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Purpose: The temporary cessation and profound changes in ophthalmic care delivery that occurred as a result of the coronavirus disease 2019 (COVID-19) pandemic have yet to be fully understood. Our objective is to assess patients’ self-reported impact of health care lockdown measures on their fears and anxieties during the crisis period of the COVID-19 pandemic in New York City. Methods: We conducted a digital, self-reported, patient care survey distributed by an e-mail at Columbia University’s Department of Ophthalmology outpatient faculty practice. Inclusion criteria were age greater than or equal to 18 years, a diagnosis of either retinal disease or glaucoma, and a canceled or rescheduled ophthalmology established patient appointment during the acute phase of the COVID-19 pandemic in New York City. Patients without an e-mail address listed in their electronic medical records were excluded. The survey occurred between March 2, 2020, to May 30, 2020. Primary measures were survey responses to assess key areas of patient anxiety or concern during the pandemic including the safety of care delivery in a COVID pandemic, difficulties contacting or being seen by their ophthalmologist, concern of vision loss or disease progression, and concern over missed or access to treatments. Secondary measures were correlating survey response to factors such as visual acuity, intraocular pressure, diagnosis, disease severity, follow-up urgency, recent treatments, and diagnostic testing data. Results: Of the 2594 surveys sent out, 510 (19.66%) were completed. Over 95% of patients were at least as concerned as in normal circumstances about their ocular health during the peak of the pandemic. Overall, 76% of respondents were more concerned than normal that they could not be seen by their ophthalmologist soon enough. Increased concern over ocular health, disease progression, and access to care all showed positive correlations (P

Purpose To evaluate the changes in the choroidal structure in the setting of retinal vein occlusion (RVO). Methods Changes in the structure of the choroid were studied in sixty-four eyes with unilateral central or branch RVO using optical coherence tomography (OCT) with enhanced depth imaging and OCT-angiography (OCT-A). Choroidal vascularity index (CVI), Haller layer/choroidal thickness (H/C) ratio, and choriocapillaris flow density were used to compare the structural characteristics of the choroid with fellow eyes and the eyes of thirty-four age-, gender-, and systemic co-morbidity-matched controls. Results Eyes with RVO had a higher H/C ratio but a lower choriocapillaris flow density compared to both fellow and control eyes (p < 0.001). CVI was significantly lower in both eyes of the patients with RVO compared with control eyes (p < 0.05) with a more robust decrease in the eye that had developed RVO (p < 0.001). The H/C ratio (r = 0.303p < 0.001), CVI (r = - 0.268,p = 0.001), and choriocapillaris flow density (r = - 0.237,p = 0.003) were all correlated with logMAR visual acuity, and other clinical features. Conclusion Retinal vein occlusions alter the hemodynamic properties of the choroid leading to structural changes. These changes may be secondary to a compensatory mechanism to supply oxygen to hypoxic retina.

Background: This study sought to determine the presence of SARS-CoV-2 virus on surfaces that trainees and faculty of an academic eye clinic came into contact with during daily life at the time of the COVID-19 pandemic in New York City. Methods: This cross-sectional analysis involved collection of at least two samples by teams on four different days (November 9, 2020 - December 18, 2020) using sterile swabs (Puritan HydraFlock, Garden Grove, CA). Collection sites were grouped into four zones depending on proximity and amount of time personnel spent there. Samples were transported to the laboratory in transport medium and RNA was extracted using the QIAamp DSP Viral RNA Mini Kit (Qiagen, Germantown, MD). Presence of viral RNA was investigated using the Luna Universal Probe One-step RT-qPCR kit (New England Biolabs, Ipwsich, MA). Results: 834 samples were submitted. Two were positive for SARS-CoV-2 RNA. The first was a sample from a patient bathroom sink handle in the main emergency department. The second was a nasal swab sample from a staff member who had been assigned to collect samples. Prior to this positive result, this asymptomatic staff member had tested positive for COVID-19, had quarantined for two weeks, and had received a negative test. Conclusion: Though COVID-19 is currently widespread in the United States, this study shows that health care personnel working in New York City at the Columbia University Irving Medical Center have a low chance of encountering viral RNA on surfaces they are in close contact with during daily life.

Purpose We correlated quantitative fundus autofluorescence (qAF) with other fundus features in patients exhibiting central serous chorioretinopathy (CSC). Methods Short wavelength fundus autofluorescence (SW-AF, 488 nm excitation) was measured by qAF. Using nonnormalized images qAF values were calculated within eight concentric segments (qAF8) located at an eccentricity of 7° to 9°. Horizontal spectral domain optical coherence tomography (SD-OCT) scans and near-infrared fundus autofluorescence images (NIR-AF) were studied. Results Thirty-six eyes of 20 patients (mean age 48.7± 8.5 years) diagnosed with CSC were studied. Thirteen patients had bilateral disease; four patients were female. In 22 eyes CSC was present in the macula; in one eye the lesion was in a peripapillary location, 10 involved both locations, and three were unaffected. Serous retinal detachment, retinal pigmented epithelial detachment (PED), outer retinal atrophy and subRPE hypertransmission were all features identifiable by SD-OCT. NIR-AF images were helpful in detecting foveal and parafoveal lesions. Sampling for retina-wide elevations in SW-AF intensity by measuring qAF8 did not indicate a generalizable relationship amongst CSC-diagnosed eyes. However, color-coded qAF images revealed alterations in SW-AF topography and intensity relative to healthy eyes at the same locations. Thus zones of higher than normal qAF intensity were found in association with SD-OCT detectable PED; loss of ellipsoid zone and interdigitation zone; and hyperreflectivity in outer retina. Pronounced decreases in qAF colocalized with serous retinal detachment and with outer retinal degeneration that included hypertransmission of SD-OCT signal into the choroid. Conclusions Localized elevations in qAF reflect increased bisretinoid in association with CSC lesions. Translational relevance Foci of elevated qAF at some stages of CSC contribute to the natural history of the disease.

