss worldwide. Despite the fact that there are currently treatments for nvAMD, there are no treatments in practice to prevent disease onset or progression of GA. This topic is at the forefront of ophthalmic research demonstrated by the recent advances in disease characterization, genetic and environmental risk factor classification, biomarker discovery and mechanism of pathogenesis categorization. There are also numerous clinical treatment trials underway, targeting proposed pathways and biomarkers associated with GA that are promising., Recent Findings: With several clinical trials of potential treatments underway and numerous recent publications on disease diagnosis and classification, the understanding of GA pathogenesis has increased substantially. Although the exact mechanism of pathology is still elusive, recent literature has highlighted the utilization of current and new ophthalmic imaging modalities and discovery of objective and functional markers that can lead to earlier diagnosis and treatment., Summary: Herein, we will provide an overview and discussion of the current status of GA including advances in mechanism of pathogenesis, diagnosis, classification and current treatment modalities., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Optical coherence tomography (OCT) imaging is inherently susceptible to distortion artifacts due to the natural curvature of the eye. This study proposes a novel model for widefield OCT angiography (OCTA) distortion correction and analyzes the effects of this correction on quantification metrics., Methods: Widefield OCTA images were obtained on normal subjects at five fixation spatial positions. Radial and field distortion correction were applied and images stitched together to form a corrected widefield montage image. Vessel area density (VAD), vessel complexity index (VCI), and flow impairment area were quantified on the original and corrected montage images., Results: This model allows for distortion correction and montaging of widefield images. There were either statistically insignificant or small magnitude changes in vessel density and vessel complexity between uncorrected and corrected widefield images. There was a significant and large difference in flow impairment area, both in the macular (+8.2%, P=0.049) and peripheral areas (+17.2%, P=0.011), following correction. The relationship between pre- and post-correction flow impairment area was non-linear., Conclusions: Distortion correction of widefield OCTA images can result in clinically and statistically significant differences in important quantification metrics. This effect appears to be most pronounced in the periphery., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-791). The special issue “Advanced Optical Imaging in Biomedicine” was commissioned by the editorial office without any funding or sponsorship. RKW served as the unpaid Guest Editor of the special issue and serves as an unpaid Deputy Editor of Quantitative Imaging in Medicine and Surgery. JD reports grants from National Institutes of Health, grants and non-financial support from Carl Zeiss Meditec Inc, grants from Air Force Office of Scientific Research, grants from Champalimaud Vision Award, non-financial support from Topcon Medical Systems, Inc., non-financial support from Optovue, Inc., during the conduct of the study. RKW reports grants from National Institutes of Health, grants and non-financial support from Carl Zeiss Meditec Inc, grants from Research to Prevent Blindness, during the conduct of the study. NKW reports grants from National Institutes of Health, grants and non-financial support from Carl Zeiss Meditec Inc, grants from Research to Prevent Blindness, grants from Air Force Office of Scientific Research, grants from Champalimaud Vision Award, grants and non-financial support from Macula Vision Research Foundation, grants from Beckman-Argyros Award in Vision Research, non-financial support from Topcon Medical Systems, Inc., non-financial support from Nidek Medical Products, Inc., non-financial support from Optovue, Inc., during the conduct of the study. The other authors have no other conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

This is a case report detailing a pars plana vitrectomy and resection of a retinal capillary hemangioblastoma in a 19-year-old female with a history of von Hippel-Lindau syndrome with secondary retinal detachment and sub-retinal exudates limiting her vision. Intraoperatively, long duration endolaser and generous endodiathermy applied to the feeder vessels are essential to minimize bleeding. Complete and careful resection of the lesion and installation of a silicone oil tamponade are recommended. This technique can allow for retinal reattachment and improvement in visual acuity in advanced cases of secondary retinal detachment.

Purpose: To discuss the evolution of noninvasive diagnostic methods in the identification of choroidal nevus and determination of risk factors for malignant transformation as well as introduce the novel role that artificial intelligence (AI) can play in the diagnostic process., Methods: White paper., Results: Longstanding diagnostic methods to stratify benign choroidal nevus from choroidal melanoma and to further determine the risk for nevus transformation into melanoma have been dependent on recognition of key clinical features by ophthalmic examination. These risk factors have been derived from multiple large cohort research studies over the past several decades and have garnered widespread use throughout the world. More recent publications have applied ocular diagnostic testing (fundus photography, ultrasound examination, autofluorescence, and optical coherence tomography) to identify risk factors for the malignant transformation of choroidal nevus based on multimodal imaging features. The widespread usage of ophthalmic imaging systems to identify and follow choroidal nevus, in conjunction with the characterization of malignant transformation risk factors via diagnostic imaging, presents a novel path to apply AI., Conclusions: AI applied to existing ophthalmic imaging systems could be used for both identification of choroidal nevus and as a tool to aid in earlier detection of transformation to malignant melanoma., Translational Relevance: Advances in AI models applied to ophthalmic imaging systems have the potential to improve patient care, because earlier detection and treatment of melanoma has been proven to improve long-term clinical outcomes.

