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Purpose: To compare the diagnostic ability of the vessel parameters in macular and peripapillary regions measured using spectral-domain optical coherence tomography angiography (SD-OCTA) in differentiating primary open-angle glaucoma (POAG) from healthy eyes., Methods: POAG patients and healthy subjects underwent 6 × 6-mm scans centered on the macula and optic nerve head. Commercially available automatic segmentation created en face images from SD-OCTA of the superficial retinal layer (SRL) of the macular (m) and peripapillary (cp) regions. Vessel area density (VAD), vessel skeleton density (VSD), vessel complexity index (VCI), and flux were calculated. Area under curve (AUC) statistics controlled for age and intereye correlation., Results: Of 126 eyes from 79 patients who underwent SD-OCTA macula and peripapillary imaging, 50 eyes from 35 POAG patients and 37 healthy eyes from 25 control subjects had good quality imaging and were studied. Diagnostic accuracies of four perfusion parameters, VAD, VSD, VCI, and flux, were significantly greater in the peripapillary compared with the macular regions. For VAD, the cpAUC was 0.84 and mAUC was 0.73 (AUC difference: P = 0.026). For VSD, the cpAUC was 0.84 and mAUC was 0.72 (Δ P = 0.015). For VCI, the cpAUC was 0.80 and mAUC was 0.70 (Δ P = 0.045). For flux, the cpAUC = 0.87 and mAUC was 0.76 (Δ P = 0.0091)., Conclusions: Peripapillary perfusion parameters performed better than macular perfusion parameters for glaucoma diagnosis, supporting the idea that glaucomatous superficial retinal vascular changes are more pronounced in the peripapillary region., Translational Relevance: The diagnostic accuracy of OCTA perfusion parameters of the superficial retinal microcirculation was greater for the peripapillary region than the macular region in the diagnosis of glaucoma.

Objective: To characterize features of extra-vascular optical coherence tomography angiography (OCTA) signals corresponding to hyperreflective intraretinal fluid across various exudative maculopathies., Design: Multicenter, retrospective, observational study., Participants: Eyes with various forms of exudative maculopathy including diabetic retinopathy (DR), retinal vein occlusion (RVO), and neovascular-age related macular degeneration (nvAMD)., Methods: Patients with extra-vascular OCTA signal identified on en face OCTA images were included in this study. This signal was readily distinguishable from projection artifacts. The regions with the extra-vascular motion signal on OCTA were named "Suspended Scattering Particles in Motion (SSPiM)." Depth-encoded, color, en face OCTA images (3mm × 3mm) centered on the fovea and their corresponding structural OCT scans were used to quantify features of SSPiM and its corresponding hyperreflective fluid. Longitudinal data were collected when available., Main Outcome Measures: Anatomic location, the association with hyperreflective material, changes in location and appearance of SSPiM over time, and replication of SSPiM OCTA signal in an in vitro phantom., Results: Seventy-six eyes in 62 patients with various forms of exudative maculopathy were evaluated; 60 eyes with DR, 9 eyes with RVO, and 5 eyes nvAMD, 1 eye with macroaneurysm, and 1 eye with radiation retinopathy. Intraretinal accumulations of fluid with increased OCT signal intensity corresponded to regions of SSPiM in several exudative maculopathies. An in vitro phantom model demonstrates that particulate matter in suspension can generate similar OCTA signal. SSPiM showed an anatomic preference for vascular-avascular junctions. The hyperreflective fluid corresponding to SSPiM appeared more frequently in Henle's fiber layer (HFL) than the inner nuclear layer (INL) and was highly associated with hyperreflective material (HRM) found bordering the fluid. In five of eight longitudinal cases, the resolution of SSPiM resulted in the formation of confluent HRM. Clinically, this appeared as hard exudate on funduscopic images., Conclusions: Clinical data suggest that SSPiM is a novel imaging feature of retinal vascular diseases that was not appreciated prior to the use of OCTA. We characterized several novel features of SSPiM and demonstrated that at least in some cases it resolves with residual hard exudate.

Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non-neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement strategies may delay disease progression or restore vision. A prospective, interventional, U.S. Food and Drug Administration-cleared, phase 1/2a study is being conducted to assess the safety and efficacy of a composite subretinal implant in subjects with advanced NNAMD. The composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), consists of a polarized monolayer of human embryonic stem cell-derived RPE (hESC-RPE) on an ultrathin, synthetic parylene substrate designed to mimic Bruch's membrane. We report an interim analysis of the phase 1 cohort consisting of five subjects. Four of five subjects enrolled in the study successfully received the composite implant. In all implanted subjects, optical coherence tomography imaging showed changes consistent with hESC-RPE and host photoreceptor integration. None of the implanted eyes showed progression of vision loss, one eye improved by 17 letters and two eyes demonstrated improved fixation. The concurrent structural and functional findings suggest that CPCB-RPE1 may improve visual function, at least in the short term, in some patients with severe vision loss from advanced NNAMD., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: To report the clinical presentation, multimodal imaging, and management of a patient with metastatic melanoma who presented with cystoid macular edema (CME)., Observations: We report a case of a 71-year-old Caucasian male with metastatic melanoma who presented with bilateral cystoid macular edema after being on treatment with a programmed T cell death ligand 1 inhibitor, MPDL3280, for 1 year. Multimodal imaging techniques, including color fundus photographs, autofluorescence, spectral domain optical coherence tomography (OCT), fluorescein angiography (Spectralis, Heidelberg, Germany), and spectral-domain OCT angiography (Zeiss; California, USA) were performed to evaluate the etiology of his CME and to monitor his response to treatment. Clinical examination and multimodal imaging revealed 1 + chronic vitreous cells, an epiretinal membrane, and mild macular edema in both eyes. Fundus autofluorescence showed paravenous hypoautofluorescence in the right eye and scattered hypoautofluorescent spots in the left eye. Optical coherence tomography angiography (OCTA) revealed mild drop out of superficial vessels in the peri-foveal region bilaterally. These findings were concerning for melanoma-associated retinopathy, drug-related uveitis, or activation of a previous chronic autoimmune process. The patient was started on prednisone 30 mg oral daily and ketorolac tromethamine 0.5% 1 drop four times daily. He was then treated with bilateral sustained-release dexamethasone intravitreal implants (Ozurdex). He had complete resolution of CME, and was tapered off of oral steroids within 6 weeks., Conclusions and Importance: Melanoma-associated retinopathy can be accompanied by CME, which presents a diagnostic and therapeutic dilemma in cases where a new drug has been recently initiated. By treating the condition locally, the ophthalmologist may be able to taper systemic immunosuppression more quickly.

Purpose This study demonstrates a standardized approach to measuring retinal thickness (RT) using spectral domain optical coherence tomography (SD-OCT) in commonly used animal models of disease and reports a normative data set for future use. Materials and Methods Twenty normal eyes of 4 adult animal models (5 rats, 5 rabbits, 5 canines, and 5 mini-pigs) were used. Manual measurements were made on the commercially available Heidelberg Spectralis™ SD-OCT to determine the total, inner, and outer retinal thickness (RT) at fixed distances from the optic nerve head (ONH) (1, 2, 3, 4, 5, and 6 mm away) in order to control for normal variation in retinal thickness. Analysis of variance (ANOVA) with P value <0.05 indicated statistical significance. Results Total RT significantly decreased with increasing distance from the ONH for the canine, mini-pig, and rabbit vascular models. Inner RT significantly decreased for the canine, mini-pig, rabbit vascular, and rabbit avascular models; and outer RT significantly decreased for only the canine model. Among the animal models, RT at similar distances from the ONH were significantly different for total, inner, and outer RT. Conclusion There are significant differences in the total, inner, and outer RT of normal canine, mini-pig, rabbit, and rat retinas with SD-OCT using a standardized approach. These measurements provide a normative reference for future studies and illustrate a standardized method of assessing RT.

