Faculty Bibliography

PURPOSE: To describe a new set of findings in eyes with pseudoxanthoma elasticum, specifically large defects in Bruch membrane. METHODS: Retrospective review of the optical coherence tomography image obtained with the Heidelberg Spectralis of the posterior pole of patients with pseudoxanthoma elasticum. Large dehiscences in Bruch membrane were defined as any defect in Bruch membrane greater than 250 microm in diameter that was not contiguous with a visible angioid streak. RESULTS: There were 28 eyes of 14 patients, with a mean age of 53.6 years; 10 were female. Large dehiscences in Bruch membrane were seen in nine eyes of six patients, and all were within peripapillary atrophy manifested by loss of the choroid and retinal pigment epithelium. The edges of Bruch membrane showed an abrupt termination in the optical coherence tomography images, and often with an upturned edge surrounding the region devoid of Bruch membrane. The mean refractive error of the patients was -2.1 diopters (D) in the right eye and -2.5 D in the left. CONCLUSION: Pseudoxanthoma elasticum shares peripapillary atrophy and large dehiscences of Bruch membrane with pathologic myopia. Although theories of pathologic myopia involve stresses from ocular expansion, those of pseudoxanthoma elasticum typically do not. The Bruch membrane defect in pseudoxanthoma elasticum may be related to fragility secondary to abnormal calcification and to the surrounding abiotrophy of surrounding affected tissues of the posterior pole of the eye.

PURPOSE: To validate a model-driven method (RefMoB) of automatically describing the four outer retinal hyperreflective bands revealed by spectral-domain optical coherence tomography (SDOCT), for comparison with histology of normal macula; to report thickness and position of bands, particularly band 2 (ellipsoid zone [EZ], commonly called IS/OS). METHODS: Foveal and superior perifoveal scans of seven SDOCT volumes of five individuals aged 28 to 69 years with healthy maculas were used (seven eyes for validation, five eyes for measurement). RefMoB determines band thickness and position by a multistage procedure that models reflectivities as a summation of Gaussians. Band thickness and positions were compared with those obtained by manual evaluators for the same scans, and compared with an independent published histological dataset. RESULTS: Agreement among manual evaluators was moderate. Relative to manual evaluation, RefMoB reported reduced thickness and vertical shifts in band positions in a band-specific manner for both simulated and empirical data. In foveal and perifoveal scans, band 1 was thick relative to the anatomical external limiting membrane, band 2 aligned with the outer one-third of the anatomical IS ellipsoid, and band 3 (IZ, interdigitation of retinal pigment epithelium and photoreceptors) was cleanly delineated. CONCLUSIONS: RefMoB is suitable for automatic description of the location and thickness of the four outer retinal hyperreflective bands. Initial results suggest that band 2 aligns with the outer ellipsoid, thus supporting its recent designation as EZ. Automated and objective delineation of band 3 will help investigations of structural biomarkers of dark-adaptation changes in aging.

PURPOSE: To investigate the interactions among multimodal imaging findings and multimodal vision testing in neovascular age-related macular degeneration. METHODS: Patients enrolled in a prospective study of neovascular age-related macular degeneration with at least 3 previous intravitreal anti-vascular endothelial growth factor injections. Each patient underwent multimodal fundus imaging including spectral domain optical coherence tomography and fundus autofluorescence, and multimodal vision testing, including visual acuity, contrast sensitivity, reading speed, and microperimetry. RESULTS: There were 73 eyes of 49 consecutive patients enrolled. Generalized estimating equations' modelling showed that the significant independent predictors of visual acuity were the area of confluent hypoautofluorescence and involvement of the foveal center with either granular or confluent hypoautofluorescence (P < 0.001). Contrast sensitivity was negatively correlated with the area of confluent hypoautofluorescence (P < 0.001), involvement of the foveal center with granular hypoautofluorescence (P = 0.017), and subfoveal choroidal thickness (P = 0.042). The only significant predictor of reading speed was the size of confluent hypoautofluorescence (P < 0.001). The size of the defect in the ellipsoid zone (P < 0.001) and the presence of intraretinal fluid (P = 0.045) were correlated with microperimetry score. CONCLUSION: Confluent absence of autofluorescence was a highly significant predictor of vision testing and serves as an easy parameter to obtain in patients with neovascular age-related macular degeneration.