Purpose: Further insight into the flow characteristics of the vascular features associated with diabetic retinopathy (DR) may improve assessment and treatment of disease progression. The variable interscan time analysis (VISTA) algorithm is an extension of OCT angiography (OCTA) that detects relative blood flow speeds, which then can be depicted on a color-coded map. This study used VISTA to analyze relative blood flow speeds in the microvascular changes associated with DR., Design: Cross-sectional study., Participants: Thirteen patients with varying severities of DR treated at New England Eye Center, Boston, Massachusetts., Methods: OCT angiography images centered at the fovea were obtained on a prototype swept-source OCT device, and the VISTA algorithm was applied to visualize relative blood flow speeds., Main Outcome Measures: Descriptive flow analysis of the retinal vascular features of DR was conducted on the VISTA-generated images., Results: Twenty-six eyes were included in this study. Of these, 3 eyes had mild nonproliferative DR (NPDR), 6 eyes had moderate NPDR, 4 eyes had severe NPDR, 9 eyes had proliferative DR, and 4 eyes were normal controls. Microaneurysms, intraretinal microvascular abnormalities (IRMAs), and neovascularization appeared to originate from areas of relatively slow blood flow speeds. Microaneurysms showed relatively slower flow, IRMAs showed turbulent, intermediate to slow flow, and venous beading and looping presented with relatively high flow speeds that tapered progressively. Neovascularization of venous origin demonstrated slower flow speeds, whereas that of arterial origin showed relatively high flow speeds. Additionally, increased disease severity was associated with globally slower flow speeds, with particularly slower flow around the foveal avascular zone., Conclusions: The VISTA algorithm seems to be a useful extension of OCTA that overcomes some of the limitations of normal gray-scale OCTA. It seems to have some potential in providing relevant insight into the pathogenesis of the microvascular changes associated with DR. These findings may assist in improving our understanding of the pathogenic changes that take place in DR., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: This work aims to compare spatial relationships between the crystalline lens and vitrectomy instruments of different gauges., Methods: Eight phakic eyes recovered from deceased donors were used after fixation. Valved trocars (27-gauge, 25-gauge, and 23-gauge) were sequentially placed in the superotemporal quadrant 4 mm posterior to the limbus in each eye. Intraocular relationships of vitrectomy and curved endolaser probes were measured for each gauge., Results: There were no significant differences in maneuverability between instruments of different gauges. The mean distance from instrument to lens at the geometric center of the globe was 5.5 mm. Vitrectomy probes of all gauges could access the peripheral retina on both sides of the sclerotomy in the 3 to 4 o'clock position adjacent to the sclerotomy without touching the lens. The instruments could be advanced without lens touch to contact the retina within at least 2 mm of the ora serrata 180° away from the insertion site., Conclusions: Vitrectomy and curved endolaser probes achieved similar maneuverability relative to the lens regardless of gauge. This study confirms that small-gauge vitrectomy instruments have a considerable range of safe access to the peripheral retina in phakic eyes from a single sclerotomy., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Jayanth Sridhar has received consulting fees from Alcon Laboratories. None of the other authors have any relevant financial disclosures., (© The Author(s) 2020.)

In this paper we present a fully automated graph-based segmentation algorithm that jointly uses optical coherence tomography (OCT) and OCT angiography (OCTA) data to segment Bruch's membrane (BM). This is especially valuable in cases where the spatial correlation between BM, which is usually not visible on OCT scans, and the retinal pigment epithelium (RPE), which is often used as a surrogate for segmenting BM, is distorted by pathology. We validated the performance of our proposed algorithm against manual segmentation in a total of 18 eyes from healthy controls and patients with diabetic retinopathy (DR), non-exudative age-related macular degeneration (AMD) (early/intermediate AMD, nascent geographic atrophy (nGA) and drusen-associated geographic atrophy (DAGA) and geographic atrophy (GA)), and choroidal neovascularization (CNV) with a mean absolute error of ∼0.91 pixel (∼4.1 μm). This paper suggests that OCT-OCTA segmentation may be a useful framework to complement the growing usage of OCTA in ophthalmic research and clinical communities., Competing Interests: The authors declare that there are no conflicts of interest related to this article., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

We describe a novel method for non-rigid 3-D motion correction of orthogonally raster-scanned optical coherence tomography angiography volumes. This is the first approach that aligns predominantly axial structural features such as retinal layers as well as transverse angiographic vascular features in a joint optimization. Combined with orthogonal scanning and favorization of kinematically more plausible displacements, subpixel alignment and micrometer-scale distortion correction is achieved in all 3 dimensions. As no specific structures are segmented, the method is by design robust to pathologic changes. Furthermore, the method is designed for highly parallel implementation and short runtime, allowing its integration into clinical workflow even for high density or wide-field scans. We evaluated the algorithm with metrics related to clinically relevant features in an extensive quantitative evaluation based on 204 volumetric scans of 17 subjects, including patients with diverse pathologies and healthy controls. Using this method, we achieve state-of-the-art axial motion correction and show significant advances in both transverse co-alignment and distortion correction, especially in the subgroup with pathology., Competing Interests: SBP: IP related to VISTA-OCTA (P). MFK: Optovue (C, P), currently with Siemens Healthineers. EMM: IP related to VISTA-OCTA (P). NKW: Optovue (C), Carl Zeiss Meditec (F), Heidelberg Engineering (F), Nidek (F). JSD: Optovue (C, F), Topcon (C, F), Carl Zeiss Meditec (C, F). JGF: Optovue (I, P), Topcon (F), IP related to VISTA-OCTA (P)., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Purpose: To determinate the variation in thickness of the individual choroidal layers in patients with central serous chorioretinopathy treated with half-fluence photodynamic therapy., Methods: Twenty-two eyes were evaluated with spectral-domain optical coherence tomography. The images were taken before photodynamic therapy, 3 months, and 6 months after the treatment. Two investigators performed these measurements: 1) choroidal thickness (CT), 2) Haller layer thickness, defined as the most external layer containing a 100-μm vessel, and 3) choriocapillaris + Sattler layer (C&S). Nine measurements were taken in the macular region., Results: Choroidal thickness before photodynamic therapy was 471.8 µm ± 145.8. The Haller layer was 358.4 µm ± 122.6, and C&S was 114.3 µm ± 27.8. At 3-month follow-up, CT was 441.1 µm ± 150.7, Haller layer 348.8 µm ± 127.6, and C&S 92.4 µm ± 27.9. At 6-month follow-up, CT was 420.4 µm ± 118.4, Haller layer 331.8 µm ± 97.2, and C&S 89.5 µm ± 28.0. Using a multilevel mixed-effects linear regression, CT was found to be reduced at both 3 months (P < 0.03) and at 6 months (P < 0.001), Haller layer showed no significant reduction at 3 months (P = 0.483) or at 6 months (P = 0.055), and C&S showed reduction at 3 months (P < 0.001) and at 6 months (P < 0.001). Fellow nonaffected eyes showed no statistical variation at 3-month and 6-month follow-up., Conclusion: Reduction in CT in patients affected by central serous chorioretinopathy after half-fluence photodynamic therapy occurs primarily in the choriocapillaris and medium diameter vessel layers of the choroid in a short- and medium-term follow-up.