Retina has the highest metabolic activity in the human body and consumes a much higher amount of oxygen and nutrients per weight than any other organ. Its oxygen consumption is several folds greater than that of the central nervous system. The main reason for high oxygen demand is to fuel ionic pumps that continuously move positively charged electrolytes out of photoreceptors in the dark. This high oxygen demand gives rise to two separate vascular networks: retinal and choroidal. The presumed reason for such a privileged oxygen supply is the evolutionary need of vision for survival. Retina is highly sensitive to systemic vascular events that block the supply of oxygen and other nutrients, despite the fact that it has approximately 100 times more photoreceptors than are required for seeing. Thus, systemic vasculopathies that may alter retinal blood flow, such as hypertension, atherosclerosis, and diabetes, almost always constitute a risk for retinal dysfunction.

Glaucoma is a chronic neurodegenerative disease of the optic nerve and a leading cause of irreversible blindness, worldwide. While the experimental research using animal models provides growing information about cellular and molecular processes, parallel analysis of the clinical presentation of glaucoma accelerates the translational progress towards improved understanding, treatment, and clinical testing of glaucoma. Optic nerve axon injury triggers early alterations of retinal ganglion cell (RGC) synapses with function deficits prior to manifest RGC loss in animal models of glaucoma. For testing the clinical relevance of experimental observations, this study analyzed the functional correlation of localized alterations in the inner plexiform layer (IPL), where RGCs establish synaptic connections with retinal bipolar and amacrine cells. Participants of the study included a retrospective cohort of 36 eyes with glaucoma and a control group of 18 non-glaucomatous subjects followed for two-years. The IPL was analyzed on consecutively collected macular SD-OCT scans, and functional correlations with corresponding 10–2 visual field scores were tested using generalized estimating equations (GEE) models. The GEE-estimated rate of decrease in IPL thickness (R = 0.36, P0.05). These findings support early localized IPL alterations in correlation with progressing visual field defects in glaucomatous eyes. Considering the experimental data, glaucoma-related increase in IPL thickness/density might reflect dendritic remodeling, mitochondrial redistribution, and glial responses for synapse maintenance, but decreased IPL thickness/density might correspond to dendrite atrophy. The bridging of experimental data with clinical findings encourages further research along the translational path.

Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care.

Karahan, Eyyüp (Balikesir Author), Purpose: To evaluate the mechanical compression of retinal nerve fiber layer (RNFL) by intraretinal cysts in macular edema and its relief with anti-vascular endothelial growth factor (anti-VEGF) treatment. Methods: Optical coherence tomography scans were used to measure RNFL thickness and reflectance at seven preselected points at and around the peak of the edema before and after anti-VEGF treatment in 10 patients (11 eyes) with branch retina vein occlusion (BRVO) and diabetic macular edema (DME). Scans through nonedematous retina and from the fellow eyes were taken as controls. Correlations were sought between the changes in retinal and RNFL thickness, RNFL reflectance, and the size of the intraretinal cysts. Results: Postinjection RNFL thickness decreased significantly only at peak point of the edema (18.1 +/- 2.7 vs. 13.8 +/- 1.2 mu m; P = 0.038), at its nasal edge (20.1 +/- 2.7 vs. 15.5 +/- 1.4 mu m; P = 0.026), and 500 mu m away from its nasal border (35.7 +/- 6.0 vs. 20.1 +/- 2.7 mu m; P = 0.006) suggesting focal stagnation of the axoplasmic flow owing to compression at its peak point. Significant postinjection decreases in RNFL reflectivity were also noted at peak point of the cyst (164.9 +/- 10.3 vs. 141.5 +/- 12.6 arbitrary units [AU]; P = 0.037), at its nasal edge (166.8 +/- 7.8 vs. 135.1 +/- 10.2 AU; P = 0.02), and 1500 mu m away from temporal edge (160.2 +/- 6.2 vs. 141.1 +/- 6.4 AU; P = 0.022). Cyst proximity to RNFL (D-50 = 50 mu m) was the only determinant significantly affecting the magnitude of the RNFL thickness change after anti-VEGF treatment (P = 0.001). Conclusions: Intraretinal cysts due to BRVO and DME locally compress overlying axons and induce anatomic changes suggestive of axoplasmic stagnation. This compression can be relieved with anti-VEGF treatment. Translational Relevance: Focal compression of RFNL by retinal cysts may indicate a need for early treatment of macular edema to prevent axonal loss, especially in patients with low axonal reserve., Research to Prevent Blindness (RPB) Slomo and Cindy Silvian Foundation, New York, NY, USA Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK)

Aside from vitamins and antioxidants recommended by the Age-Related Eye Disease Study, there is no effective therapy for "dry," or atrophic age-related macular degeneration (AMD) which represents 90% of the cases. Therapies are needed to slow or retard the development of geographic atrophy (GA), and understanding Bruch's membrane pathology is part of this process. Alterations in human Bruch's membrane precede the progression of AMD by contributing to the damage of retinal pigment epithelial (RPE) cells. Given the lack of sufficient animal models to study AMD, ex vivo models of aged human Bruch's membrane serve as a useful tool to study the behavior of RPE cells from immortalized and primary cell lines as well as RPE lines derived from induced pluripotent stem cells (iPSCs). Here, we present a detailed method that allows one to determine the effects of RPE cell behavior seeded on harvested human Bruch's membrane explants from human donors, including attachment, apoptosis and proliferation, ability to phagocytize photoreceptor outer segments, establishment of polarity, and gene expression. This assay provides an ex vivo model of aged Bruch's membrane to assess the functional characteristics of RPE cells when seeded on aged/compromised extracellular matrix.