PURPOSE: To investigate the vascular appearance of choroidal neovascularization (CNV) treated with recurrent intravitreous anti-vascular endothelial growth factor (VEGF) injections, which have been proposed to cause transient vascular normalization along with decreased vascularity and leakage. DESIGN: Retrospective case series with Perspective on the topic. METHODS: Patients with treated CNV secondary to age-related macular degeneration from a community based retinal referral practice were evaluated with optical coherence tomography angiography employing split-spectrum amplitude decorrelation. The choroidal neovascular morphology of the 17 eyes of 14 consecutive patients were described. RESULTS: The mean age of the patients, 8 men and 6 women, was 78.4 (standard deviation [+/-] 9.3) years. The mean greatest linear dimension of the lesion was 3600 microns. The mean number of anti-VEGF injections was 47 (+/-21). The vascular diameter of the vessels in the CNV appeared large even in small lesions, with feeder vessels approaching the size of the major arcade vessels of the retina. The vessels had few branch points and many vascular anastomotic connections among larger vessels. There was a paucity of capillaries visualized within the lesions. CONCLUSIONS: The findings of this study do not support the hypothesis of vascular normalization in eyes receiving recurrent periodic antiangiogenic treatment. The observed "abnormalization" of the vessels may be explained by periodic pruning of angiogenic vascular sprouts by VEGF withdrawal in the face of unimpeded arteriogenesis. As the eye is a readily accessible VEGF laboratory, features expressed therein may also apply to neovascularization elsewhere in the body, such as in tumors.

PURPOSE: To examine the colocalization error between the infrared reflectance (IR) scanning laser ophthalmoscope (SLO) and spectral domain optical coherence tomography (SD-OCT) images of the Heidelberg Spectralis. METHODS: The IR and corresponding horizontal raster SD-OCT images were compared in 10 healthy volunteers examined with 3 Heidelberg Spectralis + OCT instruments. The center points of retinal vessels selected by random uniform sampling in scanning laser ophthalmoscope-IR images were compared with colocalizing points in corresponding SD-OCT images by two masked readers. The error of colocalization was measured in the SD-OCT image. The point positions were recorded using Cartesian coordinates measured in microns. The error of colocalization was evaluated using a fixed-effects generalized least squares regression model with location and instrument as predictor variables. RESULTS: A total of 1,617 points in the IR and SD-OCT images were analyzed, and the mean error of colocalization was 42.2 +/- 32.4 mum. The Heidelberg Spectralis instrument used was not a significant predictor of colocalization error (P = 0.15). The colocalization errors were negatively correlated with x-coordinate position (P < 0.001). CONCLUSION: There is a mean colocalization error between the IR and SD-OCT images produced by the Heidelberg Spectralis that is on the scale of many features being evaluated in the fundus. The variability in these measurements means the confidence interval for the exact colocalization is much larger. Because of the magnitude and variability of the error, the colocalization feature of the Heidelberg Spectralis should be used as a rough guide, not an absolute determinant.

PURPOSE: To evaluate eyes with refractile drusen using clinical imaging and to identify candidate histologic correlates of refractile drusen. METHODS: Refractile drusen were defined as drusenoid material containing small refractile spherules. Retrospective analysis of color, autofluorescence, and spectral domain optical coherence tomography images of eyes with refractile drusen was performed to characterize the morphology and topography of these lesions. Macular sections from donor eyes were processed with a von Kossa stain for calcium phosphate and viewed by light microscopy. Punches of retinal pigment epithelium-choroid from donors with geographic atrophy were prepared for transmission electron microscopy. RESULTS: Fundus findings of 14 eyes of 10 patients with age-related macular degeneration (age, 82.9 +/- 5.6 years) were evaluated. A generalized loss of autofluorescence signal over refractile drusen appeared to spread over a larger area than each druse, for drusen located centrally. By color fundus photography, refractile drusen showed corresponding depigmentation around drusen that were located in the center of the macula. Optical coherence tomography imaging of refractile drusen showed hyperreflective dots. In the histologic specimens, drusen contained many small spherules rich in calcium phosphate. Ultrastructural examination of the spherules showed complex assemblies consisting of concentric shells containing thin layers of calcium. CONCLUSION: Refractile drusen appear to be a stage of drusen regression marked by loss of retinal pigment epithelium, thus contributing to the development of geographic atrophy. Calcium-containing spherules appear to account for the glistening appearance.

PURPOSE:: To demonstrate the evolution and treatment response of Type 3 neovascularization using spectral domain optical coherence tomography. METHODS:: We retrospectively analyzed 40 eyes treated with intravitreal anti-vascular endothelial growth factor therapy for Type 3 neovascularization over a variable follow-up period. RESULTS:: In 17 eyes, spectral domain optical coherence tomography captured the development of Type 3 neovascularization from punctate hyperreflective foci that preceded any outer retinal defect. The more mature Type 3 lesions were associated with outer retinal disruption and adjacent cystoid macular edema. In addition, 37 of 40 Type 3 lesions (93%) were associated with an underlying pigment epithelial detachment, of which 26 (70%) were drusenoid, 6 (16%) serous, and 5 (14%) mixed. Type 3 vessels appeared to leak fluid into the pigment epithelial detachment cavity, creating serous pigment epithelial detachments as large as 925 mum in maximal height. Treatment with anti-vascular endothelial growth factor agents led to prompt involution of the lesion and resorption of the intraretinal and subretinal pigment epithelium fluid after one or two injections (median = 1). CONCLUSION:: In some eyes with age-related macular degeneration, the earliest sign of Type 3 neovascularization is punctate hyperreflective foci above the external limiting membrane. The mature Type 3 lesions and associated serous pigment epithelial detachments are highly responsive to anti-vascular endothelial growth factor therapy.