Aflibercept monotherapy or bevacizumab first for diabetic macular edema.

PURPOSE: Clinical outcome and switch patterns with bevacizumab first treatment strategy for patients with newly diagnosed neovascular age-related macular degeneration (nAMD). METHODS: Retrospective observational study of the number of intravitreal injections of bevacizumab and treatment switch in patients who started intravitreal bevacizumab injections between January 1, 2016 and December 30, 2018. RESULTS: From January 1 2016 to December 31 2018, 608 eyes of 565 patients started intravitreal injections of bevacizumab for a new diagnosis of nAMD. Average visual acuity (VA) at presentation was 0.60 logarithm of the minimum angle of resolution (logMAR), which improved to 0.47 after six injections (P < 0.001) and decreased to 0.63 at the last follow-up (P = 0.543). Switch of treatment was recommended for 190 eyes (31.3%), and of them, 91 patients (15%) were switched during the first 6 months and defined as primary failure of bevacizumab. The switch of treatment resulted in a statistically significant improvement in VA in the first 6 months after the switch. The gain in VA was not sustainable over time. CONCLUSION: Bevacizumab first treatment strategy produced results that were comparable to previous real-world outcomes publications of ranibizumab and aflibercept treatment with low rates of failure of bevacizumab treatment. Treatment switch to second-line treatment yielded a significant VA improvement, mainly in patients with primary bevacizumab failure.

Peripapillary and fovea avascular zone optical coherence tomography angiography parameters in exfoliation glaucoma versus primary open-angle glaucoma versus healthy eyes.

Purpose: To examine the differences in the peripapillary vascular parameters and foveal-avascular-zone (FAZ) vascularity parameters between primary open-angle-glaucoma (POAG) patients versus exfoliation-glaucoma (XFG) patients versus healthy subjects. Methods: This is cross-sectional study and a comparative clinical study. POAG and XFG patients and healthy subjects underwent a comprehensive ophthalmic examination, including visual field optical coherence tomography (OCT) and OCT angiography (OCTA) of the optic disc and FAZ. Differences in peripapillary vessel density (VD), perfusion density (PD), and FAZ area and circularity were examined between all groups, as well as correlations between clinical parameters and vascularity parameters for each glaucoma group. Results: A total of 109 subjects (one eye for each patient) were analyzed, including 45 with POAG, 30 with XFG, and 34 controls. The average peripapillary VDs were the lowest among the XFG patients and the highest among the controls (P < 0.05, ANOVA). The average peripapillary PD of the central ring was the lowest in the XFG group and the highest in the control group (P = 0.02, ANOVA). A significant negative correlation was found between the average peripapillary VDs and PDs of the inner ring and full ring and disease severity of the POAG patients. There was a significant positive correlation between the average peripapillary PDs of the central rings and full ring and the central macular thickness of the XFG patients (P < 0.01 and P < 0.04, respectively, Pearson correlation). Conclusion: The peripapillary vascular parameters of the POAG and XFG patients were lower compared to those of normal participants. A correlation between clinical characteristics of POAG and XFG patients and PD was found. This may hint to a vascular mechanism in glaucoma either primary or secondary to intra-ocular pressure/OAG damage.

Peripheral Exudative Hemorrhagic Chorioretinopathy with and without treatment-Clinical and multimodal imaging characteristics and prognosis.

PURPOSE: To describe clinical and imaging characteristics of patients with Peripheral Exudative Hemorrhagic Chorioretinopathy (PEHCR), prognosis and treatment response. METHODS: In this retrospective cohort study medical records of patients diagnosed with PEHCR in a tertiary medical center between 2008 and 2018 were reviewed. Collected data included demographics, medical history, ophthalmologic examination and multi-modal imaging including fundus autofluorescence, optical coherence tomography (OCT), ultrasound (US), fluorescein angiography and indocyanine green angiography when available. Bevacizumab treatment results were analyzed when applied. RESULTS: 35 eyes of 32 patients were included, with a female predominance (56.25%) and an average age of 79.0±9.87 years at presentation. Most common OCT and US findings were subretinal mass (68.75%), pigment epithelial detachment (30.00%) and atrophic changes (21.86%). Median follow-up period was 18.00 months (range 0-102). Visual acuity (VA) remained stable (39.29%) or improved (25.00%) in most cases available for follow-up. Treatment with intravitreal bevacizumab induced a statistically significant clinical resolution in 88.89% of eyes available for follow-up (8/9 eyes) (p = 0.02). CONCLUSIONS: PEHCR is presented with high clinical variability and generally good prognosis. This is the first publication demonstrating a statistically significant clinical resolution of disease following intravitreal bevacizumab injections.