Purpose: Induction of focal retinal detachment (RD) for subretinal delivery of stem cells and gene therapy is increasingly common. In order to determine if this procedure has an adverse impact on the retina, we use spectral-domain optical coherence tomography (SD-OCT) to evaluate the pre- and postoperative retinal anatomy of the incidentally detached normal retina surrounding large submacular hemorrhages (SMH) during surgical displacement procedures., Methods: Retrospective, observational study of human subjects with monocular SMH evaluated before and after surgical displacement using clinical exam, fundus photography, and SD-OCT. Manual measurements of the inner retinal thickness (IRT), outer retinal thickness (ORT), and full retinal thickness (FRT) were made in regions involving the SMH and surrounding normal retina. Comparison of retinal thickness measurements was made using the Wilcoxon signed-rank test., Results: Seven eyes were included in this study. All eyes successfully underwent surgical displacement of SMH. Visual acuity improved in 6/7 subjects and was unchanged in the remaining subject. Incidental RD of the normal retinal regions surrounding the SMH did not cause any significant change in IRT, ORT, or FRT that was detectable by SD-OCT. In contrast, mean FRT overlying regions with SMH was significantly greater before surgery compared to after displacement of SMH or normal adjacent retina., Conclusions: Surgically induced focal RD does not cause detectable retinal changes in the incidentally detached normal retina surrounding large SMH. Therefore, surgical induction of focal RD should not be considered to have the same adverse impact on the retina as pathologic RD.

OCT has revolutionized the practice of ophthalmology over the past 10-20 years. Advances in OCT technology have allowed for the creation of novel OCT-based methods. OCT-Angiography (OCTA) is one such method that has rapidly gained clinical acceptance since it was approved by the FDA in late 2016. OCTA images are based on the variable backscattering of light from the vascular and neurosensory tissue in the retina. Since the intensity and phase of backscattered light from retinal tissue varies based on the intrinsic movement of the tissue (e.g. red blood cells are moving, but neurosensory tissue is static), OCTA images are essentially motion-contrast images. This motion-contrast imaging provides reliable, high resolution, and non-invasive images of the retinal vasculature in an efficient manner. In many cases, these images are approaching histology level resolution. This unprecedented resolution coupled with the simple, fast and non-invasive imaging platform have allowed a host of basic and clinical research applications. OCTA demonstrates many important clinical findings including areas of macular telangiectasia, impaired perfusion, microaneurysms, capillary remodeling, some types of intraretinal fluid, and neovascularization among many others. More importantly, OCTA provides depth-resolved information that has never before been available. Correspondingly, OCTA has been used to evaluate a spectrum of retinal vascular diseases including diabetic retinopathy (DR), retinal venous occlusion (RVO), uveitis, retinal arterial occlusion, and age-related macular degeneration among others. In this review, we will discuss the methods used to create OCTA images, the practical applications of OCTA in light of invasive dye-imaging studies (e.g. fluorescein angiography) and review clinical studies demonstrating the utility of OCTA for research and clinical practice., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To quantitatively evaluate the retinal microvasculature in human subjects with retinal venous occlusions (RVO) using optical coherence tomography angiography (OCTA)., Design: Retrospective, cross-sectional, observational case series., Participants: Sixty subjects (84 eyes) were included (20 BRVO, 14 CRVO, 24 unaffected fellow eyes, and 26 controls)., Methods: OCTA was performed on a prototype, spectral domain-OCTA system in the 3x3mm central macular region. Custom software was used to quantify morphology and density of retinal capillaries using four quantitative parameters. The vasculature of the segmented retinal layers and nonsegmented whole retina were analyzed., Main Outcome Measures: Fractal dimension (FD), vessel density (VD), skeletal density (SD), and vessel diameter index (VDI) within the segmented retinal layers and nonsegmented whole retina vasculature., Results: Nonsegmented analysis of RVO eyes demonstrated significantly lower FD (1.64±0.01 vs 1.715±0.002; p<0.001), VD (0.32±0.01 vs 0.432±0.002; p<0.001), and SD (0.073±0.004 vs 0.099±0.001; p<0.001) compared to controls. Compared to the fellow eye, FD, VD and SD were lower (p<0.001), and VDI was higher (p<0.001). FD, VD, and SD progressively decreased as the extent (or type) of RVO increased (control vs BRVO vs CRVO; p<0.001). In the unaffected fellow eye FD, VD and SD showed significant differences when compared to control eyes or affected RVO eyes (p<0.001)., Conclusions: Quantitative OCTA of the central 3x3mm macular region demonstrates significant differences in capillary density and morphology among subjects with BRVO and CRVO compared to controls or unaffected fellow eyes in all vascular layers. The unaffected fellow eyes also demonstrate significant differences when compared to controls. OCTA allows for noninvasive, layer-specific, quantitative evaluation of RVO-associated microvascular changes.

Purpose: To describe a case of small retinal vessel vasculopathy postvaccination., Methods: We report the case of a 41-year-old white man who presented with a "second blind spot," describing a nasal scotoma in the right eye that started 4 days after vaccinations against Neisseria meningitidis and the yellow fever virus, and after a 2-month period of high stress and decreased sleep. Clinical examination, Humphrey visual field testing, and multimodal imaging with fundus photographs, autofluorescence, fluorescein angiography, and spectral domain optical coherence tomography and angiography were performed., Results: Clinical examination revealed a well-circumscribed, triangular area of retinal graying of about 1-disk diameter in size, located at the border of the temporal macula. This corresponded to a deep scotoma similar in size to the physiologic blind spot on Humphrey visual field 24-2 testing. There was mild hypoautofluoresence of this lesion on autofluorescence, hypofluorescence on fluorescein angiography, and focal attenuation of a small artery just distal to the bifurcation of an artery supplying the involved area. Spectral domain optical coherence tomography through the lesion conveyed hyperreflectivity most prominent in the inner and outer plexiform layers, with extension of the hyperreflectivity into the ganglion cell and inner nuclear layers. Spectral domain optical coherence tomography angiography demonstrated arteriolar and capillary dropout, more pronounced in the superficial retinal layer compared to the deeper retinal layer. At 1-month follow-up, his scotoma improved with monitoring, with reduction from -32 dB to -7 dB on Humphrey visual field testing. There was clinical resolution of the area of graying and decreased hyperreflectivity on spectral domain optical coherence tomography, with atrophy of the inner retina. Spectral domain optical coherence tomography angiography showed progression of arteriolar and capillary dropout, more so in the superficial than in the deep capillary plexus., Conclusion: We describe a case of small artery occlusion in a previously healthy patient, 4 days after vaccination against N. meningitidis and yellow fever. Fluorescein angiography yielded greater diagnostic value than OCTA for evaluating the occlusion, whereas spectral domain optical coherence tomography angiography enabled better visualization of capillary dropout and layer-specific assessment. Further research is required to determine whether vaccination in general, or directed specifically at N. meningitidis or yellow fever, is associated with small vessel vasculopathy and the underlying pathogenesis.

