Faculty Bibliography

PURPOSE/OBJECTIVE:To evaluate the various patterns of subretinal fluid (SRF) in eyes with age-related macular degeneration (AMD) in the absence of macular neovascularisation (MNV) and to assess the long-term outcomes in these eyes. METHODS:This retrospective study included only eyes with non-neovascular AMD and associated SRF. Eyes with evidence of MNV were excluded. Spectral-domain optical coherence tomography (SD-OCT) was obtained at baseline and at follow-up, and qualitative and quantitative SD-OCT analysis of macular drusen including drusenoid pigment epithelial detachment (PED) and associated SRF was performed to determine anatomic outcomes. RESULTS:Forty-five eyes (45 patients) were included in this analysis. Mean duration of follow-up was 49.7±36.7 months. SRF exhibited three different morphologies: crest of fluid over the apex of the drusenoid PED, pocket of fluid at the angle of a large druse or in the crypt of confluent drusen or drape of low-lying fluid over confluent drusen. Twenty-seven (60%) of the 45 eyes with fluid displayed collapse of the associated druse or drusenoid PED and 24 (53%) of the 45 eyes developed evidence of complete or incomplete retinal pigment epithelial and outer retinal atrophy. CONCLUSION/CONCLUSIONS:Non-neovascular AMD with SRF is an important clinical entity to recognise to avoid unnecessary anti-vascular endothelial growth factor therapy. Clinicians should be aware that SRF can be associated with drusen or drusenoid PED in the absence of MNV and may be the result of retinal pigment epithelial (RPE) decompensation and RPE pump failure.

PURPOSE/OBJECTIVE:To quantify retinal vasculature changes in Stargardt disease1 with volume-rendered optical coherence tomography angiography (OCTA). METHODS:OCTA volumes from heathy subjects and two subgroups of STGD1 patients with the presence/absence of definitely decreased autofluorescence (DDAF) areas were compared. OCTA vessel surface area (VSA) and vessel volume (VV) were measured in central zones (Z) of 1, 2 and 3mm diameter. RESULTS:29 eyes of 15 STGD1 patients (20/9 eyes with/without DDAF) and 30 eyes of 15 controls contributed data. An enlarged foveal avascular zone was found in STGD1 patients without and even more with DDAF associated with a vessel rarefication in central and also paracentral zones with unnoticeable autofluorescence. VSA and VV were reduced in both STGD1 subgroups for all zones (P<0.0001). STGD1 eyes with compared to without DDAF showed reduced VSA and VV in Z2+3 (both P<0.05). CONCLUSION/CONCLUSIONS:Volume-rendering of OCTA in STGD1 shows a reduced retinal flow in the central macula. This is most likely secondary to loss of neurosensory tissue with disease progression and therefore not likely be favorably influenced by gene transfer and retinal pigment epithelial transplantation. Retinal blood flow assessed by 3D-volume rendered OCTA could serve as surrogate marker for vascular changes of the central retina.

PURPOSE/OBJECTIVE:To provide an image-based description of retinal features associated with risk for development of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD), as visualized with multimodal imaging anchored by structural optical coherence tomography. DESIGN/METHODS:Consensus meeting METHODS: As part of the Classification of Atrophy Meeting program, an international group of experts analyzed and discussed retinal multimodal imaging features in eyes with AMD associated with GA and/or risk of progression to GA. Attendees undertook pre-meeting grading exercises that were reviewed during the meeting sessions. Meeting presentations illustrated established and investigational multimodal imaging features and associated histology. These different features were then each discussed openly by the entire group to arrive at consensus definitions. These definitions were applied to 40 additional images that were graded independently by attendees, to further refine the consensus definitions and descriptions. RESULTS:Consensus was reached on images with descriptors for 12 features. These features included components of outer retinal atrophy (e.g., ellipsoid zone disruption), components of complete retinal pigment epithelium (RPE) and outer retinal atrophy (e.g., RPE perturbation with associated hypo- or hyper-transmission), features frequently seen in eyes with atrophy (e.g., refractile drusen) and features conferring risk for atrophy development (e.g., hyperreflective foci, drusen, and subretinal drusenoid deposits). CONCLUSIONS:An International consensus on terms and descriptions was reached on multimodal imaging features associated GA and with risk for GA progression in eyes with AMD. We believe this information will be useful to clinicians who manage patients with AMD, researchers who study AMD disease interventions and pathogenesis, and those who design clinical trials for therapies targeting earlier AMD stages than GA expansion.

