Faculty Bibliography

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.

PURPOSE/OBJECTIVE:To evaluate the vascular characteristics of the choriocapillaris in eyes with pachychoroid as compared with normal controls. METHODS:Eyes with pachychoroid disease were defined as those with a history of central serous chorioretinopathy or peripapillary pachychoroid syndrome. Pachychoroid without disease was defined as eyes with no history of disease with a subfoveal choroidal thickness ≥ the age-adjusted 95 percentile thickness. Frame averaged optical coherence tomography angiography images of the choriocapillaris obtained with a Zeiss Plex Elite were binarized, skeletonized, and evaluated for vascular branching parameters. RESULTS:There were 7 normal controls, 10 pachychoroid without disease, and 17 pachychoroid disease subjects. Mean choriocapillaris vessel segment length was 12.19 µm in eyes with pachychoroid disease as compared with 11.48 µm for normal controls and 11.62 µm for pachychoroid without disease (P=.003 and P=.006, respectively). The branches per mm were fewer in pachychoroid disease, 1215, as compared to normal controls, 1471, or pachychoroid without disease, 1384, (P<.001, and P = .002, respectively). The choriocapillaris vessel diameter was larger, but the fractal dimension was smaller in pachychoroid disease eyes as compared to normal or pachychoroid without disease eyes. There was no statistically significant difference between normal controls and pachychoroid without disease for any measured vascular parameter of the choriocapillaris. CONCLUSIONS:Choriocapillaris vascular parameters suggest that pachychoroid is not necessarily pathologic. It is possible choroidal thickening is an epiphenomenon and there are more significant vascular parameters that are related to disease. These concepts may help guide future prospective studies.

PURPOSE/OBJECTIVE:To longitudinally characterize structural/angiographic findings of retinal-choroidal anastomosis (RCA) in macular telangiectasia type 2 (MacTel2). METHODS:Combined retrospective/prospective review of MacTel2 patients with >2 visits and >2 months follow-up, including examination, fundus photography, fluorescein angiography, spectral-domain optical coherence tomography (SD-OCT), and projection-resolved OCT angiography. RESULTS:There were 24 eyes of 12 patients with mean age 61.1 (±7.3 [SD]) years and median follow-up 447 (range 81-1511) days. There were 5 eyes diagnosed with new RCA after not having any previously. RCA was diagnosed in 8 (33%) eyes initially and eventually 13 (54%). In the 8 eyes initially diagnosed with RCA, the number of RCAs and outer retinal hyperrflective lesions increased over the follow-up. The RCAs were found in clusters, generally temporal to the fovea. RCA was uniformly associated with complete retinal subsidence, defined as the loss of outer nuclear layer substance such that the middle retinal layers sank down toward retinal pigment epithelium (RPE), was also present in each case. Each RCA colocalized with a region of hyperreflectivity, previously termed outer retinal hyperreflective lesion (ORHL). There was a lack of fluorescein leakage, lipid, hemorrhage, or any structural correlates to fluid exudation, and no signs of subretinal/sub-RPE neovascularization. CONCLUSION/CONCLUSIONS:De novo RCA development appears to be associated with retinal subsidence, and after RCAs form, they increase in number and topographic distribution over time. Initially after formation, there was no sign of exudation. These data suggest descent of the deep capillary plexus occurs with RCA, devoid subretinal/sub-RPE neovascularization in MacTel2.