Purpose: To quantify retinal capillary density and morphology in uveitis using spectral-domain optical coherence tomography angiography (SD-OCTA)., Design: Cross-sectional, observational study., Methods: Healthy and uveitic subjects were recruited from 2 tertiary care eye centers. Prototype SD-OCTA devices (Cirrus; Carl Zeiss Meditec, Inc, Dublin, California, USA) were used to generate 3 × 3-mm 2 OCTA images centered on the fovea. Subjects were placed into 3 groups based on the type of optical microangiography (OMAG) algorithm used for image processing (intensity and/or phase) and type of retinal segmentation (automatic or manual). A semi-automated method was used to calculate skeleton density (SD), vessel density (VD), fractal dimension (FD), and vessel diameter index (VDI). Retinal vasculature was assessed in the superficial retinal layer (SRL), deep retinal layer (DRL), and nonsegmented retinal layer (NS-RL). A generalized estimating equations model was used to analyze associations between the OCTA measures and disease status within each retinal layer. A P value < .05 was accepted as significant. Reproducibility and repeatability were assessed using the intraclass correlation coefficient (ICC)., Results: The SD, VD, and FD of the parafoveal capillaries were lower in uveitic eyes compared with healthy eyes in all retinal segments. In addition, SD and VD were significantly lower in the DRL of subjects with uveitic macular edema. There was no correlation in any capillary parameters and anatomic classification of uveitis., Conclusions: Quantitative analysis of parafoveal capillary density and morphology in uveitis demonstrates significantly lower capillary density and complexity. SD-OCTA algorithms are robust enough to detect these changes and can provide a novel diagnostic index of disease for uveitis subjects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: A subretinal implant termed CPCB-RPE1 is currently being developed to surgically replace dystrophic RPE in patients with dry age-related macular degeneration (AMD) and severe vision loss. CPCB-RPE1 is composed of a terminally differentiated, polarized human embryonic stem cell-derived RPE (hESC-RPE) monolayer pre-grown on a biocompatible, mesh-supported submicron parylene C membrane. The objective of the present delivery study was to assess the feasibility and 1-month safety of CPCB-RPE1 implantation in Yucatán minipigs, whose eyes are similar to human eyes in size and gross retinal anatomy., Methods: This was a prospective, partially blinded, randomized study in 14 normal-sighted female Yucatán minipigs (aged 2 months, weighing 24-35 kg). Surgeons were blinded to the randomization codes and postoperative and post-mortem assessments were performed in a blinded manner. Eleven minipigs received CPCB-RPE1 while three control minipigs underwent sham surgery that generated subretinal blebs. All animals except two sham controls received combined local (Ozurdex™ dexamethasone intravitreal implant) and systemic (tacrolimus) immunosuppression or local immunosuppression alone. Correct placement of the CPCB-RPE1 implant was assessed by in vivo optical coherence tomography and post-mortem histology. hESC-RPE cells were identified using immunohistochemistry staining for TRA-1-85 (a human marker) and RPE65 (an RPE marker). As the study results of primary interest were nonnumerical no statistical analysis or tests were conducted., Results: CPCB-RPE1 implants were reliably placed, without implant breakage, in the subretinal space of the minipig eye using surgical techniques similar to those that would be used in humans. Histologically, hESC-RPE cells were found to survive as an intact monolayer for 1 month based on immunohistochemistry staining for TRA-1-85 and RPE65., Conclusions: Although inconclusive regarding the necessity or benefit of systemic or local immunosuppression, our study demonstrates the feasibility and safety of CPCB-RPE1 subretinal implantation in a comparable animal model and provides an encouraging starting point for human studies.

Purpose: To quantify changes in retinal microvasculature in diabetic retinopathy (DR) by using spectral-domain optical coherence tomography angiography (SD-OCTA)., Methods: Retrospective, cross-sectional, observational study of healthy and diabetic adult subjects with and without DR. Retinal microvascular changes were assessed by using SD-OCTA images and an intensity-based optical microangiography algorithm. A semiautomated program was used to calculate indices of microvascular density and morphology in nonsegmented and segmented SD-OCTA images. Microvascular density was quantified by using skeleton density (SD) and vessel density (VD), while vessel morphology was quantified as fractal dimension (FD) and vessel diameter index (VDI). Statistical analyses were performed by using the Student's t-test or analysis of variance with post hoc Tukey honest significant difference tests for multiple comparisons., Results: Eighty-four eyes with DR and 14 healthy eyes were studied. Spearman's rank test demonstrated a negative correlation between DR severity and SD, VD, and FD, and a positive correlation with VDI (ρ = -0.767, -0.7166, -0.768, and +0.5051, respectively; P < 0.0001). All parameters showed high reproducibility between graders (ICC = 0.971, 0.962, 0.937, and 0.994 for SD, VD, FD, and VDI, respectively). Repeatability (κ) was greater than 0.99 for SD, VD, FD, and VDI., Conclusions: Vascular changes in DR can be objectively and reliably characterized with SD, VD, FD, and VDI. In general, decreasing capillary density (SD and VD), branching complexity (FD), and increasing average vascular caliber (VDI) were associated with worsening DR. Changes in capillary density and morphology were significantly correlated with diabetic macular edema.

Purpose: To describe a case of tamoxifen toxicity superimposed on central serous chorioretinopathy (CSCR). We review the role of estrogen and the effect of tamoxifen on ocular tissues., Observations: A 32-year-old Hispanic female with infiltrating ductal carcinoma of the left breast (T2N1M0, triple-positive), status post chemotherapy and bilateral mastectomy, presented with complaint of a floater and decreased central vision of the right eye (OD). Symptoms began three weeks after initiating tamoxifen and five months after the last cycle of chemotherapy and dexamethasone. Visual acuity (VA) was 20/30 OD at presentation. Clinical examination and multimodal imaging revealed subretinal fluid (SRF) and pigment epithelial detachment (PED) suggestive of CSCR. After one month of monitoring, VA improved to 20/20; there was SRF resolution, small PED, and focal ellipsoid zone (EZ) band loss. Two weeks later, after undergoing surgery and starting a topical steroid, she returned with count fingers (CF) VA and large SRF OD. Steroid cessation improved SRF after one month, but VA was unchanged. Tamoxifen was discontinued, and VA improved to 20/100 with near-complete resolution of SRF at three weeks, and significant reduction in choroidal thickness at two months. At final follow-up, VA was 20/200, and there was focal EZ band loss sub-foveally, minimal SRF, and small PED., Conclusions and Importance: Treatment with tamoxifen may lead to ocular toxicity and can complicate the recovery course of patients affected with CSCR. Variations in levels of the estrogen receptor-alpha (ER-α) and treatment with tamoxifen (ER-α partial agonist) may lead to loss of the protective effect of estrogen in the retinal pigment epithelial cells in premenopausal women. Furthermore, tamoxifen toxicity can lead to focal photoreceptor loss. Treatment in these cases should be coordinated together with the oncologist.

Age-related macular degeneration (ARMD) is the leading cause of blindness in subjects older than 50 years of age in the developed world. There are two types of ARMD, neovascular (NV) and nonneovascular (NN). While anti-VEGF-based therapies have significantly decreased the visual morbidity associated with NV-ARMD, there are no effective treatments for NN-ARMD. A detailed discussion of NV-ARMD and related therapies is the topic of another section of this special supplement. This review will focus mainly on NN-ARMD. Vision loss in nonneovascular ARMD is highly correlated with the loss of RPE cells and areas of geographic atrophy (GA). Pilot studies using subretinal transplantation of autologous or allogeneic RPE during the past 20 to 30 years have demonstrated that stem cell-derived RPE have the potential to rescue photoreceptor function and restore vision. New methods of differentiating RPE from human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) have created a potentially unlimited supply of RPE cells to meet the demands of future commercially viable stem cell products. Thanks to fundamental advances in stem cell biology, vitreoretinal surgery, and noninvasive retinal imaging, stem cell-based therapies for NN-ARMD are emerging and several clinical trials are in progress. However, there are major regulatory, safety, and technical challenges that remain. This review will focus on summarizing the most promising aspects of stem cell-based therapy for NN-ARMD and highlighting areas that require further research.

Background and Objective: To demonstrate vitreoretinal traction as a mechanism of abnormal retinal vascular perfusion., Patients and Methods: Retrospective report of three cases demonstrating vitreoretinal traction concurrent with abnormal retinal perfusion. Subjects were retrospectively identified based on clinical records from two tertiary care retina subspecialty practices. All subjects underwent complete ophthalmic examination and ancillary testing as necessary for their standard clinical care. Vascular perfusion was assessed by one or more methods, including wide-field fluorescein angiography and optical coherence tomography angiography (OCTA). Vitreoretinal traction was assessed by clinical examination; intraoperative surgical observations; and fundus imaging, including wide-field, red-free, and color images as well as OCT., Results: Three cases are shown in which vitreoretinal traction was clearly documented and correlated with abnormal retinal vascular perfusion. Abnormal vascular perfusion correlated with the distribution of vessels affected by vitreoretinal traction in all cases. Vascular perfusion normalized in all cases after surgery was used to relieve vitreoretinal traction., Conclusion: The authors demonstrate that vitreoretinal traction can alter retinal vascular perfusion in a reversible fashion. These results suggest that there can be a direct mechanical effect of vitreous traction on retinal vascular perfusion. Further advances in wide-field imaging, wide-field OCT, and OCTA will help better evaluate this cause of retinal vascular insufficiency., (Copyright 2016, SLACK Incorporated.)