Aside from vitamins and antioxidants recommended by the Age-Related Eye Disease Study, there is no effective therapy for "dry," or atrophic age-related macular degeneration (AMD) which represents 90% of the cases. Therapies are needed to slow or retard the development of geographic atrophy (GA), and understanding Bruch's membrane pathology is part of this process. Alterations in human Bruch's membrane precede the progression of AMD by contributing to the damage of retinal pigment epithelial (RPE) cells. Given the lack of sufficient animal models to study AMD, ex vivo models of aged human Bruch's membrane serve as a useful tool to study the behavior of RPE cells from immortalized and primary cell lines as well as RPE lines derived from induced pluripotent stem cells (iPSCs). Here, we present a detailed method that allows one to determine the effects of RPE cell behavior seeded on harvested human Bruch's membrane explants from human donors, including attachment, apoptosis and proliferation, ability to phagocytize photoreceptor outer segments, establishment of polarity, and gene expression. This assay provides an ex vivo model of aged Bruch's membrane to assess the functional characteristics of RPE cells when seeded on aged/compromised extracellular matrix.

WOS: 000435291400003 PubMed ID: 29613980 Purpose:The purpose of this article was to report the efficacy of intravitreal bevacizumab to resolve secondary angle-closure glaucoma caused by biliary tract carcinoma metastasis to the iris.Materials and Methods:A 52-year-old white woman who was under systemic chemotherapy for biliary tract carcinoma presented with a metastatic tumor in the left iris. At presentation, her visual acuity was at the 20/50 level. The tumor was occupying the nasal half of the iris, and had already occupied 5.5 clock hours of the angle, resulting in intraocular pressure elevation to 34mmHg. Several small clumps of tumor seeds were also observed on the iris and along the angle. Her intraocular pressure remained high despite full medical therapy with dorzolamide, timolol, brimonidine, and oral acetozolamide. Because of the vascularized nature of the tumor, antivascular endothelial growth factor (anti-VEGF) treatment with 3 repeated injections of bevacizumab (1.25mg/0.05mL) was applied 1-month apart. Bevacizumab treatment resulted in an abrupt decrease in tumor mass and disappearance of tumoral seeds from the anterior chamber. The patient's vision improved to 20/20, and intraocular pressure decreased to normal levels.Conclusions:Anti-VEGF treatment with intravitreal bevacizumab can restore sight and achieve intraocular pressure control in metastatic iris tumors complicated with secondary glaucoma. Anti-VEGF drugs are viable alternatives for the treatment of secondary angle-closure glaucoma induced by metastatic iris tumors and can prevent enucleation of these eyes. Research to Prevent Blindness Inc., New York City, NY; Slomo and Cindy Silvian Foundation, New York, NY; TUBITAK, Ankara, Turkey Supported in part by an unrestricted grant from Research to Prevent Blindness Inc., New York City, NY, Slomo and Cindy Silvian Foundation, New York, NY, and TUBITAK, Ankara, Turkey.

PURPOSE To describe intraocular use of bevacizumab for a metastatic breast carcinoma of the iris resistant to advanced systemic chemotherapy protocols, for which conventional treatment would be local radiotherapy or brachytherapy. METHODS Case report. RESULTS A 65-year-old woman, who was previously diagnosed with breast carcinoma and treated with radical mastectomy coupled with radiotherapy and chemotherapy, presented with an iris mass in her left eye. Four successive intravitreal injections of bevacizumab resulted in progressive regression of the tumor to an almost indiscernible size at 8 months, along with blunting of the highly complex tumor vascular network on fluorescein angiography. At 12 months, the patient's visual acuity remained 20/20, and no ocular or systemic adverse effects were encountered. CONCLUSION Intravitreal bevacizumab can offer a simpler and safer solution to treat metastatic iris tumors compared with other treatment options. This report of bevacizumab for treating iris metastasis from breast carcinoma may broaden the treatment options for similar neoplasms of the iris.

PURPOSE To test define characteristic fundus autofluorescence patterns of different exudative age-related macular degeneration subtypes. METHODS Cross-sectional study. Fifty-two patients with choroidal neovascularization because of three different neovascular age-related macular degeneration subtypes were included in the study. Macular and peripheral fundus autofluorescence patterns of study subjects were compared in a masked fashion. RESULTS Fundus autofluorescence patterns of all three neovascular age-related macular degeneration subtypes revealed similar patterns. However, peripapillary hypo-autofluorescence was more common among patients with polypoidal choroidal vasculopathy (88.2%) compared with patients with retinal angiomatous proliferation (12.5%) and patients without retinal angiomatous proliferation and polypoidal choroidal vasculopathy (21.1%) (P < 0.0001). CONCLUSION Presence of peripapillary fundus autofluorescence defects in neovascular age-related macular degeneration maybe suggestive of polypoidal choroidal vasculopathy as a variant of neovascular age-related macular degeneration.

To evaluate the efficacy of intravitreal triamcinolone (IVTA) in eyes with clinically definite diabetic macular edema (DME) by using the parameters visual acuity (VA), central macular thickness (CMT) and macular hydration (MH). Medical records of patients who received IVTA (4 mg/0.1 mL) for DME were reviewed. Optically non-reflective areas which appear dark spaces within the 1000 μm from the center of the macula on OCT scan defined as MH. Best corrected logarithm of minimum angle of resolution (logMAR) visual acuity, CMT as determined by optical coherence tomography (OCT) and MH quantified from the OCT scans by using metamorph analysis were evaluated before the injection and at 1, 3 and 6 months in all, and up to 12 months in some eyes, after the IVTA injection. The correlations between these variables were also studied. 28 eyes of 27 patients were included in the study. Eyes with DME treated by a single IVTA injection responded with a trend towards significant improvement in logMAR VA at 1 (p < 0.0001) and 3 months (p < 0.0001), but no significant improvement in relation to baseline at 6 months was observed (p = 0.07). CMT was significantly reduced at 1 month (p < 0.0001), 3 months (p < 0.0001) and 6 months (p = 0.01) compared to baseline. Like the trend observed in VA improvement, MH also significantly reduced at 1 month (p < 0.0001) and 3 months (p < 0.0001), but not at 6 months (p = 0.14) compared to baseline. There was no correlation between the VA ratio and the CMT ratio (r = 0.18, p = 0.36), but there was a significant correlation between the VA ratio and the MH ratio (r = 0.85, p < 0.0001). There was also an inverse relationship between MH ratio and the age of the patients (r = −0.7089, p = 0.0001). Macular hydration seems to be a better parameter than macular thickness for determining the effectiveness of IVTA treatment in a subset of eyes with DME. Although the treatment effect is temporary, younger patients with DME were more prone to respond with a greater reduction in MH after IVTA injection.