Background: Optical coherence tomography angiography (OCTA) can image the retinal vasculature in vivo, without the need for contrast dye. This technology has been commercially available since 2014, however, much of its use has been limited to the research setting. Over time, more clinical practices have adopted OCTA imaging. While countless publications detail OCTA's use for the study of retinal microvasculature, few studies outline OCTA's clinical utility. BODY: This review provides an overview of OCTA imaging and details tips for successful interpretation. The review begins with a summary of OCTA technology and artifacts that arise from image acquisition. New methods and best practices to prevent image artifacts are discussed. OCTA has the unique ability among retinovascular imaging modalities to individually visualize each retinal plexus. Slabs offered in standard OCTA devices are reviewed, and clinical uses for each slab are outlined. Lastly, the use of OCTA for the clinical interpretation of retinal pathology, such as diabetic retinopathy and age-related macular degeneration, is discussed., Conclusion: OCTA is evolving from a scientific tool to a clinical imaging device. This review provides a toolkit for successful image interpretation in a clinical setting.

Purpose: To evaluate the repeatability and reproducibility of photoreceptor density assessment with manual cell counting in healthy participants imaged with the Heidelberg Spectralis High Magnification Module (HMM)., Design: Precision study, evaluation of diagnostic test or technology., Participants: Eleven eyes of 8 participants., Methods: Images were acquired using the Spectralis HMM by a single operator during 2 separate imaging sessions. The 3 highest-quality images of each eye from each session were selected for analysis and coregistered. For a subset of participants, a second operator acquired images in 1 session, and images with the best quality were selected for analysis. Photoreceptor densities were obtained by manual counts in squares of 0.0625 mm 2 located in the parafovea. Repeatability (intragrader and intrasession) and reproducibility (interoperator, intergrader, and intersession) were assessed by calculating the intraclass correlation coefficient (ICC) from linear mixed effects models. Bland-Altman plots, coefficients of repeatability, and Pearson correlation results were reported., Main Outcome Measures: Intragrader, intrasession, intersession, interoperator, and intergrader ICC estimates and their 95% confidence intervals for photoreceptor density measurements in the parafovea., Results: Twenty-four eyes of 13 healthy participants were imaged initially. Of these, 11 eyes (45.83%) of 8 participants that had at least 3 acceptable images in each session were included in this study. Mean parafoveal photoreceptor density was 14 988 cells/mm 2 (standard deviation, 1403.15 cells/mm 2 ). Intragrader ICC was 0.84 (95% confidence interval, 0.57-0.95), intrasession ICC was 0.69 (95% confidence interval, 0.17-0.86), intersession ICC was 0.88 (95% confidence interval, 0.53-0.96), interoperator ICC was 0.70 (95% confidence interval, 0-0.95), and intergrader ICC was 0.22 (95% confidence interval, 0-0.71)., Conclusions: Images obtained with the HMM allow for photoreceptor mosaic visualization in the macular area, mainly in the parafovea. Although densities obtained are in accordance with other reported methods in the literature, variability within and between images of the apparent cell mosaic were observed, and this study did not demonstrate high repeatability or reproducibility for quantitative assessments using the manual counting method., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Importance: Amid an explosion of interest in deep learning in medicine, including within ophthalmology, concerns regarding data privacy, security, and sharing are of increasing importance. A model-to-data approach, in which the model itself is transferred rather than data, can circumvent many of these challenges but has not been previously demonstrated in ophthalmology., Objective: To determine whether a model-to-data deep learning approach (ie, validation of the algorithm without any data transfer) can be applied in ophthalmology., Design, Setting, and Participants: This single-center cross-sectional study included patients with active exudative age-related macular degeneration undergoing optical coherence tomography (OCT) at the New England Eye Center from August 1, 2018, to February 28, 2019. Data were primarily analyzed from March 1 to June 20, 2019., Main Outcomes and Measures: Training of the deep learning model, using a model-to-data approach, in recognizing intraretinal fluid (IRF) on OCT B-scans., Results: The model was trained (learning curve Dice coefficient, >80%) using 400 OCT B-scans from 128 participants (69 female [54%] and 59 male [46%]; mean [SD] age, 77.5 [9.1] years). In comparing the model with manual human grading of IRF pockets, no statistically significant difference in Dice coefficients or intersection over union scores was found (P > .05)., Conclusions and Relevance: A model-to-data approach to deep learning applied in ophthalmology avoided many of the traditional hurdles in large-scale deep learning, including data sharing, security, and privacy concerns. Although the clinical relevance of these results is limited at this time, this proof-of-concept study suggests that such a paradigm should be further examined in larger-scale, multicenter deep learning studies.