Purpose: To noninvasively evaluate the retinal microvasculature in human subjects with retinal venous occlusions using optical coherence tomography angiography and assess potential clinical applications., Methods: This was a prospective, observational study of adult human subjects with clinical and imaging findings demonstrating retinal venous occlusion. Subjects underwent complete ophthalmic examination and fluorescein angiography as appropriate for their standard of care. Optical coherence tomography angiography was performed on a prototype spectral domain-OCTA system in 3 mm × 3 mm and 6 mm × 6 mm regions centered on the fovea and parafoveal areas. Retinal vasculature was assessed within three horizontal slabs consisting of the superficial, middle, and deep retina. The vasculature within each slab was reconstructed using intensity contrast-based algorithms and visualized as en-face images. Optical coherence tomography angiograms were manually segmented to verify the accuracy of the automated segmentation algorithms., Results: Optical coherence tomography angiography was able to demonstrate almost all of the clinically relevant findings in 25 subjects with acute and chronic retinal venous occlusion. These findings were consistent with clinical, anatomic, and fluorescein angiographic findings including areas of impaired vascular perfusion, retinal atrophy, vascular dilation, shunt vessels, and some forms of intraretinal edema., Conclusion: Optical coherence tomography angiography is an investigational method that generates high-resolution, noninvasive angiograms that qualitatively illustrate most of clinically relevant findings in retinal venous occlusion. Optical coherence tomography angiography corresponds well with fluorescein angiograms and in many cases provides more detailed anatomic and blood flow information. Optical coherence tomography angiography, in conjunction with standard spectral domain-OCT, is at least equally as effective as fluorescein angiography for evaluation and management of the macular complications of retinal venous occlusions.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. AMD is classified as either neovascular (NV-AMD) or non-neovascular (NNV-AMD). Cumulative damage to the retinal pigment epithelium, Bruch's membrane, and choriocapillaris leads to dysfunction and loss of RPE cells. This causes degeneration of the overlying photoreceptors and consequential vision loss in advanced NNV-AMD (Geographic Atrophy). In NV-AMD, abnormal growth of capillaries under the retina and RPE, which leads to hemorrhage and fluid leakage, is the main cause of photoreceptor damage. Although a number of drugs (e.g., anti-VEGF) are in use for NV-AMD, there is currently no treatment for advanced NNV-AMD. However, replacing dead or dysfunctional RPE with healthy RPE has been shown to rescue dying photoreceptors and improve vision in animal models of retinal degeneration and possibly in AMD patients. Differentiation of RPE from human embryonic stem cells (hESC-RPE) and from induced pluripotent stem cells (iPSC-RPE) has created a potentially unlimited source for replacing dead or dying RPE. Such cells have been shown to incorporate into the degenerating retina and result in anatomic and functional improvement. However, major ethical, regulatory, safety, and technical challenges have yet to be overcome before stem cell-based therapies can be used in standard treatments. This review outlines the current knowledge surrounding the application of hESC-RPE and iPSC-RPE in AMD. Following an introduction on the pathogenesis and available treatments of AMD, methods to generate stem cell-derived RPE, immune reaction against such cells, and approaches to deliver desired cells into the eye will be explored along with broader issues of efficacy and safety. Lastly, strategies to improve these stem cell-based treatments will be discussed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Objective: Optical coherence tomography angiography (OCTA) is a novel, non-invasive OCT technique capable of imaging the retinal vasculature. This study aims to evaluate the retinal microvasculature in diabetic human subjects with OCTA and assess potential clinical applications., Patients and Methods: Cross-sectional study of 33 subjects with diabetic retinopathy. OCTA was performed on 3 mm × 3 mm sections using a swept-source OCTA prototype and a phase- and intensity-based contrasting algorithm. OCT angiograms were studied with corresponding clinical examination and fluorescein angiograms, when available, to assess accuracy and clinical utility., Results: OCTA was able to demonstrate most clinically relevant vascular changes in subjects with diabetic retinopathy, including microaneurysms, impaired vascular perfusion, some forms of intraretinal fluid, vascular loops, intraretinal microvascular abnormalities, neovascularization, and cotton-wool spots that were largely consistent with fluorescein angiography., Conclusion: OCTA generates high-resolution angiograms that illustrate many of the clinically relevant findings in diabetic retinopathy and offers a novel complement or alternative to fluorescein angiography. Although currently an investigational technique, OCTA in combination with standard OCT imaging is at least as good as fluorescein angiography in the evaluation of the macular complications of diabetic retinopathy., (Copyright 2015, SLACK Incorporated.)

Purpose: To describe the clinical and multimodal imaging characteristics of a patient with unilateral asymptomatic dark retinal lesions corresponding to ellipsoid zone hyporeflectivity on optical coherence tomography (OCT)., Methods: The authors report a case of a 35-year-old man with HIV who presents with asymptomatic dark geographic retinal lesions corresponding to ellipsoid zone hyporeflectivity on OCT. Multimodal imaging techniques, including fundus color and widefield photographs, autofluorescence, spectral domain OCT (Spectralis, Heidelberg, Germany), prototype spectral domain OCT (Carl Zeiss Meditec, Dublin, CA) with OCT angiography, and en face images, were performed to evaluate and characterize the morphology of these lesions., Results: Clinical examination and multimodal imaging reveal geographic darkening of the retina. Optical coherence tomography conveys hyporeflectivity of the ellipsoid zone band, which occurs abruptly and is present only in the areas of geographic retinal darkening. Optical coherence tomographic angiography shows a qualitatively similar appearance of the vasculature from the superficial retina through the avascular retina and the choriocapillaris, on both sides of the demarcation of retinal darkening, and also as compared to the unaffected eye. En face images from spectral domain OCT reveal an abrupt darkening of the tissue that localizes and is limited to the ellipsoid zone, with similar topographic appearance across the demarcation line., Conclusion: Geographic areas of darkening with photoreceptor hyporeflectivity have been described previously as "dark without pressure." In this case, the authors demonstrate photoreceptor hyporeflectivity that localizes to the clinically darkened areas, without topographic qualitative differences on en face spectral domain OCT images. The authors term these dark areas as geographic areas of retinal darkening because of ellipsoid nonreflectivity (GARDEN) spots.

Early diagnosis of glaucoma, which is a leading cause for visual impairment, is critical for successful treatment. It has been shown that Imaging polarimetry has advantages in early detection of structural changes in the retina. Here, we theoretically and experimentally present a snapshot Mueller Matrix Polarimeter fundus camera, which has the potential to record the polarization-altering characteristics of retina with a single snapshot. It is made by incorporating polarization gratings into a fundus camera design. Complete Mueller Matrix data sets can be obtained by analyzing the polarization fringes projected onto the image plane. In this paper, we describe the experimental implementation of the snapshot retinal imaging Mueller matrix polarimeter (SRIMMP), highlight issues related to calibration, and provide preliminary images acquired from the camera.

The authors propose an effective technique to isolate whole, intact vitreous core and cortex from post mortem enucleated porcine eyes. While previous studies have shown the results of such dissections, the detailed steps have not been described, precluding researchers outside the field from replicating their methods. Other studies harvest vitreous either through aspiration, which does not maintain the vitreous structure anatomy, or through partial dissection, which only isolates the vitreous core. The proposed method isolates the whole vitreous body, with the vitreous core and cortex intact, while maintaining vitreous anatomy and structural integrity. In this method, a full thickness scleral flap in an enucleated porcine eye is first created and through this, the choroid tissue can be separated from the sclera. The scleral flap is then expanded and the choroid is completely separated from the sclera. Finally the choroid-retina tissue is peeled off the vitreous to leave an isolated intact vitreous body. The proposed vitreous dissection technique can be used to study physical properties of the vitreous humor. In particular, this method has significance for experimental studies involving drug delivery, vitreo-retinal oxygen transport, and intraocular convection.