Mammalian target of rapamycin inhibitors for the treatment of astrocytic hamartoma in tuberous sclerosis complex (TSC).

PURPOSE: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder. Fifty percent of patients with TSC will develop retinal astrocytic hamartoma (RAH). The mammalian target of rapamycin (mTOR) inhibitors interferes with the pathological mechanisms of TSC. Treatment of RAH with mTOR inhibitors has been described in only a few isolated case reports. The purpose of this study was to assess the effect of mTOR inhibitors on RAH in a small cohort of patients. METHODS: The medical records of all consecutive patients with ocular manifestations of TSC that were treated with mTOR inhibitors at the Sheba Medical Center from January 2014 to December 2018 were retrospectively reviewed. Data collection included demographics, medical history, ocular presentation, ocular treatment, and treatment outcome. Tumor size was assessed by a masked observer, before and after treatment. Lesion measurements were made with Heidelberg SD-OCT (HRA + OCT SPECTRALIS), and fundus photos were taken with RetCam3® (Natus, USA) and analyzed by "ImageJ" software. RESULTS: Eleven patients with tuberous sclerosis and astrocytic hamartoma were treated with mTOR inhibitors in the study period. Of them, 6 children (11 eyes, 20 tumors) had proper imaging of tumor size before and after treatment. The analysis included these 11 eyes. All six patients had non-ocular manifestations of TSC, including dermatologic (n = 5), neurologic (n = 5), and renal (n = 3) involvement. Ocular involvement included in five eyes (45%) tumors near the optic disc and in four eyes (37%) foveal tumors. The mean follow-up duration was 2.15 ± 1.4 years (range 10 months to 4.5 years). The average tumor base reduction in the treated group was 17.8% ± 15.9. The average maximal thickness at baseline was 414 ± 174 µm (range 152-686 µm). There was a 14% ± 7.1 reduction after treatment. None of the tumors showed evidence of growth at the final follow-up. CONCLUSION: The findings of this study suggest that mTOR inhibitors can reduce tumor size and that they can be considered as an optional treatment in certain conditions. This preliminary report is the first to quantitatively assess pre- and posttreatment tumor size, in young patients.

Kelly Punch Punctoplasty and Simple Punctal Dilatation Are Equally Effective for Punctal Stenosis: A Prospective Study.

PURPOSE: To examine the clinical, imaging, and histopathologic differences between Kelly punch punctoplasty and punctal dilatation, both with mini Monoka stent insertion. METHODS: This is a prospective, comparative clinical study. Patients with bilateral punctal stenosis and for whom surgery was advised participated in the study. The right eye underwent Kelly punch punctoplasty and the left eye simple punctal dilatation, both with mini Monoka stents were participated. Data were collected and analyzed before and 3 months following the procedure and included the degree of epiphora (Munk score) and punctal size as measured by anterior segment optical coherence tomography (AC- OCT). All specimens removed by the Kelly punch punctoplasty were sent for histopathologic evaluation, including Masson's trichome muscle staining. RESULTS: The study included 46 eyes of 23 patients (4 males and 19 females) whose mean age at presentation was 60.43 ± 14.81 years (range 19-84 years). There was a significant decrease in the Munk score after both punctoplasties compared with baseline values (P < 0.01, matched pairs). There were no significant differences between groups in the delta Munk score. There was a significant increase in punctal size after both procedures compared with baseline values as measured by AS-OCT. Horner-Duverney's muscle was visible in only 3 of the 23 (13.04%) specimens from patients who underwent the Kelly punch punctoplasty. CONCLUSIONS: The Kelly punch punctoplasty and the simple dilator punctoplasty, both with stents, are equally effective treatments for epiphora due to acquired punctal stenosis. Only a few specimens removed during the Kelly punch method show muscle fibers.

