Faculty Bibliography

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 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.

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.

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.

PURPOSE/OBJECTIVE:To investigate the reflectivity of the structural optical coherence tomography images of the inner choroid as it relates to potential structural composition. METHODS:The reflectivity of slab images 29 - 49 µm and 45 - 65 µm below the RPE, obtained with the Zeiss Plex Elite 9000, were evaluated. The mean and standard deviation of a group of subjects with no ocular disorders were determined. Binarization of the images was done a threshold level established at the mean plus one standard deviation for each slab depth. The proportion of area binarized was evaluated with generalized estimating equations. Representative histologic images obtained from autopsy donors were stained with Masson's trichrome, a staining method helpful in evaluating collagen and ground substance of tissue. RESULTS:There were 67 eyes of 38 subjects with a mean age of 44.5 (range 22 - 82) years. Using generalized estimating equations, age was found to be a significant predictor for the proportion of binarized pixels in both the 29 - 49 µm (P=.034) and the 45 - 65 µm (P<.001) slabs. The histologic specimens illustrated the loss of ground substance with increasing compaction of collagen fibers in the choroidal stroma with advancing age. CONCLUSIONS:The reflectivity from the inner choroid is not uniform and changes with age. As suggested by the histologic specimens, we propose the OCT reflectance from the inner choroid is related, in part, to the packing density of collagen fibers present there.

PURPOSE/OBJECTIVE:To evaluate the choroidal vascular patterns of patients with pachychoroid-related diseases in eyes images with wide-field indocyanine green (ICG) angiography. METHODS:Retrospective study of wide-field ICG angiographic images of patients with pachychoroid, peripapillary pachychoroid syndrome, central serous chorioretinopathy (CSC), and pachychoroid-associated neovascularization that were evaluated for anastomoses between vortex vein systems, which are ordinarily separated by a watershed zone. RESULTS:There were 21 subjects with a mean age of 57.4 years and 15 were male. Among the 42 eyes evaluated, CSC was found in 24 eyes (57.1%), peripapillary pachychoroid syndrome in 5 (11.9%), pachychoroid associated neovascularization in 7 (16.7%), and pachychoroid in 6 (14.3%). Every eye showed anastomosis between the superonasal, superotemporal, and inferotemporal vortex vein systems. The inferonasal vortex vein system was less likely to demonstrate anastomosis except for peripapillary pachychoroid syndrome, which showed anastomosis in all eyes. The anastomotic connections were prominent in the central macula in the central serous chorioretinopathy and pachychoroid-associated neovascularization cases, and around the nerve in the peripapillary pachychoroid syndrome cases. Although the large choroidal veins were particularly prominent in the neovascular cases, the number was fewer in the macular region than in other pachychoroid-related diseases in this series. Compared with a control group of 9 eyes, the inferotemporal-superotemporal-superonasal anastomotic connections were more common in the case group (P<.001), and inferonasal quadrant (p=.023 right, P=.01, left eye). CONCLUSIONS:Intervortex venous anastomosis is common in pachychoroid, CSC, peripapillary pachychoroid syndrome, and pachychoroid-associated neovascularization. This finding has important implications concerning pathogenesis and classification of disease.