Purpose: To investigate optical coherence tomography-derived reflectivity and optical density (OD) characteristics of persistent subretinal fluid (SRF) in eyes after surgical repair of macula-off rhegmatogenous retinal detachment., Methods: Retrospective case series of nine eyes with macula-off rhegmatogenous retinal detachment that underwent surgical repair with either scleral buckling or vitrectomy with or without scleral buckling. Major inclusion criteria included 1) availability of high-quality optical coherence tomography scans at 2 or more time points, and 2) sufficient SRF for optical coherence tomography sampling without including tissue edges. Demographic, clinical, and optical coherence tomography imaging data were collected on all eyes. Optical density and SRF height measurements were obtained using a manual image segmentation method with ImageJ. Optical density measurements were standardized by conversion to optical density ratios to facilitate comparison between different visits and eyes. Correlations were assessed for significance through both univariate and multivariate regression analyses., Results: Optical density ratio measurements increased with time after surgery, and this was statistically significant (P = 0.001, R = 0.331). Subretinal fluid height measurements decreased in all eyes. There was a significant correlation between optical density ratios and log of SRF height (P ≤ 0.001, R = 0.485). In multivariate analysis, neither optical density ratios nor SRF height was a statistically significant predictor of visual acuity., Conclusion: Changes in optical density ratios of the residual SRF after retinal detachment repair may be representative of changes in the SRF composition over time. This is in agreement with previous biochemical studies and may serve as a noninvasive method of assessing SRF content in vivo.

Purpose: The purpose of this study was to report a unique case of persistent fetal vasculature presenting as peripapillary choroidal neovascularization., Methods: Ophthalmologic examination, examination under anesthesia, fluorescein angiogram, chart review, review of relevant literature. A 2-year 4-month-old white girl was referred for decreased vision and suspicious retinal findings., Results: Fundus examination of the right eye demonstrated a peripapillary macular scar with old subretinal hemorrhage, subretinal fluid consistent with peripapillary neovascular net, a persistent fetal vascular stalk, and a central posterior lenticular opacity. Fluorescein angiogram of the right eye showed normal arterial filling in the early phase, normal arteriovenous transit, and late staining with mild leakage., Conclusion: This is a unique case of persistent fetal vasculature presenting with the findings of subretinal exudates and choroidal neovascularization that has not been described before. Although the etiology of the choroidal neovascularization is unclear, we postulate it may be a result of the traction from the persistent fetal vasculature stalk in the peripapillary region. These findings may also be secondary to an optic disk anomaly that was not detected on examination.

Purpose: To report the clinical features and visual and anatomical outcomes in three patients with Staphylococcus lugdunensis endophthalmitis after intravitreal injection., Methods: This study was a retrospective, interventional case series conducted at a single, tertiary care retina referral practice under the approval of Western Institutional Review Board. Records of three eyes with culture-positive S. lugdunensis endophthalmitis after intravitreal injection with Lucentis or Avastin were reviewed. All patients were treated between November 2011 and March 2012., Results: All three patients developed symptoms of endophthalmitis 2 to 3 days after intravitreal injection and were culture positive for S. lugdunensis. Initial visual acuity ranged from 20/200 to light perception. Final visual acuity ranged from 20/100 to hand motion. Duration of follow-up ranged from 4 months to 10 months. One patient was treated with vitreous tap and injection of ceftazidime and vancomycin. Two patients underwent immediate vitrectomy and injection of intravitreal ceftazidime and vancomycin. One patient developed a retinal detachment requiring pars plana vitrectomy and silicone oil. All three patients demonstrated an early and aggressive course., Conclusion: This case series demonstrates that S. lugdunensis endophthalmitis can follow an aggressive course atypical for coagulase-negative organisms. Accurate identification of S. lugdunensis is important for management and prognosis. However, identification of S. lugdunensis is confounded by potential false-positive coagulase tests and the lack of routine speciation by microbiology laboratories.

Purpose: To describe the diversity of clinical findings associated with familial exudative vitreoretinopathy (FEVR) using wide-field angiography and to update the current classification system., Design: Retrospective case series at a single tertiary referral vitreoretinal practice., Participants: A total of 174 eyes of 87 subjects were studied., Methods: A retrospective chart review was conducted of patients with a diagnosis of FEVR between January 2011 and January 2013 at a single tertiary care retina practice. Data were collected from patient charts, including sex, gestational age at birth, age at presentation, referring diagnosis, family history, prior ocular surgery, clinical presentation, and diagnostic imaging in each eye. Inclusion criteria included clinical diagnosis of FEVR in patients referred to our clinic for evaluation of decreased vision. Patients were excluded if a diagnosis of FEVR could not be made., Main Outcome Measures: Clinical and angiographic findings., Results: A total of 87 subjects met the inclusion criteria for this study. A broad spectrum of previously undescribed clinical and angiographic findings were associated with FEVR on wide-field angiography. These findings can be grossly divided into anatomic and functional changes. Anatomic changes include aberrant circumferential peripheral vessels, venous and arterial tortuosity, late-phase disc leakage, central and peripheral telangiectasias, capillary anomalies, and capillary agenesis. Functional changes include venous-venous shunting, delayed arteriovenous transit, and delayed or absent choroidal perfusion on fluorescein angiography., Conclusions: Familial exudative vitreoretinopathy has a wide range of unrecognized or under-recognized clinical and angiographic findings that are easily identified using wide-field fluorescein angiography. These novel findings have led to an update of the original FEVR classification scheme and more complete characterization of early stages of FEVR., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: To noninvasively evaluate the retinal microvasculature in healthy human subjects with optical coherence tomography angiography (OCTA)., Patients and Methods: Cross-sectional, observational study of five healthy subjects. OCTA was performed on 3 × 3 mm(2) sections centered on the fovea, nasal macula, and temporal macula. Retinal vasculature was assessed within three horizontal slabs consisting of the inner, middle, and outer retina. The vasculature within each retinal slab was reconstructed using phase-based and intensity contrast-based algorithms and visualized as separate en face images., Results: OCTA in healthy subjects demonstrates capillary networks consistent with previous histological studies. No retinal vessels were found in the outer retina. OCT angiography of the inner and middle retinal layers showed region-specific vascular patterns that consistently corroborated qualitative findings from past histological studies., Conclusion: OCTA generates high-resolution, noninvasive angiograms qualitatively similar to conventional fluorescein angiography. OCTA may serve as a bridge to assess some features of the retinal microvasculature between conventionally performed angiograms., (Copyright 2014, SLACK Incorporated.)

Purpose: This pilot study was aimed to demonstrate the clinical feasibility of using hyperspectral computed tomographic spectroscopy to measure blood oxygen content in human retinal vessels., Methods: All procedures were performed under a University of Southern California Institutional Review Board-approved protocol and after obtaining informed consent. Fifty-seven subjects with and without diabetic retinopathy were dilated for standard fundus photography. Fundus photographs and retinal vascular oxygen measurements (oximetry) were made using a custom-made hyperspectral computed tomographic imaging spectrometer coupled to a standard fundus camera. Oximetry measurements were made along arteries (Aox) and veins (Vox) within vessel segments that were 1 to 2 disk diameters from the optic disk., Results: For all control subjects (n = 45), mean Aox and Vox were 93 ± 7% and 65 ± 5% (P = 0.001), respectively. For all diabetic subjects (n = 12), mean Aox and Vox were 90 ± 7% and 68 ± 5% (P = 0.001), respectively. In subjects with proliferative diabetic retinopathy, Aox was significantly lower, and Vox was significantly higher than other groups (85 ± 4% and 71 ± 4%, respectively; P = 0.04, analysis of variance). There was a highly significant difference in the arteriovenous difference between subjects with proliferative diabetic retinopathy and those in the control group (14 vs. 26%, P = 0.003)., Conclusion: Hyperspectral computed tomographic spectroscopy is a clinically feasible method for measurement and analysis of vascular oxygen content in retinal health and disease. This study uses the techniques relevant to oximetry; however, the breadth of spectral data available through this method may be applicable to study other anatomical and functional features of the retina in health and disease.