Naevus of Ota: clinical characteristics and proposal for a new ocular classification and grading system.

INTRODUCTION: Naevus of Ota is a congenital condition that may involve the skin, eyeball and even intracranial structures usually in the distribution of the ophthalmic and maxillary divisions of the trigeminal cranial nerve. The purpose of this study was to summarise our experience with the ocular clinical presentation, imaging, outcome, treatment of complications and to offer a new classification of patients with naevus of Ota. METHODS: We retrospectively reviewed the patients' medical records and the following parameters were retrieved and analysed: demographics, clinical presentation complications and treatment of complications. Imaging characteristics of patients with naevus of Ota were compared with images from the same period of time of 57 age-matched and gender-matched patients without naevus of Ota (control group). RESULTS: The series was composed of 40 patients (18 males, 22 females) whose mean age at diagnosis was 35.27 years (range 0.5-77 years). Thirty-three patients (82.5%) were type I naevus of Ota according to the Tanino classification, three patients (7.5%) were type II, one patient (2.5%) was type III and three patient (7.5%) were type IV (bilateral naevus of Ota). We further classified all cases in according to the ocular involvement extent. Three patients developed malignant transformation to choroidal melanoma and four patients developed glaucoma. CONCLUSIONS: In this study, a new clinical classification based on the involved ocular component and extent of the involvement (in quadrants) of the globe is suggested first. Further studies are needed to assess whether our clinical ocular classification can assist in identifying patients at risk for developing glaucoma and malignant transformation.

Development of global visual processing: From the retina to the perceptive field.

Young children exhibit poorer visual performance than adults due to immaturity of the fovea and of the fundamental processing of visual functions such as masking and crowding. Recent studies suggest that masking and crowding are closely related to the size of the fundamental processing unit-the perceptive field (PF). However, while it is known that the retina and basic visual functions develop throughout childhood, it is not clear whether and how changes in the size of the PF affect masking and crowding. Furthermore, no retinal and perceptual development data have been collected from the same cohort and time. Here we explored the developmental process of the PF and the basic visual functions. Psychophysical and imaging methods were used to test visual functions and foveal changes in participants ranging from 3-17 years old. Lateral masking, crowding and contrast sensitivity were tested using computerized tasks. Foveal measurements were obtained from spectral-domain optical coherence tomography (OCT). The children patterns below 6 years exhibited high crowding, while the expected facilitation was found only at a larger target-flanker distance than required for children above 6 years, who exhibited the typical adult. Foveal thickness and macular volume for the children below 6 years were significantly lower than for the older group. Significant correlation was found for contrast sensitivity, foveal thickness and macular volume with age and between contrast sensitivity and foveal thickness. Our data suggest that the developmental processes at the retina and visual cortex occur in the same age range. Thus, in parallel to maturation of the PF, which enables reduction in crowding, foveal development contributes to increasing contrast sensitivity.

Blue Autofluorescence Fundus Imaging for Monitoring Retinal Degeneration in Royal College of Surgeons Rats.

PURPOSE: Development of a method for noninvasive longitudinal follow-up of retinal degeneration in the whole retina for Royal College of Surgeons (RCS) rats, a commonly used model of retinitis pigmentosa associated with mutations in the MER-proto-oncogene tyrosine kinase (MERTK) gene. METHODS: Pigmented RCS rats at postnatal (p) days p28 to p84 were subjected to a biweekly spectral-domain optical coherence tomography (SD-OCT), blue laser fundus autofluorescence (BL-FAF) imaging, and multicolor fundus imaging. Wild-type (WT; Long Evans) rats were tested as control. RESULTS: Hyperautofluorescence developed throughout the fundus at p42, concomitant with a significant increase in SD-OCT thickness and reflectivity of the debris zone (DZ) layer as well as thinning of the photoreceptor outer nuclear layer (ONL). From p56 to p84, discrete hypofluorescent lesions surrounded by hyperfluorescent flecks were demonstrated around the optic disc that gradually spread throughout the retina. The hypofluorescent lesions were associated with loss of ONL and gradual thinning of the DZ layer. No hypofluorescent BL-FAF lesions were observed in WT rats. CONCLUSIONS: This study suggests that BL-FAF imaging may present a new method for noninvasive longitudinal follow-up of retinal degeneration in nearly the whole retina in RCS rats. TRANSLATIONAL RELEVANCE: A clinical test was developed that may be implemented in translational studies in the RCS rat model of MERTK-associated retinitis pigmentosa.