Commercially available vitreoretinal surgical forceps were modified with layer-by-layer (LbL) films designed to render them the ability to specifically adhere human the inner limiting membrane. Surgical forceps with two different geometries were etched, polished, and silanized before deposition of the films composed of poly (allylamine hydrochloride), poly (styrene sulfonate), and cationic gold nanoparticles. Stability and integrity of the LbL films was scrutinized by exposing the modified forceps to commercial disinfectant Cidex-OPA and then placing the instruments in a physiological-like HEPES buffer (pH 7.4, 5 mM, 154 mM NaCl). Surface topography analysis with scanning electron microscopy revealed that the geometry of the surgical instrument may affect the integrity of the film. Analysis of the HEPES buffer with inductively coupled plasma mass spectrometry demonstrated that gold nanoparticles did not leach from the LbL film after 60 min. SCANNING 33:397–401, 2011. © 2011 Wiley Periodicals, Inc.

Acute idiopathic blind spot enlargement (AIBSE) syndrome is characterized by an enlarged blind spot that can occur either as an isolated finding or as a part of several other chorioretinopathies, such as acute zonal occult outer retinopathy (AZOOR), acute macular neuroretinopathy (AMN), multiple evanescent white dot syndrome (MEWDS), and multifocal choroiditis and panuveitis (MCP). Current belief is that these entities are a spectrum of outer retinal inflammatory disorders that regardless of etiology may result in overlapping clinical features. 1–3

ICON is a fusion protein composed of factor VII, the natural ligand for tissue factor, conjugated to the Fc domain of a human IgG1 immunoglobulin. It binds to the tissue factor expressed on neovascular endothelia and initiates a cytolytic immune attack that destroys the neovascular tissue. We previously showed that mouse factor VII-Fc chimeric antibody (mICON) dramatically decreases the frequency of choroidal neovascularization in a laser-induced choroidal neovascularization model in mice. Herein, we determined the safety and efficacy of mICON in destroying subretinal choroidal neovascularization in pig eyes.mICON (150-1200 microg) was administered into the midvitreous cavity of the pig eye either before (on Day 0) or after (on Day 10) induction of choroidal neovascularization with laser photocoagulation. On Day 14, the incidence of choroidal neovascularization was determined using confocal microscopy. We also determined the binding specificity (% binding to choroidal neovascularization/% binding to non-choroidal neovascularization areas) of mICON to tissue factor expressed on endothelial cells of laser-induced choroidal neovascularization.We observed that mICON selectively destroyed choroidal neovascularization in a dose-dependent manner (r = -0.93; EDB50B = 571.3 microg). Obliteration of the choroidal neovascular complex was more prominent at doses300 microg (p0.05). No systemic or local complications (including retinal tear/detachment, inflammation, infection, cataract, or glaucoma) were observed. Binding specificities of hICON (2.2 +/- 0.2) and mICON (3.4 +/- 0.4) were significantly higher than that of anti-von Willebrand antibody (0.1 +/- 0.01, p0.001).Both hICON and mICON bound to the neovascular endothelia of choroidal neovascularization with greater specificity than anti-von Willebrand antibody. Furthermore, mICON can selectively obliterate already established choroidal neovascularization, which suggests that it may be useful for immunotherapy in patients with exudative (wet) macular degeneration.

We have shown previously that Bruch's membrane (BM) aging decreases retinal pigment epithelium (RPE) phagocytosis. Herein, we determine the effects of BM reengineering on RPE phagocytosis.BM explants were dissected from young and old donor eyes. Some old BM explants were reengineered by cleaning with Triton X-100 and/or coating with extracellular matrix (ECM) ligands. ARPE-19 cell-derived ECM (ARPE-ECM) modified ("aged") by sodium nitrite was subjected to similar treatments. ARPE-19 cells were then cultured to confluence onto the different surfaces. Fluorescently-labeled bovine rod outer segments (ROS) were fed to cells with or without αVβ5 integrin antibody. Image acquisition and phagocytosis quantification was performed by fluorescence microscopy and ImageJ analysis.Cleaning old donor-derived BM with detergent does not increase the uptake of ROS, but a combination of cleaning and coating with ECM ligands significantly increases RPE phagocytosis (54.9 ± 6.2 vs. 83.5 ± 6.5 arbitrary units; P < 0.05) to levels closer to young donor BM (123.6 ± 9.9 arbitrary units). Similar effects were observed on nitrite-modified ARPE-ECM subjected to the same treatments. Incubation of αVβ5 blocking antibody with ROS significantly decreased RPE phagocytosis.The detrimental effects of aging BM on RPE phagocytosis can be reversed by reengineering the BM surface with detergent cleaning and recoating with ECM ligands.These results demonstrate that the therapeutic success of transplanted RPE cells may require, at least in part, reengineering of diseased BM to make it a more suitable environment for attachment, survival and proper functioning of the RPE.