Objective: To describe the prevalence and severity of familial exudative vitreoretinopathy (FEVR) in asymptomatic relatives of known symptomatic FEVR patients., Design: Uncontrolled and retrospective case series at a single tertiary referral vitreoretinal practice., Participants: A total of 148 eyes of 74 subjects were studied., Methods: A retrospective chart review was conducted of patients with a diagnosis of FEVR between January 2011 and January 2013 at a single tertiary care retina practice. Data were collected from patient charts, including sex, gestational age at birth, age at presentation, referring diagnosis, family history, prior ocular surgery, clinical presentation, and diagnostic imaging in each eye. Inclusion criteria included confirmed clinical diagnosis of FEVR in patients referred to our clinic for evaluation of decreased vision. Patients were excluded if a definitive diagnosis of FEVR could not be made., Main Outcome Measures: Clinical and angiographic findings., Results: A total of 74 subjects from 17 separate families met the inclusion criteria for this study. There were an average of 4.4 subjects per family included in this study. The cohort was 55% male and included 17 patients and 57 family members who agreed to undergo genotyping, examination, and diagnostic imaging. Forty-three percent of FEVR patients had detectable mutations in FZD4, NDP, or TSPAN12. Only 8% of the cohort reported a positive family history of FEVR in a first-degree relative. Among the index patients, 76% had clinical stage 3, 4, or 5 FEVR and 24% had stage 1 or 2 FEVR. Among the asymptomatic family members screened, 58% demonstrated clinical or angiographic findings consistent with stage 1 or 2 FEVR and 21% demonstrated clinical or angiographic findings consistent with stage 3, 4, or 5 FEVR., Conclusions: Asymptomatic family members of FEVR patients frequently have early manifestations of FEVR (stage 1 or 2). Early-stage FEVR may progress to more advanced stages, which can result in vision loss. These data support the use of angiographic screening and clinical examination in immediate relatives of patients with symptomatic FEVR., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the pathogenesis, clinical characteristics, management, and outcomes of patients in whom vitreomacular traction evolved pursuant to treatment of choroidal melanoma with transpupillary thermotherapy., Design: Retrospective, uncontrolled, observational, interventional case series., Methods: Vitreomacular traction with macular distortion, macular edema, and vision loss developed in 6 eyes of 6 patients after successful transpupillary thermotherapy for choroidal melanoma. Clinical examination, fluorescein angiography, fundus photography, and spectral-domain optical coherence tomography were performed. Symptomatic patients underwent pars plana vitrectomy (PPV). Primary outcome measures include visual acuity and resolution of macular distortion by clinical examination, spectral-domain optical coherence tomography, or both., Results: In all 6 patients, the malignant lesions were treated successfully. The posterior hyaloid was attached in all eyes before transpupillary thermotherapy. All eyes demonstrated focal hyaloidal contraction and vitreomacular traction between the transpupillary thermotherapy scar and the macula. Mean time from transpupillary thermotherapy to PPV for treatment of vitreomacular traction was 23 ± 18 months. Mean length of follow-up was 11 months. Mean logarithm of the minimal angle of resolution visual acuity before transpupillary thermotherapy was 0.23 ± 0.38. Mean visual acuity after transpupillary thermotherapy was 0.53 ± 0.42. Mean visual acuity before membrane peel was 0.65 ± 0.34. Mean visual acuity after membrane peel was 0.44 ± 0.21. All patients undergoing PPV showed visual improvement., Conclusions: Hyaloidal contraction can occur after transpupillary thermotherapy and is a reversible cause of vision loss. The mechanism of vision loss resulting from hyaloidal contraction is flat vitreomacular traction. PPV and membrane peeling are effective in improving macular anatomic features and visual function., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Endogenous endophthalmitis (EE) is a rare but devastating infection that occurs secondary to seeding of the intraocular cavity from an extraocular focus. Recent reports suggest the increasing prevalence and incidence of Klebsiella pneumoniae as a causative organism in Asian countries. Analysis of the largest cohorts published to date suggests that K. pneumoniae endogenous endophthalmitis (KPEE) is 10 to 15 times more prevalent than other causes of EE. The incidence of KPEE among patients with systemic Klebsiella infection appears to be >100-fold more common than other causes of EE. The exact reason for these observations is not clear, but a number of studies now suggest that Klebsiella serotypes K1 and K2 have virulence factors that enhance their survival in diabetic patients and increase their pathogenicity. Here, we report two cases of KPEE in the USA. We also review the recent clinical and basic science literature on the prevalence, incidence, and pathophysiology of this emerging and devastating infection.

Purpose: The purpose of this study is to quantify the normal retinal thickness (RT) and retinal nerve fiber layer thickness (RNFLT), and to obtain cross-sectional area measurements of the main retinal artery and vein in the rabbit animal model using spectral domain optical coherence tomography (SD-OCT)., Materials and Methods: Fifteen eyes of 15 adult rabbits were used to obtain SD-OCT scans. RT, RNFLT and cross-sectional areas of the main retinal artery and vein were measured with a custom-made software grading tool (OCTOR) on selected B-scans at the edge of the optic nerve head and at 1, 2, 3 and 4 mm from the nerve. Statistical comparisons were made using the analysis of variance test with post hoc comparison., Results: In the nasal and temporal retina, the average RT and RNFLT decreased significantly with eccentricity from the optic disc. There was a statistically significant greater RT and RNFLT at the edge of the optic disc as compared with values at 1, 2, 3 and 4 mm from the disc edge (p < 0.01). Mean cross-sectional area of the primary retinal vein was significantly larger than the retinal artery (p < 0.01)., Conclusions: We have quantified the cross-sectional dimensions of RT, RNFLT and the major retinal vessels in the rabbit retina with SD-OCT. These findings are novel anatomic features of the rabbit retina, which should be considered in any studies using this animal model.

Background: Good knowledge, attitude and practice (KAP) of the physicians allow them to handle their patients in such a way that they prevent themselves from contracting, and their patients from spreading, the infection. However, the Iranian standardized KAP questionnaire of physicians about viral hepatitis is not available. So, we developed a standard questionnaire., Objectives: The purpose of this study was to provide a standard questionnaire as a basic tool for assessment of the present situation of the KAP of clinicians. It can also be used for evaluating educational programs and interventions on physicians in addition to any trends in their KAP about viral hepatitis., Patients and Methods: In order to design and standardize a 29-item self-administered questionnaire, we developed a cross sectional pilot study on 60 Iranian physicians. Ten experts in the field of liver diseases and/or designing the questionnaire answered questions about its validity. Cronbach's Alpha (on 60 physicians that participated in a congress) and factor analysis (on 370 persons; participants of two viral hepatitis congresses in Tehran and Zanjan and physicians of two university hospitals in Ahvaz) were used in the analysis., Results: Reliability was 0.7 according to Cronbach's Alpha score. Face validity was higher than 80%. Content validity of the whole parts of the questionnaire was 96.25% for clarity, 91.56% for relevancy, 96.25% for simplicity and 98.44% for consistency of each question with the questions' set. Factor analysis showed that 13 components account for 67.4% of the total variance., Conclusions: This study provided evidence that our questionnaire is a feasible, valid and reliable measure of physicians' KAP status in Iran. The factor analysis did not reveal a strong cluster structure. This questionnaire should be interpreted as a one-dimensional element by the sum of all items, rather than a multi-dimensional instrument.

Purpose: To study the variation in intravascular oxygen saturation (oximetry) during an acute retinal vein occlusion (RVO) using hyperspectral computed tomographic spectroscopy based oximetry measurements., Methods: Thirty rabbits were dilated and anesthetized for experiments. Baseline oximetry measurements were made using a custom-made hyperspectral computed tomographic imaging spectrometer coupled to a fundus camera. RVO were induced using argon green laser following an intravenous injection of Rose Bengal. RVO induction was confirmed by fluorescein angiography. Retinal oximetry measurements were repeated in arterial and venous branches one hour after RVO induction and up to 4 weeks afterwards. Comparison of retinal oximetry before and after vein occlusion was made using the Student T-test., Results: One hour after RVO induction, we observed statistically significant reductions in the intravascular oxygen saturation in temporal retinal arteries (85.1 ± 6.1% vs. 80.6 ± 6.6%; p<0.0001) and veins (71.4 ± 5.5% vs. 64.0 ± 4.7%; p<0.0001). This decrease was reversible in animals that spontaneously recannulated the vein occlusion. There were no statistically significant differences in oxygen saturation in the nasal control arteries and veins before and after temporal vein RVO induction., Conclusions: We demonstrate, for the first time, acute changes in the intravascular oxygen content of retinal vessels 1 hour after RVO. These changes are reversible upon spontaneous recannulation of retinal vessels. This study demonstrates that hyperspectral computer tomographic spectroscopy based oximetry can detect physiological variations in intravascular retinal oxygen saturation. The study also provides the first qualitative and quantitative evidence of the variation in retinal vascular oxygen content directly attributable to an acute retinal vein occlusion.