Purpose: Assess epidermolysis bullosa (EB)-related corneal pathology using anterior segment optical coherence tomography (AS-OCT) and correlate imaging with clinical metrics in EB patients versus age-matched controls., Methods: EB patients and controls were recruited during an EB conference (July 2018) and at Tufts Medical Center (June-August 2019). Subjects completed a questionnaire, had best corrected visual acuity (BCVA) tested, and underwent AS-OCT scanning. Stromal and epithelial thickness were measured. Depth, length, and type of the three largest lesions were assessed by a masked examiner using a novel pathology grading system. Multivariate analysis of AS-OCT findings and clinical metrics was performed., Results: 62 EB patients and 60 age-matched controls were enrolled. Mean BCVA was 1.8 lines worse in patients (p < 0.001). Vision loss was associated with increased stromal thickness. Discrete lesions were seen in 60.2% of patient eyes, averaging 1.71 ± 1.75 lesions in patients and 0.14 ± 0.42 in controls (p < 0.001). Mean primary lesion depth was 151.88 ± 97.49 μm in patients. Patients showed significant stromal thickening versus controls and lesions were most common in the periphery and inferiorly. Differences in frequency and duration of abrasions and severity of pain were all statistically and clinically significant in patients versus controls (p < 0.001)., Conclusions: AS-OCT can visualize and quantify differences in the corneas of EB patients compared with age-matched controls. Novel findings include quantification of average depth, length, and severity of discrete lesions, and sparing of the superior quadrant from stromal thickening in EB patients. These results support use of AS-OCT and a questionnaire in clinical trials for new EB therapies., (Copyright © 2020. Published by Elsevier Inc.)

Binarization is a critical step in analysis of retinal optical coherence tomography angiography (OCTA) images, but the repeatability of metrics produced from various binarization methods has not been fully assessed. This study set out to examine the repeatability of OCTA quantification metrics produced using different binarization thresholding methods, all of which have been applied in previous studies, across multiple devices and plexuses. Successive 3 × 3 mm foveal OCTA images of 13 healthy eyes were obtained on three different devices. For each image, contrast adjustments, 3 image processing techniques (linear registration, histogram normalization, and contrast-limited adaptive histogram equalization), and 11 binarization thresholding methods were independently applied. Vessel area density (VAD) and vessel length were calculated for retinal vascular images. Choriocapillaris (CC) images were quantified for VAD and flow deficit metrics. Repeatability, measured using the intra-class correlation coefficient, was inconsistent and generally not high (ICC < 0.8) across binarization thresholds, devices, and plexuses. In retinal vascular images, local thresholds tended to incorrectly binarize the foveal avascular zone as white (i.e., wrongly indicating flow). No image processing technique analyzed consistently resulted in highly repeatable metrics. Across contrast changes, retinal vascular images showed the lowest repeatability and CC images showed the highest.

Purpose: With the increasing prevalence of diabetes, fast, noninvasive identification of proliferative diabetic retinopathy (PDR) becomes essential. This study evaluated the utility of optical coherence tomography angiography (OCTA) to characterize intraretinal microvascular abnormalities (IRMA) and retinal neovascularization (NV)., Methods: Patients with severe non-PDR or PDR were imaged with fluorescein angiography and widefield swept-source OCTA (Zeiss Plex Elite 9000; Carl Zeiss Meditec, Dublin, CA). Regions suspicious for IRMA or retinal NV were identified and the OCTA, including flow overlay on the co-registered structural optical coherence tomography, and fluorescein angiography images were graded by two masked readers., Results: Ninety-six foci of irregular vasculature were analyzed, comprised of 70 IRMA and 26 retinal NV lesions from 14 eyes. Compared with fluorescein angiography, OCTA with flow overlay demonstrated specificity of 99% and sensitivity of 92% in identifying IRMA and NV. Neovascularization differed from IRMA on OCTA by demonstrating supraretinal flow breaching the internal limiting membrane and posterior hyaloid (P < 0.001). Intraretinal microvascular abnormalities were distinguished from NV by outpouching of the internal limiting membrane (P = 0.035). Vascular flow was reduced in the presence of fibrosis., Conclusion: Optical coherence tomography angiography, through flow overlay, has utility to image and differentiate IRMA and NV, which are key features distinguishing severe non-PDR and PDR, respectively. Noninvasive widefield OCTA may be a useful tool to diagnose high-risk diabetic retinopathy eyes.