Purpose: The purpose of this study was to evaluate the ability of different methods to induce choroidal neovascularization (CNV) in the domestic pig. Methods: A total of 26 Danish landrace pigs was used. A sample of 22 eyes in 12 pigs underwent retinal photocoagulation with a xenon lamp, six eyes in four pigs underwent retinal photocoagulation with a diode laser, and mechanical rupture of Bruch's membrane (BM) was induced in 12 pigs following surgical debridement of the retinal pigment epithelium without damage to the neuroretina. Results: All 12 pigs (100%) in the group with mechanical rupture of BM developed CNV. The induced membranes were morphologically similar to CNV membranes in humans. Induced CNV was found in 13 of 22 (54%) xenon lamp-treated animals and in five of six (83%) diode laser-treated animals. The CNV in these groups was small and the morphology of the induced lesions was dominated by retinal gliosis and retinal neovascularization, probably due to a marked destruction of the neuroretina. Conclusions: Surgical debridement of the retinal pigment epithelium followed by mechanical rupture of BM is a reproducible method of producing CNV in the domestic pig, whereas photocoagulation gives rise to glially derived subretinal fibrovascular membranes and primarily retinal neovascularization.

Purpose To explore the use of adult human photoreceptor transplantation as a treatment for advanced retinitis pigmentosa (RP). Design Prospective noncomparative case series. Participants Eight patients with advanced RP. Intervention Transplantation of adult human cadaver photoreceptor sheets harvested with the excimer laser. No immunosuppression was used postoperatively. Patients were followed for 12 months postoperatively. Main outcome measure Visual acuity and retinal function measured by psychophysical, electrophysiologic, and clinical testing. Results Best-corrected visual acuity (Bailey-Lovie chart), median reading speed, contrast sensitivity, and visual fields for the operated eye were not statistically significantly improved postoperatively. The amplitude and latency of the maculoscope electroretinogram, as well as the log threshold for dark adaptation, did not change between the operated and control (unoperated) eye. There was no detectable homograft reaction on slit-lamp biomicroscopy or fluorescein angiography. The only adverse effect observed was one patient who complained of monocular diplopia after retinal transplantation and subsequent cataract surgery. Conclusions Allogeneic adult human photoreceptor transplantation is feasible in RP but was not associated with rescue of central vision or a delay in visual loss. However, any possible slowing in the rate of retinal degeneration will take many years to determine.

Vitreolysin™ is a purified 35.9 kDa extracellular neutral protease produced by Paenibacillus polymyxa. It can selectively cleave the attachment of the posterior vitreous cortex from the inner limiting membrane (ILM) due to its high affinity for type IV collagen and fibronectin, which contributes to the attachment between these two structures [see chapter II.E. Vitreo-retinal interface and inner limiting membrane]. The low affinity of Vitreolysin™ for vitreous type II collagen allows it to induce a posterior vitreous detachment (PVD) without disrupting the delicate macromolecular structure of the vitreous (Figure VI.G-1). This direct enzymatic action on the posterior vitreous cortex-ILM interface prevents vitreous liquefaction and resultant vitreoretinal traction which is a common way of PVD induction for many indirectly acting enzymes [1]. There are several other advantages of Vitreolysin™, such as lack of a known natural inhibitor, which insures reliable enzymatic activity even in complex vitreoretinal diseases where several enzyme inhibitors within the serum may leak into the eye. Vitreolysin™’s activity can be quenched by its own titratable autolysis, which ensures a fine control on its degradation and removal. Vitreolysin™ is a highly stable molecule with a long shelf life in lyophilized form. Early preclinical studies also revealed high rates (80–100 %) of PVD induction at picomolar concentrations.

PURPOSE: To report the histopathology after retinal pigment epithelial cell transplantation and subfoveal membranectomy in age-related macular degeneration. METHODS: An 85-year-old white woman with bilateral choroidal neovascularization underwent subfoveal membranectomy combined with transplantation of a sheet of human adult retinal pigment epithelium (retinal pigment epithelium) under the foveal center in the right eye. The patient was immunosuppressed postoperatively with prednisone, cyclosporine, and azathioprine. The patient died from congestive heart failure 114 days after surgery. RESULTS: A patch of hyperpigmentation was visible at the transplant site under the foveola after surgery. Mound-like clusters of individual round, large densely pigmented cells were present in the subretinal space and outer retina in this area. There was loss of the photoreceptor outer segments and native retinal pigment epithelium in the center of the transplant bed, with disruption of the outer nuclear layer predominantly over regions of multilayered pigmented cells. Cystic spaces were present in the inner and outer retina. A residual intra-Bruchs membrane component of the original choroidal neovascular complex was present under the transplant site. CONCLUSIONS: The transplant site contained clusters of round, pigmented cells that did not form a uniform monolayer in most areas. The morphology at the transplant site is consistent with the lack of visual improvement seen after surgery in this patient.

Purpose: To report simultaneous occurrence of multiple evanescent white dot syndrome (MEWDS) and multifocal choroiditis (MFC) in the same eye of a 33-year-old Caucasian woman.Methods: Review of clinical and fluorescein angiographic features of a patient who presented with decreased visual acuity and was followed for 3 months.Results: Patient presented with concurrent lesions of MEWDS and MFC occurring in the same eye. During the follow-up period MEWDS lesions resolved and MFC lesions evolved into chorioretinal scars.Conclusions: Simultaneous development of MEWDS and MFC may indicate a possible common causal entity.

A principal cause of blindness is subretinal neovascularization associated with age-related macular degeneration. Excised neovascular membranes from patients with age-related macular degeneration demonstrated a pattern of Fas+ new vessels in the center of the vascular complex, surrounded by FasL+ retinal pigment epithelial cells. In a murine model, Fas (CD95)-deficient (Ipr) and FasL-defective (gld) mice had a significantly increased incidence of neovascularization compared with normal mice. Furthermore, in gld mice there is massive subretinal neovascularization with uncontrolled growth of vessels. We found that cultured choroidal endothelial cells were induced to undergo apoptosis by retinal pigment epithelial cells through a Fas-FasL interaction. In addition, antibody against Fas prevented vascular tube formation of choroidal endothelial cells derived from the eye in a three-dimensional in vitro assay. Thus, FasL expressed on retinal pigment epithelial cells may control the growth and development of new subretinal vessels that can damage vision.