OPTICAL DENSITY RATIO OF THE SUBRETINAL FLUID IN CHOROIDAL MELANOMA AND METASTASIS.

PURPOSE: To investigate the optical density (OD) characteristics and clinical relevance of subretinal fluid in choroidal melanoma and choroidal metastasis. METHODS: Medical records of patients with choroidal melanoma and choroidal metastasis who underwent optical coherence tomography examinations at diagnosis before any intervention and whose optical coherence tomography scans showed sufficient subretinal fluid for sampling were reviewed. The highest quality B-scan containing subretinal fluid was analyzed. Optical density measurements obtained using ImageJ and optical density ratios (ODRs) were calculated as subretinal fluid OD divided by vitreous OD. Patient details and diagnosis were masked during measurements. Nonparametric tests for independent samples were used to detect differences in ODR between groups. RESULTS: Of the 39 cases of choroidal tumors that met the inclusion criteria, 14 were diagnosed as metastases and 25 as malignant melanoma. There were no significant differences between the groups in age, optical coherence tomography acquisition and parameters of quality, and vitreous OD. Optical density ratio values were significantly lower in metastases cases (mean 0.68, SD ±0.18) than in melanoma cases (0.95 ± 0.33, P = 0.006). Receiver operating characteristic curve analysis yielded an optimal cutoff of ODR = 0.771 (sensitivity = 78.6%, specificity = 72.0%). CONCLUSION: Optical density ratio can serve as an additional test to differentiate between choroidal melanoma and choroidal metastases.

Subretinal Fluid Optical Density and Spectral-Domain Optical Coherence Tomography Characteristics for the Diagnosis of Circumscribed Choroidal Hemangioma.

PURPOSE: To investigate spectral domain-optical coherence tomography (SD-OCT) features of untreated circumscribed choroidal hemangioma (CCH), and the optical density (OD) of the associated subretinal fluid (SRF). PROCEDURES: This international retrospective multicenter study conducted at 5 tertiary retina referral centers included 34 patients with symptomatic CCH imaged on SD-OCT. CCH surface, size, and overlying retinal changes and OD ratio (ODR) were evaluated. RESULTS: The mean ODR of the SRF was 0.808 ± 0.287. Tumor base measured on ultrasound correlated significantly with the ODR (p = 0.012). ODR values in cases of CCH were similar to those of choroidal metastasis, but significantly lower than those of choroidal melanoma (p = 0.006). Thirty-two out of 34 cases (94%) presented with a regular smooth choroidal surface. OCT demonstrated SRF overlying the CCH in 29 eyes (85%). The presence of SRF correlated significantly with a larger basal tumor diameter (p = 0.035). OCT displayed sub- and intraretinal hyperreflective foci, correlating with both larger maximal retinal thickness overlying the tumor (p = 0.031) and the amount of SRF (p = 0.016) in 29 eyes (85%). CONCLUSION: CCH displays typical findings on SD-OCT. ODR is a new important tool in the differential diagnosis of choroidal tumors and should be considered for enhancing the accuracy of diagnosing CCH. This benefit is especially relevant for cases in which the presentation of CCH is atypical.

Different Clinical Courses on Long-Term Follow-Up of Age-Related Macular Degeneration Patients Treated with Intravitreal Anti-Vascular Endothelial Growth Factor Injections.