Background: The short-term effects of anti-vascular endothelial growth factor (anti-VEGF) treatment on macular neovascularization (MNV) morphology is well described, but long-term studies on morphologic changes and correlation of such changes to the type of MNV have not been conducted. This study aims to determine if different types of MNVs in neovascular AMD (nAMD) behave differently with anti-VEGF treatment as visualized on optical coherence tomography angiography (OCTA)., Methods: Treatment-naïve nAMD patients were retrospectively screened for baseline and follow-up OCTA imaging 10 or more months after initial treatment. Images were graded for MNV type, area, activity, mature versus immature vessels, vessel density, presence of atrophy, atrophy location and area. Growth rate was calculated as the percent change in lesion area from baseline over the years of follow-up. In addition, the occurrence of complete regression and the percent of lesions that grew, remained stable, and shrunk per type was also evaluated., Results: Forty-three eyes from 43 patients with a mean follow-up of 2 years were evaluated. On structural OCT, 26 lesions were classified as pure type 1 MNVs, 12 MNVs had a type 2 component, and 5 MNVs had a type 3 component. Of these cases, 2 mixed-type MNVs were considered to have completely regressed. There was no significant differences in MNV area and growth rate between type 1 and type 2 lesions, but all cases of type 3 lesions shrunk in the follow-up period. There was no correlation between the number of injections per year and growth rate, endpoint MNV area or endpoint activity status for any MNV type. There was no significant association between the development of atrophy and the number of injections, baseline MNV area, baseline vessel density, or lesion growth rate., Conclusions: In nAMD, complete regression of an MNV network exposed to anti-VEGF is rare. This work emphasizes the role of anti-VEGF as anti-leakage rather than vascular regression agents in nAMD., Competing Interests: Competing interestsAEM: Novartis, Optos, Optovue, Eschenbach (personal fees). MQEM: Novartis, Bayer, Allergan (personal fees). JGF: Topcon (grants); Optovue, Carl Zeiss Meditech (patents); Optovue (consultant, personal financial interest). CRB: Carl Zeiss Meditec, Optovue, Genentech, Allergan (speaker fees). JSD: Carl Zeiss Meditec, Optovue (funding), Aldeyra, Allergan, Aura Biosciences, Bausch Health, Beyeonics, Merck, Novartis, Roche (Consulting); Eleven Oncology, Eye-Point Pharma (Director of Entity); Hemera Biosciences (stock/options). NKW: Nidek, Topcon (Speaker fees); Topcon, Roche/Genentech, Regeneron, Apellis, Astellas, Boehringer Ingelheim, Novartis (Consulting); Roche Genentech, Astellas, Boehringer Ingelheim, Novartis, Carl Zeiss Meditech, Topcon, Carl Zeiss Meditec (Advisory role); Gyroscope (Officer of entity). ESL, ECG, LSMM, SG, IND, AYA, EM, NM, UC, AW, MEH: No disclosures., (© The Author(s) 2020.)

Purpose: Understanding the precision of measurements on and across optical coherence tomography angiography (OCTA) devices is critical for tracking meaningful change in disease. The purpose of this study is to investigate the repeatability and reproducibility of vessel area density and vessel skeleton density measurements from various commercial OCTA devices in diabetic eyes., Methods: Patients were imaged three consecutive times each on three different OCTA devices. En face OCTA images of the superficial capillary plexus, deep capillary plexus, and full retinal layer were exported for analysis. Vessel area density and vessel skeleton density were calculated. The coefficient of repeatability (CoR) was calculated to assess the repeatability of these measurements, and linear mixed models were utilized to assess the reproducibility of these measurements., Results: Forty-four eyes from 27 diabetic patients were imaged. Normalized CoR values ranged between 3.44 and 6.65% when calculated for vessel area density and between 1.35 and 23.39% when calculated for vessel skeleton density. When stratified by disease severity, the swept-source OCTA device consistently produced the smallest CoR values for vessel area density in the full retinal layer. Vessel area density measurements were repeatable across the two spectral-domain devices in the full retinal layer when all severities were combined, as well as in diabetic patients without retinopathy, mild nonproliferative diabetic retinopathy (NPDR), and moderate NPDR., Conclusion: Vessel area density measured in the full retinal layer may be a more precise measure than vessel skeleton density to follow diabetic retinopathy patients both on the same device and across devices.

Especially since the incorporation of swept laser sources, optical coherence tomography angiography (OCTA) has enabled quantification of choriocapillaris perfusion. A critical step in this process is binarization, which makes angiographic images quantifiable in terms of perfusion metrics. It remains challenging to have confidence that choriocapillaris perfusion metrics reflect the reality of pathophysiologic flow, largely because choice of binarization method can result in significantly different perfusion metric outcomes. This commentary discusses a proof-of-concept case involving comparative assessment of binarization methods for a set of dry age-related macular degeneration OCTA data. One of these methods was deemed preferable based on superior agreement with suspected physiologic and pathophysiologic characteristics, thus demonstrating the principle that, in the absence of gold standards for measurement of choriocapillaris perfusion, the best available approximations of pathophysiology may be used to guide choice of binarization method., Competing Interests: Disclosure: P.X. Braun, None; N. Mehta, None; I. Gendelman, None; A.Y. Alibhai, None; C.R. Baumal, Genentech (C), Carl Zeiss Meditec, Inc. (S); J.S. Duker, Carl Zeiss Meditec, Inc. (F, C), Optovue, Inc. (F, C); N.K. Waheed, Topcon Medical Systems, Inc. (F), Nidek Medical Products, Inc. (F, S), Carl Zeiss Meditec, Inc. (F), Optovue, Inc. (C), (Copyright 2020 The Authors.)