The authors report a rare presentation of bilateral Klebsiella pneumoniae endophthalmitis in an ambulatory patient without other known medical conditions. A 51-year-old Chinese woman presented with severe bilateral reduction in vision, photophobia, pain, and eyelid swelling. Hospital admission and evaluation revealed vitreous, blood, and urine cultures positive for K. pneumoniae (K1 serotype). Additional work-up revealed endocarditis, multiple liver abscesses, brain abscesses, and left lobar pneumonia. The patient underwent multiple bilateral intravitreal antibiotic injections. Ultimate visual acuity was no light perception in both eyes. K. pneumoniae endogenous endophthalmitis is a severe but potentially subclinical disease. Early diagnosis requires a high index of suspicion and recognition of risk factors including Asian ancestry and other sources of systemic infection including, most commonly, liver abscess., (Copyright 2011, SLACK Incorporated.)

Diagnosis of retinal vascular diseases depends on ophthalmoscopic findings that most often occur after severe visual loss (as in vein occlusions) or chronic changes that are irreversible (as in diabetic retinopathy). Despite recent advances, diagnostic imaging currently reveals very little about the vascular function and local oxygen delivery. One potentially useful measure of vascular function is measurement of hemoglobin oxygen content. In this paper, we demonstrate a novel method of accurately, rapidly and easily measuring oxygen saturation within retinal vessels using in vivo imaging spectroscopy. This method uses a commercially available fundus camera coupled to two-dimensional diffracting optics that scatter the incident light onto a focal plane array in a calibrated pattern. Computed tomographic algorithms are used to reconstruct the diffracted spectral patterns into wavelength components of the original image. In this paper the spectral components of oxy- and deoxyhemoglobin are analyzed from the vessels within the image. Up to 76 spectral measurements can be made in only a few milliseconds and used to quantify the oxygen saturation within the retinal vessels over a 10-15 degree field. The method described here can acquire 10-fold more spectral data in much less time than conventional oximetry systems (while utilizing the commonly accepted fundus camera platform). Application of this method to animal models of retinal vascular disease and clinical subjects will provide useful and novel information about retinal vascular disease and physiology.

Background and Aims: Health care workers (HCWs) are at risk of contracting and spreading hepatitis B virus (HBV) and hepatitis C virus (HCV) to others. The aim of this study was to evaluate knowledge, attitudes and behavior of physicians concerning HBV and HCV., Methods: A 29-item questionnaire (reliability coefficient = 0.7) was distributed at two national/regional congresses and two university hospitals in Iran. Five medical groups (dentists, general practitioners, paraclinicians, surgeons and internists) received 450 questionnaires in 2009, of which 369 questionnaires (82%) were filled out., Results: Knowledge about routes of transmission of HBV and HCV, prevalence rate and seroconversion rates secondary to a needlestick injury was moderate to low. Concern about being infected with HBV and HCV was 69.4±2.1 and 76.3±2 (out of 100), respectively. Complete HBV vaccination was done on 88.1% of the participants. Sixty percent had checked their hepatitis B surface antibody (anti-HBs), and 83.8% were positive. Only 24% of the surgeons often used double gloves and 28% had reported a needlestick. There was no significant correlation between the different specialties and: concern about HBV and HCV; the underreporting of needlestick injuries; and correct knowledge of post-needlestick HBV infection., Conclusions: Although our participants were afraid of acquiring HBV and HCV, knowledge about routes of transmission, prevalence, protection and post-exposure seroconversion rates was unsatisfactory. By making physicians aware of possible post-exposure prophylaxis, the underreporting of needlestick injuries could be eliminated. Continuous training about HBV and HCV transmission routes, seroconversion rates, protection, as well as hepatitis B vaccination and checking the anti-HBs level, is a matter of necessity.

Purpose: To detect differences in retinal thickness among patients of different race, gender, and age using Stratus OCT., Design: Cross-sectional study., Methods: In a multicenter, university-based study, 126 patients with no history of ocular disease were enrolled (78 diabetics without retinopathy and 48 nondiabetics). Optical coherence tomography measurements were performed using Stratus OCT. Statistical comparisons of center point foveal thickness and mean foveal thickness were made using generalized estimating equations adjusting for diabetic status, race, age, and gender., Results: The study population consisted of 36% male subjects, 39% Caucasian, 33% African-American, and 28% Hispanic. Mean foveal thickness was 191.6 +/- 2.7 microm and 194.5 +/- 2.7 microm for diabetics and nondiabetics, respectively (P = .49). Mean foveal thickness in male subjects was significantly larger than in female (201.8 +/- 2.7 microm and 186.9 +/- 2.6 microm, respectively; P < .001). Mean foveal thickness was 200.2 +/- 2.7 microm for Caucasian, 181.0 +/- 3.7 microm for African-American, and 194.7 +/- 3.9 microm for Hispanic subjects. Mean foveal thickness was significantly less for African-American than Caucasian (P < .0001) or Hispanic subjects (P = .005). Center point foveal thickness and mean foveal thickness showed a significant increase with age., Conclusions: There are statistically significant differences in retinal thickness between subjects of different race, gender, and age. When compared to Caucasian and Hispanic subjects, African-American race is a predictor of decreased mean foveal thickness; and male sex (regardless of race) is a significant predictor of increased mean foveal thickness. Mean foveal thickness is similar among diabetics and nondiabetics when data are controlled for age, race, and sex. These results suggest that studies comparing OCT measurements should carefully control for age-based, race-based, and gender-based variations in retinal thickness., ((c) 2010 Elsevier Inc. All rights reserved.)

Purpose: To use optical coherence tomography (OCT) to quantify intraretinal cystoid spaces (ICSs) and the outer nuclear layer (ONL) in patients with neovascular age-related macular degeneration (AMD) and to investigate the correlation of these parameters with visual acuity., Methods: StratusOCT (Carl Zeiss Meditec, Inc., Dublin, CA) images were collected from 53 patients receiving their initial treatment with intravitreous ranibizumab. Images were analyzed with custom software (OCTOR) that allows accurate manual segmentation of OCT B-scans and provides thickness/volume measurements of ICS, ONL, neurosensory retina, pigment epithelial detachments (PEDs), subretinal fluid (SRF), and subretinal tissue (SRT). Univariate and multivariate analyses were used to correlate OCT parameters with best corrected Snellen visual acuity. Reproducibility was assessed with weighted kappa statistics and intraclass correlation coefficients., Results: A multivariate linear regression model with adjusted R(2) showed that ONL volume and SRT thickness significantly correlated with Snellen visual acuity (R(2) = 0.15, P = 0.002 and R(2) = 0.19, P = 0.001, respectively) with an overall model R(2) of 0.34. Adjustment of ONL volume for ICS did not improve correlation with visual acuity, and ICS volume did not independently correlate with visual acuity. Weighted kappa statistics showed excellent intergrader agreement for both ICS and ONL measurements., Conclusions: The results suggest that an increased total volume of the ONL is associated with decreased visual acuity in neovascular AMD and that the total volume of ICS does not correlate with visual acuity. Although the correlations detected in this study are modest, quantitative subanalysis of OCT images may be of greater clinical relevance in the context of more advanced OCT technology.