PURPOSE/OBJECTIVE:To analyze swept source optical coherence angiography (SS-OCTA) images acquired at different depths above and below the default location of the Zeiss PLEX Elite 9000. METHODS:Normal eyes of subjects in their 20s and 30s were evaluated. Angiographic slab images were taken at the default location of 29-49 µm below the retinal pigment epithelium (RPE) as well as 21-41 µm through 52-72 µm below in steps. The images were processed using the projection removal function from the device´s software. Raw images were evaluated, as were images that underwent a published compensation technique that adjusts for light penetration to the sampled layer. RESULTS:11 eyes of 11 subjects were evaluated for the uncompensated and the compensated sets with the projection removal function turned off and on. The default location, 29-49 µm below the RPE, showed a granular choriocapillaris appearance. This appearance remained in all slabs from each group, differing slightly throughout depth. The projection removal function modified the grayscale values and diminished projection from overlaying retinal vessels. The compensation technique altered the appearance of flow deficits and the changes induced by it were more evident on the images were the projection removal function was turned on. CONCLUSION/CONCLUSIONS:Flow images in SS-OCTA of the choriocapillaris from varying levels are similar in appearance, suggesting projection from the choriocapillaris is important in image formation, although layers of vessels in the inner choroid may contribute by various amounts. A model explaining the prominent projection artifacts observed in the choroid with SS-OCTA imaging is presented.

A panel of imaging experts was assembled to review neovascular age-related macular degeneration optical coherence tomography angiography descriptors published to date, and test agreement on use of these terms, which was found to be low. Optical coherence tomography angiography (OCTA) has been used to identify and characterize macular neovascularization (MNV) secondary to age-related macular degeneration (AMD).^1-4 Many studies have explored OCTA morphological features of MNV that might serve as biomarkers to assess disease activity and response to treatment.^1-6 The proliferation of studies however has resulted in an OCTA terminology that has been variable and inconsistent. To address inconsistency of nomenclature and allow harmonization, a multidisciplinary panel of retinal imaging experts with a history of relevant research contributions to the field was assembled with the purpose of reviewing published terminology and to recommend a reduced list of key terms pertinent to OCTA. The group was called UNICORN, because of its ultimate goal of generating a UNIfied COmmentary of the committee of inteRnational experts on the nomenclature for Neovascular AMD in OCTA. In this report we describe the first steps, which included a review of OCTA descriptors of neovascular AMD (nAMD) published to date, and an exercise that tested agreement of these terms among retinal imaging experts. Prior to the first UNICORN meeting, a non-systematic review of the literature was performed, using the search terms "optical coherence tomography angiography" or "OCT angiography" or "OCT-A", AND "neovascular macular degeneration" or "neovascular age-related macular degeneration" or "neovascular AMD" or "nAMD" or "wet age-related macular degeneration" or "wet AMD" or "wet ARMD". A dictionary of OCTA descriptors relating to the features of MNV in AMD was generated and circulated to the panel.