Background: To compare the anatomical and visual outcomes in eyes with persistent diabetic macular edema (DME) after initial anti-VEGF therapy that were retreated continuously with the same anti-VEGF drug versus those that underwent two successive cycles of medication change in anti-VEGF drugs (double anti-VEGF switch)., Methods: Retrospective review of eyes with persistent DME after 3 initial consecutive monthly anti-VEGF injections. This cohort was divided into two groups: Group 1 continued to receive the same initial anti-VEGF drug for at least 18 months while group 2 eyes were switched to different anti-VEGF medications twice. Group 1 was further subdivided into: Group 1A composed of eyes with less than 20% reduction in central subfield thickness (CRT) at month 3; and group 1B eyes with greater than or equal to 20% reduction in CRT. The percentage of eyes that achieved greater than 10 letters visual acuity (VA) gain or loss was recorded as the primary end point (through month 18 in group 1 and month 6 after 2nd switch in group 2)., Results: Group 1A, 1B and group 2 were composed of 24, 18, and 14 eyes respectively. 34.7%, 56.2% and 36.3% of eyes achieved > 10 letters gain, while 4.3%, 6.2% and 27.2% of eyes lost > 10 letters in groups 1A, 1B, and 2, respectively. Analysis of the visual acuity (VA) letter change in this time interval revealed no significant difference between all groups (p = 0.11). Mean VA and CRT measurements at the primary endpoint in all groups were 0.5, 0.39, and 0.47 logMAR (p = 0.44), and 369.7, 279.9, 321 µm, (p = 0.01) respectively., Conclusions: There was no difference in the visual outcomes between the two treatment strategies in eyes with persistent DME after 3 consecutive anti-VEGF injections. This may indicate that anti-VEGF switching-even if it is done twice-may have comparable clinical outcomes to sustained treatment with one agent., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Purpose: To develop a multiscale analysis framework for investigating the relationships between geographic atrophy (GA) growth rate and choriocapillaris (CC) blood flow impairment using optical coherence tomography (OCT) and OCT angiography (OCTA)., Design: Retrospective case series., Methods: We developed an OCT/OCTA analysis framework that quantitatively measures GA growth rates at global and local scales and CC impairment at global, zonal, and local scales. A geometric GA growth model was used to measure local GA growth rates. The utility of the framework was demonstrated on 7 eyes with GA imaged at 2 time points using a prototype 400-kHz, 1050-nm swept-source OCTA system., Results: Qualitatively, there was a trend of increasing GA growth rate with increasing CC impairment. The local analysis model enabled growth rates to be estimated at each point on the GA boundary. However, there was no generally observed trend between local GA growth rates and local CC impairment., Conclusions: The global, zonal, and local analysis framework may be useful for investigating relationships between GA growth and CC impairment at different spatial scales. The geometric GA growth model enables spatially resolved growth measurements that capture the anisotropy of GA growth and may improve the characterization of GA progression., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: To examine the baseline morphological characteristics and alterations in intraretinal microvascular abnormalities (IRMAs) in response to anti-vascular endothelial growth factor (anti-VEGF) treatment, documented by optical coherence tomography angiography (OCTA) in diabetic eyes., Methods: In this retrospective study, IRMAs were evaluated with multimodal imaging (fundus photography, fluorescein angiography, OCTA) in treatment-naïve diabetic eyes before and after anti-VEGF treatment for diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR) and compared to diabetic control eyes with similar diabetic retinopathy (DR) severity that did not receive anti-VEGF therapy. The morphological characteristics of IRMAs on enface OCTA imaging were graded by masked readers at baseline, then after anti-VEGF therapy in treated eyes or after observation in control eyes. Characterization of interval changes in an IRMA were based on the following parameters: branching, vessel caliber and area of adjacent capillary non-perfusion., Results: The treated group included 45 IRMA foci from 15 eyes of 11 patients, while the control group included 27 IRMA foci from 15 eyes of 14 patients. Following anti-VEGF treatment, enface OCTA demonstrated that 14 foci of IRMA (31%) demonstrated regression with normalization of appearance of the capillary bed, 20 IRMAs (44%) remained unchanged, six IRMAs (13%) progressed with enlargement or development of new IRMAs and five IRMAs (11%) demonstrated complete obliteration defined as IRMA disappearance with advancing capillary drop-out. In the control group, 17 IRMA (63%) remained stable, 8 IRMAs (29.6%) progressed and 2 experienced total obliteration (7.4%). The difference in rank order between the two groups was statistically significant ( p  = 0.022)., Conclusions: In eyes with DR status post anti-VEGF therapy, foci of IRMAs have a variable course demonstrating one of four possible outcomes: regression, stability, progression or complete obliteration. In contrast, none of the untreated control diabetic eyes demonstrated regression of IRMAs, consistent with known progression of DR severity in high risk eyes. Morphologic evaluation of IRMAs with OCTA may help to monitor changes in retinal blood flow as well as the response to anti-VEGF treatment., Competing Interests: Competing interestsThe authors declare that they have no competing interests relevant to this study, and their detailed financial disclosure: OS: None; NM: None; CB: Consultant, Genentech, Speaker, Carl Zeiss Meditec, Novartis; AI: Speaker, Topcon Medical Systems, Inc., Nidek Medical Products, Inc.; KL: None; EK: none; SM: None; A.YA: None; MA: None; AW: None; JD: Consultant and Financial Support, Carl Zeiss Meditec, Inc., Optovue, Inc., Novartis Pharma AG., and Roche; NW: Financial Support, Macula Vision Research Foundation, Topcon Medical Systems, Inc., Nidek Medical Products, Inc., and Carl Zeiss Meditec, Inc., Consultant, Optovue, Inc., Regeneron, and Genentech., (© The Author(s) 2020.)