PURPOSE: To assess the long-term outcome of neovascular age-related macular degeneration (AMD) treated with multiple intravitreal anti-vascular endothelial growth factor (VEGF) injections. METHODS: All patients treated with over 30 intravitreal anti-VEGF injections for neovascular AMD between 2007 and 2014 were retrospectively reviewed. RESULTS: A total of 67 eyes received 2,960 (mean 45 ± 9.1 per eye) anti-VEGF injections. Eyes with good final visual acuity (VA) had better initial VA (p = 0.020) and maintained it. Patients with moderate-to-poor final VA improved significantly after the first 3 monthly injections, and thereafter deteriorated consistently, mostly during the third (p = 0.019) and fourth (p = 0.006) years. Eyes with worse final VA had more intraretinal fluid (p = 0.05) and subretinal fibrosis (p = 0.04). CONCLUSION: Two distinct clinical courses were identified: good final VA was associated with initial and long-term stability of good VA; eyes with worse final VA had worse initial VA, progressive deterioration following the initial improvement, and more scarring and intraretinal fluid. This probably underscores the long-term benefits of early detection and treatment.

Long-Term Safety of Transplanting Human Bone Marrow Stromal Cells into the Extravascular Spaces of the Choroid of Rabbits.

Incurable neuroretinal degeneration diseases cause severe vision loss and blindness in millions of patients worldwide. In previous studies, we demonstrated that transplanting human bone marrow stromal cells (hBMSCs) in the extravascular spaces of the choroid (EVSC) of the Royal College of Surgeon rats ameliorated retinal degeneration for up to 5 months. Assessing the safety of hBMSC treatment and graft survival in a large animal is a crucial step before initiating clinical trials. Here, we transplanted hBMSCs into the EVSC compartment of New Zealand White rabbits. No immunosuppressants were used. Transplanted cells were spread across the EVSC covering over 80 percent of the subretinal surface. No cells were detected in the sclera. Cells were retained in the EVSC compartment 10 weeks following transplantation. Spectral domain optical coherence tomography (SD-OCT) and histopathology analysis demonstrated no choroidal hemorrhages, retinal detachment, inflammation, or any untoward pathological reactions in any of transplanted eyes or in the control noninjected contralateral eyes. No reduction in retinal function was recorded by electroretinogram up to 10 weeks following transplantation. This study demonstrates the feasibility and safety of transplanting hBMSCs in the EVSC compartment in a large eye model of rabbits.

A minimally invasive adjustable-depth blunt injector for delivery of pharmaceuticals into the posterior pole.

PURPOSE: To investigate the feasibility and safety of a novel minimally invasive adjustable-depth blunt injector for pharmaceuticals delivery into the posterior segment. METHODS: Indocyanine green (ICG), sodium fluorescein and iron oxide nanoparticles (IONPs) were injected using the new injector into the extravascular spaces of the choroid (EVSC) compartment of rabbits and cadaver pig eyes. Spectral domain optical coherence tomography (SD-OCT), fundus imaging and histology analysis were performed for assessment of injection safety and efficacy. RESULTS: Indocyanine green, fluorescein and IONPs were detected across the EVSC in rabbit eyes, covering over 80 per cent of the posterior eye surface. Injected IONPs were retained in the EVSC for at least 2 weeks following injection. No retinal detachment, choroidal haemorrhage or inflammation was detected in any of the injected eyes. In cadaver pig eyes, ICG was detected across the EVSC. CONCLUSIONS: This novel minimally invasive delivery system may be used to safely deliver large volumes of pharmaceuticals into a new treatment reservoir compartment - the EVSC which can serve as a depot, in close proximity to the retina, covering most of the surface of the back of the eye without insertion of surgical instruments under the central retina. This system is predicted to enhance the therapeutic effect of treatments for posterior eye disorders.

Optical Coherence Tomography: An Adjunctive Tool for Differentiating between Choroidal Melanoma and Metastasis.