Background: We aimed to identify the cytokine(s) responsible for the density-dependent growth regulation of pig retinal pigment epithelium (RPE) in vitro. Methods: Confluent monolayers of primary pig RPE were established on bovine corneal endothelial extracellular matrix-coated tissue culture well inserts wrapped with dialysis membranes with different molecular weight cutoffs (0.5–50 kDa). These confluent RPE monolayers were then cocultured with first passage porcine RPE plated at a density of 1 cell/mm2, so that the newly plated RPE was bathed with different molecular weight fractions of the confluent cell media. Growth rates of the newly plated RPE were determined 72 h after plating and the molecular weight fraction of the confluent cell medium that inhibits the RPE proliferation was determined. First passage pig RPE (1 cell/mm2) were cocultured with confluent monolayers of primary pig RPE on inserts in the presence of different amounts of TGF-β neutralizing antibody (0.1–100 µg/ml). Growth rates of the newly plated RPE were calculated 72 h after plating to determine the antibody concentration that would maximize the growth rate of the newly plated RPE in the presence of an adjacent confluent RPE monolayer. Results: The growth rate of the newly plated RPE decreased when RPE were bathed with the 10- to 25-kDa fractions of medium from an adjacent confluent RPE monolayer. This growth inhibition reached statistical significance with the 25- to 50-kDa fractions (p < 0.05), and was abolished by adding pan-specific neutralizing antibody against TGF-β (0.1–5 µg/ml). Blocking greater amounts of TGF-β in the medium with higher doses of antibody (>10 µg/ml) also inhibited the growth of the newly plated RPE, in the presence or absence of a neighboring confluent cell layer. Conclusion: The TGF-β family of cytokines mediates the density-dependent growth suppression of RPE in vitro. Neutralizing the effect of these cytokines by adding anti-TGF-β antibodies can result in more rapid growth of the RPE in vivo.

Purpose. To develop a method using the vibratome and the excimer laser to harvest a sheet of human photoreceptor cells from the retinas of cadaveric donors.Methods. Adult human photoreceptor cells were harvested as intact sheets from the retinas of cadaver eyes using a vibratome or excimer laser. The sheets were embedded in 50% gelatin (in minimum essential medium and 300 mM sucrose) and stored at 4°C. The morphology, integrity, viability and sterility of the harvested photoreceptor cells was studied.Results. Light and scanning electron microscopy demonstrated sheets of adult human photoreceptor cells with an outer nuclear layer and inner and outer segments with either method of harvest. The initial viability of the outer nuclear layer, harvested an average of 28.2 h after death, was ≥94.7%. Sheets stored up to 72 h after harvest maintained a viability of ≥86.5%. The sheet of cells harvested with the vibratome frequently fragmented (n = 25, 35%) during passage through the delivery cannula in contrast to t...

To describe a method for the harvesting and storing of intact viable sheets of adult human retinal pigment epithelial (RPE) cells.Adult human RPE cells were harvested as intact sheets from 21 cadaver eyes, using the enzyme Dispase. The sheets were embedded in 50% gelatin containing 300 mM sucrose and stored at 4 degrees C. The viability of the cells, as well as their ability to proliferate in vitro, was studied for 96 hours after harvesting. Light microscopy (LM), transmission (TEM) and scanning electron microscopy (SEM) were performed to determine the integrity and ultrastructural features of the cells. Microbiologic culture of the harvested sheets was performed to exclude contamination.LM, TEM and SEM showed intact RPE cells with well-developed microvilli, basal infoldings and intercellular connections. The initial viability of intact RPE sheets was 86%, with a progressive decline in viability with increased storage time. Cells harvested within 24 hours after death maintained greater viability than those harvested after 24 hours (p0.05). Harvested RPE cells were free of microbial contamination and rapidly proliferated when cultured in vitro.Intact sheets of adult human RPE can be isolated using the enzyme Dispase. The cells appeared suitable for retinal transplantation if harvested within 24 hours of death and maintained 82% viability for as long as 48 hours if stored at 4 degrees C.

Purpose: The purpose of the study is to identify the anatomic abnormalities associated with an absolute scotoma and the location and stability of fixation in patients with subfoveal neovascularization in age-related macular degeneration, presumed ocular histoplasmosis syndrome, and other disorders. Methods: Scanning laser ophthalmoscope microperimetry was superimposed on color fundus photographs and fluorescein angiograms of 21 eyes with subfoveal neovascular membranes secondary to age-related macular degeneration (14 eyes) and presumed ocular histoplasmosis syndrome (7 eyes). The authors determined the location and the area occupied by the absolute scotoma and each of the following subretinal lesions: subretinal hemorrhage, neurosensory retinal detachment, retinal pigment epithelial (RPE) atrophy, RPE hyperplasia, atrophy of the choriocapillaris, hard exudates, and the subfoveal neovascular membrane. The area of absolute scotoma determined by scanning laser ophthalmoscope microperimetry was superimposed on the anatomic lesions. The authors calculated the relative risk ratio (RR) of an absolute scotoma occurring in regions corresponding to each anatomic abnormality, and determined the preferred location and stability of fixation in each eye. Results: An absolute scotoma was present in areas of chorioretinal scar (RR = 107.61), RPE atrophy (RR = 9.97), subretinal hemorrhage (RR = 2.88), and the neovascular membrane (RR = 1.86). Fixation was stable in all patients with presumed ocular histoplasmosis syndrome but only 29% of patients with age-related macular degeneration. Fifty-five percent of patients with stable fixation fixated over an area of RPE hyperplasia. Conclusion: The relative risk of an absolute scotoma is highest over areas of chorioretinal scars, RPE atrophy, subretinal hemorrhage, and the neovascular membrane. Fixation is more stable in patients with subfoveal neovascularization from presumed ocular histoplasmosis syndrome than with age-related macular degeneration and frequently is present over an area of RPE hyperplasia.