Purpose: To examine the effects of enhanced depth imaging (EDI) and en face averaging on global vascular measurements of optical coherence tomography angiography (OCTA) images., Methods: All eyes were imaged with 3 mm × 3 mm fields centered at the fovea using the Carl Zeiss Cirrus 5000 spectral-domain OCTA, with and without EDI, and the Zeiss PLEX Elite 9000 swept-source OCTA. Vessel area density (VAD), vessel length (VL), and vessel diameter index (VDI) were calculated for the superficial capillary plexus (SCP) en face angiograms. For the choriocapillaris (CC), VAD and the number, total area, and average size of flow voids were calculated. These metrics were compared between SD- and SS-OCTA images, with and without en face averaging and EDI., Results: Both averaging and EDI had a significant effect on quantitative metrics. EDI images trended toward a decrease in SCP VAD. In the CC, EDI decreased average flow void size. Averaging increased CC VAD while decreasing number of flow voids, total flow void area, and average flow void size. With both averaging and EDI, SD-OCTA was not able to visualize as many CC flow voids, particularly of a smaller size, compared with SS-OCTA., Conclusions: Averaging and EDI affect quantitative metrics from SCP and CC OCTA images. EDI resulted in a trend toward decreased VAD in SCP images. Averaging had a major effect on CC imaging. Even with the combination of EDI and en face averaging, SD-OCTA images do not appear to approximate SS-OCTA images in terms of quantitative metrics. This has implications for clinical and research use of SD-OCTA for retinal imaging.

Purpose: Microperimetry (MP) allows for measurement of retinal sensitivity at precise locations and is now commonly employed as a clinical trial endpoint. Test-retest reliability is important when evaluating treatment effects in patients with geographic atrophy (GA). This study aimed to determine the test-retest variability of MP in patients with moderate to severe GA using the MAIA MP device., Methods: In this prospective study, patients with a confirmed diagnosis of foveal-involving GA were enrolled. Participants performed three MP assessments of a selected eye over two visits with the Macular Integrity Assessment (MAIA) 2 instrument (Centervue, Padova, Italy) utilizing a wide 30° grid, consisting of 93 stimuli (Goldmann III) using a 4-2 representation strategy, encompassing the entire area of GA and beyond. Mean retinal sensitivity (MS) was expressed as an average threshold value (dB) for the entire field tested. Coefficients of Repeatability at a 95% level (CoR 95 ) were calculated for Point Wise Sensitivity (PWS). Fixation stability (FS) was assessed by evaluating the area of an elliptical representation encompassing 95% of the cloud of fixation points (CFP) dataset generated by the MAIA MP, known as the bivariate contour ellipse area (BCEA)., Results: A total of 8 subjects were enrolled (21 tests), with six subjects completing 3 MP assessments. BCVA in these patients ranged from 20/100 to 20/800. The mean area of GA was 18.7 ± 12.3 mm 2 . The average time to complete one MP assessment was 13 min 9 s and mean BCEA@95% was 38.5 ± 19.3°2. The MS was 14.3 ± 4.5 dB. No significant increase in MS was noted between testing pairs 1&2 and 2&3. The preferred retinal locus was maintained in the same quadrant on successive tests. The mean CoR95 for PWS were similar for testing pairs 1&2 (± 3.50 dB) and 2&3 (± 3.40)., Conclusion: Microperimetry using a wide grid can be reliably performed in a reasonable amount of time in patients with moderate and severe vision loss secondary to GA. There was no learning effect seen between sequential assessments when analyzing MS or PWS. A change of approximately 4 dB in PWS provides a threshold for considering a true change in this patient cohort., Competing Interests: Competing interestsSheila Hickson-Curran: Janssen Pharmaceutical Companies of Johnson & Johnson (Employee). Nadia K. Waheed: Massachusetts Lions Club (Financial Support), Nidek Medical Products (Speaker fee), Genentech/Roche (Consultant), Topcon Medical Systems, Inc (Consultant), Regeneron (Consultant), Apellis (Consultant), Astellas (Consultant), Boehringer Ingelheim (Consultant), Novartis (Consultant), Optovue Inc (Consultant), Carl Zeiss Meditec Inc (Consultant), Janssen Pharmaceutical Companies of Johnson & Johnson (Consultant), Gyroscope (Officer of Entity), Boston Image Reading Center (Stock), Ocudyne (Stock). Jay S. Duker: Research to Prevent Blindness Challenge (Grant), Carl Zeiss Meditec (Financial Support), Optovue (Financial Support), Aldeyra (Consultant), Allegran (Consultant), Aura Biosciences (Consultant), Bausch Health (Consultant), Beyeonics (Consultant), Merck (Consultant), Novartis (Consultant), Roche (Consultant), Eleven Oncology (Director of Entity), Eye-Point Pharma (Director of Entity), Hemera Biosciences (Stock). The remaining authors have no conflicting interests to disclose., (© The Author(s) 2020.)