Background: Perhaps more than any other healthcare worker, it is the surgeons who are at an increased risk of exposure to hepatitis B (HB) virus, hepatitis C virus, and human immunodeficiency virus. The aim of this study was to evaluate surgeons' concerns regarding risk awareness and behavioral methods of protection against blood-borne pathogen transmission during surgery., Materials and Methods: A 31-item questionnaire with a reliability coefficient of 0.73 was used. Of 575 surgeons invited to participate from three universities and one national annual surgical society between May and July 2007, 430 (75%) returned completed forms., Results: Concern about being infected with blood-borne diseases was more than 70 (from a total score of 100). Only 12.9% of surgeons always used double gloves. Complete vaccination against HB was done in about 76% of surgeons and only 56.8% had checked their HB surface antibody (anti-HBs) level. Older surgeons never used double gloves (P = 0.001)., Conclusion: Iranian surgeons are not aware of the correct percentage of infected patients with and seroconversion rate of blood-borne diseases, do not use double gloves adequately, do not report their needlestick injuries, vaccinate against HB, and check anti-HBs after vaccination. Educational meetings, pamphlets, and facilities must be provided to health care workers, informing them of hazards, prevention, and postexposure prophylaxis to needlestick injuries, vaccination efficacy, and wearing double gloves.

Objective: There are 5.1-6.5% of people with positive anti-HBc in Iran. The aim of this study was to assess the predicting factors of response to hepatitis B vaccination in anti-HBc positive subjects., Results: Total response rate to vaccination was 79.8% (75 cases) and 67.9% (38 cases) in cases and controls, respectively. Nineteen persons (20.2%) in cases and 18 persons (32.1%) of controls had negative anti-HBs even after three doses of HB vaccination. Factor associated with decreased response to vaccination was prior history of being HBsAg positive (OR = 1.3, p = 0.01)., Methods: In a quasi-experimental study, 94 people with negative HBsAg, negative anti-HBs and positive anti-HBc (cases) and 56 persons with negative HBsAg, anti-HBs and anti-HBc (controls) were vaccinated at zero, one and six months with recombinant hepatitis B vaccine. Successful immunization was defined by anti-HBs antibody titer > or =10 mIU/mL., Conclusion: The rate of response to hepatitis B vaccination is nearly like other studies but somewhat different. Higher percent of married cases together with higher percent of positive HBsAg in spouses may explain the slight difference in the response to vaccination in cases in comparison with controls as a result of booster like effect that seldom happens because of recurrent contacts between the subjects and the HBsAg positive spouses spontaneously.

Lasting changes in neuronal connectivity require calcium-dependent gene expression. Here we report the identification of LIM domain-only 4 (LMO4) as a mediator of calcium-dependent transcription in cortical neurons. Calcium influx via voltage-sensitive calcium channels and NMDA receptors contributes to synaptically induced LMO4-mediated transactivation. LMO4-mediated transcription is dependent on signaling via calcium/calmodulin-dependent protein (CaM) kinase IV and microtubule-associated protein (MAP) kinase downstream of synaptic stimulation. Coimmunoprecipitation experiments indicate that LMO4 can form a complex with cAMP response element-binding protein (CREB) and can interact with cofactor of LIM homeodomain protein 1 (CLIM1) and CLIM2. To evaluate the role of LMO4 in vivo, we examined the consequences of conditional loss of lmo4 in the forebrain, using the Cre-Lox gene-targeting strategy. The organization of the barrel field in somatosensory cortex is disrupted in mice in which lmo4 is deleted conditionally in the cortex. Specifically, in contrast to controls, thalamocortical afferents in conditional lmo4 null mice fail to segregate into distinct barrel-specific domains. These observations identify LMO4 as a calcium-dependent transactivator that plays a key role in patterning thalamocortical connections during development.

Serine racemase (SR), localized to astrocytic glia that ensheathe synapses, converts L-serine to D-serine, an endogenous ligand of the NMDA receptor. We report the activation of SR by glutamate neurotransmission involving alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors via glutamate receptor interacting protein (GRIP) and the physiologic regulation of cerebellar granule cell migration by SR. GRIP physiologically binds SR, augmenting SR activity and D-serine release. GRIP infection of neonatal mouse cerebellum in vivo enhances granule cell migration. Selective degradation of D-serine by D-amino acid oxidase and pharmacologic inhibition of SR impede migration, whereas D-serine activates the process. Thus, in neuronal migration, glutamate stimulates Bergmann glia to form and release D-serine, which, together with glutamate, activates NMDA receptors on granule neurons, chemokinetically enhancing migration.

We report that CaM kinase IV and CREB play a critical role in mediating calcium-induced dendritic growth in cortical neurons. Calcium-dependent dendritic growth is suppressed by CaM kinase inhibitors, a constitutively active form of CaM kinase IV induces dendritic growth in the absence of extracellular stimulation, and a kinase-dead form of CaM kinase IV suppresses dendritic growth induced by calcium influx. CaM kinase IV activates the transcription factor CREB, and expression of a dominant negative form of CREB blocks calcium- and CaM kinase IV-induced dendritic growth. In cortical slice cultures, dendritic growth is attenuated by inhibitors of voltage-sensitive calcium channels and by dominant negative CREB. These experiments indicate that calcium-induced dendritic growth is regulated by activation of a transcriptional program that involves CaM kinase IV and CREB-mediated signaling to the nucleus.

Cystathionine beta-synthase (CBS) deficiency, the most common form of homocystinuria, is an autosomal recessive inborn error of homocysteine metabolism. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives (tHcy) by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma tHcy. With betaine therapy, methionine levels increase over baseline, but usually remain below 1,500 micromol/L, and these levels have not been associated with adverse affects. We report a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine levels reached 3,000 micromol/L on betaine, and who subsequently developed massive cerebral edema without evidence of thrombosis. We investigated the etiology by determining methionine and betaine metabolites in our patient, and several possible mechanisms for her unusual response to betaine are discussed. We conclude that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism is uncertain. This case cautions physicians to monitor methionine levels in CBS-deficient patients on betaine and to consider betaine as an adjunct, not an alternative, to dietary control., (Copyright 2002 Wiley-Liss, Inc.)

The pathogenesis of cranial and spinal dysraphia has been controversial. Studies of spinal dysraphia have shown that the relationships of the pia and dura to the cutaneous layers were best understood as the result of a primary abnormality of mesenchymal structures, with the nervous system lesions occurring as a result of exposure of the bare spinal cord on the body surface. This study was undertaken to determine if the relationship of the cutaneous layers in anencephaly were similar to those found in spinal dysraphia. We reviewed serial histologic sections of the cranial structures of 10 anencephalic fetuses autopsied at The Johns Hopkins Hospital. We found the dura to be continuous with the deep dermis and the pia continuous with the superficial dermis and epidermis, the same arrangement observed in myelomeningocele. The development of eyes and cranial nerves, the absence of a bony calvarium, and the meningeal-cutaneous relationships found in this study support the idea that anencephaly can originate as an abnormality of mesenchymal structures and that the brain is secondarily lost to injury in utero because of its exposed position.

Hyperosmotic solutions cause markedly enhanced spontaneous quantal release of neurotransmitter from many nerve terminals. The mechanism of this enhancement is unknown. We have investigated this phenomenon at the frog neuromuscular junction with the aim of determining the degree to which it resembles the modulation of release by stretch, which has been shown to be mediated by mechanical tension on integrins. The hypertonicity enhancement, like the stretch effect, does not require Ca2+ influx or release from internal stores, although internal release may contribute to the effect. The hypertonicity effect is sharply reduced (but not eliminated) by peptides containing the RGD sequence, which compete with native ligands for integrin bonds. There is co-variance in the magnitude of the stretch and osmotic effects; that is, individual terminals exhibiting a large stretch effect also show strong enhancement by hypertonicity, and vice versa. The stretch and osmotic enhancements also can partially occlude each other. There remain some clear-cut differences between osmotic and stretch forms of modulation: the larger range of enhancement by hypertonic solutions, the relative lack of effect of osmolarity on evoked release, and the reported higher temperature sensitivity of osmotic enhancement. Nevertheless, our data strongly implicate integrins in a significant fraction of the osmotic enhancement, possibly acting via the same mechanism as stretch modulation.