PURPOSE/OBJECTIVE:To describe imaging produced by machine learning-based segmentation of high-resolution optical coherence tomography imaging of the intermediate capillary plexus and deep capillary plexus, layers of vessels not imaged well by dye-based angiography. METHODS:Three healthy subjects with no ocular problems were imaged with spectral domain optical coherence tomography using an instrument with a scanning speed of 85,000 A-scans per second and 3 µm axial optical resolution. A random forest segmentation strategy was used to segment the intermediate capillary plexus and deep capillary plexus. The depth-resolved imaging data was visualized with the help of volume rendering. RESULTS:The high-resolution optical coherence tomography showed the intermediate capillary plexus and deep capillary plexus at the outer borders of the inner nuclear layer. These vessels could be visualized with unprecedented detail in three dimensions. There were multiple bridging vessels connecting to the whorl-like patterns of capillary mesh of the deep capillary plexus, a feature only previously imaged in histologic evaluation of excised eyes. CONCLUSION/CONCLUSIONS:High-resolution optical coherence tomography, machine learning, and advanced image display techniques have wide relevancy in studying the retina in health and disease. Application of this approach has provided images of the deeper vascular layers of the eye that approximate histologic imaging, but noninvasively.

PURPOSE/OBJECTIVE:To determine the dose-response characteristics of the anti-vascular endothelial growth factor agents ranibizumab and aflibercept in neovascular age-related macular degeneration (NAMD) using published randomized trials and observational series. METHODS:Literature review of published series from 2006 - 2018 as determined from electronic searches of PubMed and the Cochrane Library. Data extracted included treatment strategy, frequency and first year visual acuity response. Monthly or bimonthly treatment schedules were classified as Fixed, pro re nata studies as PRN, treat and extend as TE, and when no strategy was listed, as Variable. RESULTS:Of 2062 citations retrieved, 96 were deemed eligible; these 96 citations provided 120 data points of dose frequency versus visual acuity change in year 1 of treatment. The dose response curve was nonlinear, but a log transform of the number of injections per year yielded a linear relationship defined by the expression, Letters of Improvement = -6.66 + 15.7*log (Number of Injections Year 1). After accounting for the number of injections neither the drug used (ranibizumab or aflibercept) nor the strategy employed (Fixed, PRN, TE, or Variable) were significant predictors of acuity change. As a group, studies using the PRN approach had the lowest number of injections and the worst acuity improvements as a treatment strategy. CONCLUSIONS:There appears to be a predictable, mathematically defined relationship between dose frequency and visual acuity change at 1 year in NAMD. The performance of current treatment efforts, as suggested by reported series and Medicare claims data, appears to be substandard.

In central serous chorioretinopathy (CSC), the macula is detached because of fluid leakage at the level of the retinal pigment epithelium. The fluid appears to originate from choroidal vascular hyperpermeability, but the etiology for the fluid is controversial. The choroidal vascular findings as elucidated by recent optical coherence tomography (OCT) and wide-field indocyanine green (ICG) angiographic evaluation show eyes with CSC have many of the same venous patterns that are found in eyes following occlusion of the vortex veins or carotid cavernous sinus fistulas (CCSF). The eyes show delayed choroidal filling, dilated veins, intervortex venous anastomoses, and choroidal vascular hyperpermeability. While patients with occlusion of the vortex veins or CCSF have extraocular abnormalities accounting for the venous outflow problems, eyes with CSC appear to have venous outflow abnormalities as an intrinsic phenomenon. Control of venous outflow from the eye involves a Starling resistor effect, which appears to be abnormal in CSC. Similar choroidal vascular abnormalities have been found in peripapillary pachychoroid syndrome. However, peripapillary pachychoroid syndrome has intervortex venous anastomoses located in the peripapillary region while in CSC these are seen to be located in the macular region. Spaceflight associated neuro-ocular syndrome appears to share many of the pathophysiologic problems of abnormal venous outflow from the choroid along with a host of associated abnormalities. These diseases vary according to their underlying etiologies but are linked by the venous decompensation in the choroid that leads to significant vision loss. Choroidal venous overload provides a unifying concept and theory for an improved understanding of the pathophysiology and classification of a group of diseases to a greater extent than previous proposals.