Commercially available vitreoretinal surgical forceps were modified with layer-by-layer (LbL) films designed to render them the ability to specifically adhere human the inner limiting membrane. Surgical forceps with two different geometries were etched, polished, and silanized before deposition of the films composed of poly (allylamine hydrochloride), poly (styrene sulfonate), and cationic gold nanoparticles. Stability and integrity of the LbL films was scrutinized by exposing the modified forceps to commercial disinfectant Cidex-OPA and then placing the instruments in a physiological-like HEPES buffer (pH 7.4, 5 mM, 154 mM NaCl). Surface topography analysis with scanning electron microscopy revealed that the geometry of the surgical instrument may affect the integrity of the film. Analysis of the HEPES buffer with inductively coupled plasma mass spectrometry demonstrated that gold nanoparticles did not leach from the LbL film after 60 min.

Retinal trauma is a serious concern for patients undergoing inner limiting membrane (ILM) peeling to correct for various vitreoretinal interface conditions. This mechanical trauma can be prevented by modifying the surface of surgical instruments to increase adhesion to the ILM. To this effect, we have studied the effects of roughness and surface charge on the adhesive properties of ILMs by utilizing layer-by-layer (LbL) films with embedded gold nanoparticles (LbL-AuNP films). LbL films were assembled on atomic force microscopy (AFM) tipless cantilevers. Topographical analysis of these films, with and without nanoparticles, showed that LbL films with nanoparticles had a higher rms roughness compared to films alone or unmodified cantilevers. Nanoparticle-modified LbL films significantly increased the adhesion forces at the cantilever–ILM interface, compared to LbL films without particles. Surprisingly, adsorption of gold nanoparticles onto the AFM cantilevers caused increases in adhesion forces greater than those measured with LbL-AuNP films. These results have important implications for the design of surface modifications for vitreoretinal surgical instruments.

We report the study of the morphology, topography, and adhesion properties of internal limiting membrane (ILM) from patients with macular holes. The quantitative analysis of human ILM could provide essential information toward the improvement of existing surgical instruments for more efficient and safer surgical removal of ILM. Imaging in air revealed the presence of globular structures in most of the samples analyzed which were coupled with fibrillar structures in some of the samples. Modification of silicon nitride AFM tips with oppositely charged functional groups showed changes in adhesion force at the membrane-tip interface. Defining the surface characteristics of the human ILM is an initial step in the development of improved surgical tools that may allow nontraumatic stripping of ILM during surgery.

Publisher Summary In the normal human eye the vitreous gel is bordered anteriorly by the posterior lens capsule, the pars plana and pars plicata of the ciliary body, and posteriorly by the inner limiting membrane of the neural retina. The vitreous is an aqueous medium, composed mainly of water with smaller amounts of positively charged collagen stabilized by negatively charged hyaluronic acid. Currently, the surgical removal of vitreous gel, which is necessary for a broad spectrum of disease processes, is performed by mechanical means, and little use has been made of enzyme-assisted vitreous surgery. However, enzyme assisted posterior segment surgery has many theoretical and practical advantages over mechanical vitrectomy, including reducing operating time and reducing complications that occur during mechanical vitreous separation of the posterior hyaloid from the inner retinal surface. This chapter describes the enzymatic agents that have been proposed for vitreous surgery, including their current status, and advantages and disadvantages of each agent, with an emphasis on the barriers to clinical use.

Purpose To determine whether repetitive injections of intravitreal bevacizumab and/or triamcinolone acetate in patients with exudative age-related macular degeneration (AMD) results in a decrease in biological response. Design Retrospective comparative case series. Participants Forty-three eyes of 43 patients with exudative AMD. Methods Pre- and postinjection optical coherence tomography (OCT) sections of 43 patients with AMD were analyzed to determine the change in the biologic response after each subsequent injection of intravitreal bevacizumab (2.5 mg/100 μL), preservative-free triamcinolone acetonide (pfTA) (4.0 mg/100 μL), or a combination of bevacizumab (1.25 mg/50 μL) and pfTA (2.0 mg/50 μL). The retinal thickness of each OCT sector was determined and expressed as volume. Standardized volumetric change index (SVCI) was determined to identify a statistically significant change. Pre- and postinjection (6 weeks) SVCI differences were plotted as a function of time to determine the biological response after each intravitreal treatment. Main Outcome Measures Change in SVCI after intravitreal injections and the number of injections required to decrease the biological response by 50% (INJ 50 ). Results There was no difference in the age, gender, and preinjection thickness of the retina in each of the 3 groups. The SVCI after intravitreal bevacizumab injections decreased, indicating a possible tachyphylactic response to bevacizumab. This decrease in biological response was partially alleviated with the addition of pfTA. Combination of pfTA and bevacizumab increased the INJ 50 from 2.9 with bevacizumab alone to 5.1 injections. A biphasic biologic response was observed with pfTA characterized by a rapid increase in efficacy with the second injection, peaking at the third injection and gradually decreasing afterward. Conclusions Repeated intravitreal injections of bevacizumab in exudative AMD seemed to be associated with decreased bioefficacy. However, combined pharmacotherapy with triamcinolone acetate lessened this effect. Thus, multitargeted pharmacotherapy in exudative AMD may have a therapeutic benefit. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

A modified technique is presented for transscleral suture fixation of posterior chamber intraocular lenses for aphakic correction in cases with inadequate capsular support. An ab externo approach for suture externalization is described that minimizes intraocular manipulation and facilitates accurate placement of haptics in the ciliary sulcus, thereby reducing the risk of lens tilt and decentration. This technique eliminates intraocular suture knots and reduces the amount of time the globe is open during surgery by creating two intraocular suture loops in preparation for posterior chamber intraocular lens placement before creating a limbal incision. [Ophthalmic Surg Lasers Imaging 2007;38:72-75.] AUTHORS From the University of Medicine and Dentistry of New Jersey (KK), Robert Wood Johnson Medical School, Piscataway, New Jersey; the Institute of Ophthalmology and Visual Science (MZ), the University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey; the Edward S. Harkness Eye Institute (LVD), Department of Ophthalmology, Columbia University, New York, New York; and the Department of Ophthalmology and Visual Sciences (THT), Kentucky Lions Eye Center, University of Louisville, Louisville, Kentucky. Accepted for publication April 19, 2006. Supported in part by grants from Research to Prevent Blindness, Inc., the Robert L. Burch III Fund, the Foundation Fighting Blindness, the Eye Institute of New Jersey, and the New Jersey Lions Eye Research Foundation. Address correspondence to Tongalp H. Tezel, MD, 301 E. Muhammad Ali Blvd., University of Louisville, Louisville, KY 40202.