Purpose. To investigate the value of optical coherence tomography (OCT) for differentiation between choroidal melanoma and metastasis based on characteristics of the anterior choroidal surface and the chorioretinal interface. Methods. This retrospective observational case series included 29 patients with untreated choroidal melanomas and 21 patients with untreated choroidal metastases. Regularity and lobularity characteristics of the anterior choroidal surface were evaluated in a masked manner. Retinal and retinal pigment epithelium (RPE) findings were documented as well. Results. OCT demonstrated a regular and smooth anterior choroidal surface in 89.7% of the eyes with melanoma and in 47.6% of the eyes with metastasis (p = 0.002; sensitivity = 89.7%; specificity = 52.4%). The anterior choroidal contour was lobulated in 81.0% of the eyes with metastasis versus 17.2% of the eyes with melanoma (p < 0.001; sensitivity = 82.8%; specificity = 81.0%). RPE thickness and neuroretinal characteristics (e.g., retinal thickness, the presence of cysts, and the presence of subretinal fluid) were similar in both choroidal tumors. Conclusion. OCT may serve as a noninvasive adjunctive tool for the differential diagnosis of choroidal tumors. Choroidal melanomas usually demonstrate regular surfaces on OCT, while choroidal metastases usually have an irregular and lobulated surface.

25-Gauge Vitrectomy with Epiretinal Membrane and Internal Limiting Membrane Peeling in Eyes with Very Good Visual Acuity.

PURPOSE: To evaluate the efficacy and safety of pars plana vitrectomy (PPV) in patients with epiretinal membrane (ERM) and preoperative visual acuity (VA) of 20/40 or better. METHODS: 44 eyes that underwent PPV and ERM peeling were included in this retrospective study. Data retrieved included demographic information, VA and intraocular pressure (IOP) preoperatively, after 1 month, 6 months and at final visit, presence of metamorphopsia, surgical reports, and occurrence of any complications. RESULTS: Mean preoperative VA was 20/36 (0.24 ± 0.08 logMAR) and had improved to 20/27 (0.13 ± 0.11 logMAR) at the final follow-up (p < 0.001). Thirty (68.1%) eyes had improved by 1 line of vision or more, and 10 (22.7%) achieved final 20/20 vision. Significant improvement in vision was achieved earlier in eyes that underwent vitrectomy combined with cataract extraction. Preoperative OCT scans demonstrated preserved outer retinal layer structure. CONCLUSIONS: PPV and ERM peeling is a safe and effective procedure in eyes with very good preoperative VA. PPV combined with cataract extraction offers a faster improvement in VA than PPV alone with deferred cataract surgery. PPV should be considered in symptomatic eyes with ERM and VA of 20/40 or better, in order to preserve and even improve the VA.

A biological tissue adhesive and dissolvent system for intraocular tumor plaque radiotherapy: an in vivo animal model experiment.

PURPOSE: To examine a novel biological adhesive and dissolvent system for plaque placement and removal using fibrin glue and urokinase, respectively, in an in vivo animal model. METHODS: The study was performed on 23 rabbit eyes. Of these, eight underwent a technical feasibility study and ultrasonographic plaque displacement measurements, nine were examined clinically and by magnetic resonance imaging and histopathology for tissue reaction to the biological substances used, and in six the impact of fibrin glue as an orbital space occupier on intraocular pressure was assessed. In an additional ex vivo experiment, the glue's radiation attenuating properties were tested using an oncology EDR2 film. RESULTS: Plaque horizontal movement throughout follow-up (7-10 days) was negligible (0.5 ± 0.2 mm), and there was no tilting whatsoever. In the tissue response experiment, no adverse effects were recorded after application of fibrin or urokinase throughout the 21-day follow-up period. Interestingly, a circumscribed local inflammatory response was noted in tissue surrounding the fibrin glue, and persisted at 21 days. In the orbital space-occupying experiment, application of 1 cc fibrin glue did not cause a significant elevation in intraocular pressure (IOP) (P = 0.06), and in the ex vivo experiment, there was no significant difference between radiation readings with and without glue separation of the radioactive sources and film (P = 0.065). CONCLUSIONS: The adhesive and dissolvent system was feasible and safe for plaque placement and removal. It may be superior to conventional surgical plaque placement methods in eliminating the relatively common risk of plaque tilting and complications due to scleral suturing.