Background: The purpose of this study was to investigate the association between diabetic retinopathy (DR) severity and macular choriocapillaris (CC) flow deficit percentage (FD %) in different macular regions using swept-source optical coherence tomography angiography (SS-OCTA)., Methods: Diabetic patients with SS-OCTA images were graded by severity and retrospectively assessed. CC FD % was calculated in four different regions of the OCTA image: inner, middle, outer, and full-field region. The generalized estimating equations (GEE) approach for clustered eye data was used to determine effect size and significance of age and disease severity on FD % for each region., Results: 160 eyes from 90 total diabetic patients met inclusion criteria. Out of 90 patients, 33 had no DR, 17 had mild nonproliferative DR (NPDR), 8 had moderate NPDR, 10 had severe NPDR and 22 had proliferative DR. Age and DR severity had a significant positive association with FD % for each region studied with a greater effect in the two centermost regions. The increase in flow deficit percentage per year of age by region was: inner 0.12 (p < 0.001), middle 0.09 (p < 0.001), outer 0.05 (p < 0.001, full-field 0.06 (p < 0.001). The increase in flow deficit percentage per increase in diabetic retinopathy severity stage by region was: inner 0.65 (p < 0.0087), middle 0.56 (p < 0.0012), outer 0.33 (p < 0.045), full-field 0.36 (p < 0.018)., Conclusions: Topographic analysis of the CC FD % in diabetic eyes suggests that CC flow impairment corresponds to DR severity, with all studied regions of the CC significantly affected. There was greater regional impairment due to age and disease severity in the inner and middle regions., Competing Interests: Competing interestsAI: Topcon Medical Systems, Inc. (Tokyo, Japan) (S), Nidek Medical Products, Inc. (Gamagori, Aichi, Japan) (S) CRB: Carl Zeiss Meditec, Inc. (Dublin, CA, USA) (S), Genentech (South San Francisco, CA, USA), Novartis (Basel, Switzerland) (S), Allergan (Dublin, Ireland) (C) JGF: Topcon Medical Systems Inc. (Oakland, NJ, USA) (C, F), Optovue, Inc. (Fremont, CA, USA) (C, R, S), Carl Zeiss Meditec, Inc. (Dublin, CA, USA) (R) JSD: Carl Zeiss Meditec, Inc. (Dublin, CA, USA) (C, F), Optovue, Inc. (Fremont, CA, USA) (C, F) NKW: Macula Vision Research Foundation (West Conshohocken, PA, USA) (F), Topcon Medical Systems, Inc. (Oakland, NJ, USA) (F), Nidek Medical Products, Inc. (Fremont, CA, USA) (S, F), Optovue, Inc. (Fremont, CA, USA) (C), Carl Zeiss Meditec, Inc. (Dublin, CA, USA) (F) ER: Regeneron Pharmaceuticals, Inc. (Tarrytown, NY, USA) (F)., (© The Author(s) 2020.)

Purpose: To develop an optical coherence tomography angiography (OCTA)-based framework for quantitatively analyzing the spatial distribution of choriocapillaris (CC) impairment around choroidal neovascularization (CNV) secondary to age-related macular degeneration., Methods: In a retrospective, cross-sectional study, 400-kHz swept-source OCTA images from 7 eyes of 6 patients with CNV secondary to age-related macular degeneration were quantitatively analyzed using custom software. A lesion-centered zonal OCTA analysis technique-which portioned the field-of-view into zones relative to CNV boundaries-was developed to quantify the spatial dependence of CC flow deficits., Results: Quantitative, lesion-centered zonal analysis of CC OCTA images revealed highest flow-deficit percentages near CNV boundaries, decreasing in zones farther from the boundaries. Optical coherence tomography angiography using shorter (1.5 ms) interscan times revealed more severe flow deficits than OCTA using longer (3.0 ms) interscan times; however, spatial trends were similar for both interscan times. A detailed description of the OCTA processing steps and parameters was provided so as to elucidate their influence on quantitative measurements., Conclusion: Impairment of the CC, assessed by flow-deficit percentages, was most prominent closest to CNV boundaries. The lesion-centered zonal analysis technique enabled quantitative CC measurements relative to focal lesions. Understanding how processing steps, imaging/processing parameters, and artifacts can affect quantitative CC measurements is important for longitudinal, OCTA-based studies of disease progression, and treatment response.

Purpose: To combine advances in high-speed, wide-field optical coherence tomography angiography (OCTA) with image processing methods for semiautomatic quantitative analysis of capillary nonperfusion in patients with diabetic retinopathy (DR)., Methods: Sixty-eight diabetic patients (73 eyes), either without retinopathy or with different degrees of retinopathy, were prospectively recruited for volumetric swept-source OCTA imaging using 12 mm × 12 mm fields centered at the fovea. A custom, semiautomatic software algorithm was used to quantify areas of capillary nonperfusion., Results: The mean percentage of nonperfused area was 0.1% (95% confidence interval: 0.0-0.4) in the eyes without DR; 2.1% (95% confidence interval: 1.2-3.7) in the nonproliferative DR eyes (mild, moderate, and severe), and 8.5% (95% confidence interval: 5.0-14.3) in the proliferative DR eyes. The percentage of nonperfused area increased in a statistically significant manner from eyes without DR, to eyes with nonproliferative DR, to eyes with proliferative DR., Conclusion: Capillary nonperfusion area in the posterior retina increases with increasing DR severity as measured by swept-source OCTA. Quantitative analysis of retinal nonperfusion on wide-field OCTA may be useful for early detection and monitoring of disease in patients with diabetes and DR.

Purpose: To determine optical coherence tomography signs associated with macular atrophy (MA) in eyes with neovascular age-related macular degeneration and pigment epithelial detachments treated with vascular endothelial growth factor inhibitors., Methods: Optical coherence tomography scans from a subgroup of the pigment epithelial detachment cohort of the HARBOR study were analyzed for MA. Two groups were formed based on MA presence/absence at Month 24. Then, optical coherence tomography scans from each baseline visit were graded with standard reading center grading parameters including ellipsoid zone disruption, intraretinal cysts, subretinal fluid, and MA or nascent MA in the study and fellow eyes., Results: Twenty-eight eyes from 28 patients were included in the analysis. Fourteen eyes had optical coherence tomography-based MA at Month 24 and 14 did not. Macular atrophy at Month 24 was significantly associated with 1) MA/nascent MA at baseline (P = 0.0136), 2) intraretinal cysts at baseline (P = 0.0048), and 3) collapse of pigment epithelial detachments in the study eye (P = 0.0025). Macular atrophy was not associated with ellipsoid zone disruption or subretinal fluid in the study eye at baseline., Conclusion: This study suggests that some optical coherence tomography findings in eyes of patients with neovascular age-related macular degeneration were present before the start of anti-vascular endothelial growth factor therapy and may predict the development of MA.