The complement system is a major component of innate immunity. During an inflammatory reaction, the eye is potentially threatened by homologous complement attack, and unregulated complement activation could lead to tissue damage and vision loss. The complement system is continuously activated at low levels in the normal eye, and intraocular complement-regulatory proteins (CRPs) tightly regulate this spontaneous complement activation so that there is elimination of potential pathogens without the induction of destructive intraocular inflammation. The presence of a complement activation product (iC3b) during the early phase of antigen and antigen-presenting cell contact is essential for the induction of systemic tolerance to antigen injected into the anterior chamber of the eye and the establishment of ocular immune privilege. The complement system and complement-regulatory proteins control intraocular inflammation in autoimmune anterior uveitis and may play an important role in the development of age-related macular degeneration. Thus, in the eye, complement functions as a double-edged sword - on one hand it provides innate immunity against pathogens while simultaneously instructing the adaptive immune response to develop tolerance to such pathogens to avoid inadvertent tissue damage in a critical organ.

The complement system is a major component of innate immunity. During an inflammatory reaction, the eye is potentially threatened by homologous complement attack, and unregulated complement activation could lead to tissue damage and vision loss. The complement system is continuously activated at low levels in the normal eye, and intraocular complement-regulatory proteins (CRPs) tightly regulate this spontaneous complement activation so that there is elimination of potential pathogens without the induction of destructive intraocular inflammation. The presence of a complement activation product (iC3b) during the early phase of antigen and antigen-presenting cell contact is essential for the induction of systemic tolerance to antigen injected into the anterior chamber of the eye and the establishment of ocular immune privilege. The complement system and complement-regulatory proteins control intraocular inflammation in autoimmune anterior uveitis and may play an important role in the development of age-related macular degeneration. Thus, in the eye, complement functions as a double-edged sword - on one hand it provides innate immunity against pathogens while simultaneously instructing the adaptive immune response to develop tolerance to such pathogens to avoid inadvertent tissue damage in a critical organ.

Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. Over the last decade, there have been significant advances in the management of exudative AMD with the introduction of anti-VEGF drugs; however, many patients with exudative AMD continue to lose vision and there are no effective treatments for advanced exudative AMD or geographic atrophy. Initial attempts at macular reconstruction using cellular transplantation have not been effective in reversing vision loss. Herein we discuss the current status of surgical attempts to reconstruct damaged subretinal anatomy in advanced AMD. We reinforce the concept of maculoplasty for advanced AMD, which is defined as reconstruction of macular anatomy in patients with advanced vision loss. Successful maculoplasty is a three-step process that includes replacing or repairing damaged cells (using transplantation, translocation or stimulation of autologous cell proliferation); immune suppression (if allografts are used to replace damaged cells); and reconstruction or replacement of Bruch's membrane (to restore the integrity of the substrate for proper cell attachment). In the current article we will review the rationale for maculoplasty in advanced AMD, and discuss the results of initial clinical attempts at macular reconstruction. We will then discuss the role of Bruch's membrane damage in limiting transplant survival and visual recovery, and discuss the effects of age-related changes within human Bruch's membrane on the initial attachment and subsequent proliferation of transplanted cells. We will discuss attempts to repair Bruch's membrane by coating with extracellular matrix ligands, anatomic reconstitution of the inner collagen layer, and the effects of Bruch's membrane reconstruction of ultrastuctural anatomy and subsequent cell behavior. Lastly, we will emphasize the importance of continued efforts required for successful maculoplasty.

We have shown previously that aging of human Bruch's membrane affects the attachment, survival and gene expression profile of the overlying retinal pigment epithelium (RPE). Herein we determine the effects of Bruch's membrane aging on RPE phagocytosis of rod outer segments.Explants of human Bruch's membrane were prepared from cadaver donor eyes (aged 9-81years) within 48 h of death, and 6 mm punches were embedded with the basal lamina in a 96-well plate. Approximately 50,000 ARPE-19 cells per well were seeded onto the explant surface and cultured for two weeks until they reached confluence. In addition, ARPE-19 were also seeded onto RPE-derived extracellular matrix (RPE-ECM) that was unmodified or modified by nonenzymatic nitration. Bovine rod outer segments were purified by sucrose gradient centrifugation, labeled with 10 ug/ml fluorescein isothiocyanate, and added to ARPE-19 cultured on Bruch's membrane or RPE-ECM for 24 h. Phagocytic activity was quantified by flow cytometry of harvested cells.The ability of RPE to phagocytose rod outer segments decreased as a function of aging of Bruch's membrane; mean phagocytotic activity of ARPE-19 on younger Bruch's membrane was significantly higher than on older Bruch's membrane (129.7 +/- 34.8 versus 67.4 +/- 4.2 arbitrary units, respectively; p0.01). Nitrite treatment of RPE-ECM decreased rod outer segment phagocytosis compared to untreated RPE-ECM and mimicked the effects of aging of human Bruch's membrane.Aging of human Bruch's membrane decreases rod outer segment phagocytosis by ARPE-19. This effect can be mimicked by nonenzymatic nitration of extracellular matrix in vitro. Our observations may have implications for understanding the role of aging changes within Bruch's membrane on pathogenesis of age-related macular degeneration and other disorders.