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Purpose Analyze clinical features, management and outcomes of patients with sterile endophthalmitis associated with intravitreal antivascular endothelial growth factor. Methods Observational retrospective case series of patients with sterile endophthalmitis following anti-VEGF intravitreal injections. Clinical data of patients treated with intravitreal anti-VEGFs during one year have been revised. Those who have presented an episode of sterile endophthalmitis are analyzed and their causality and management are studied Results Seven patients have had a sterile endophthalmitis onset within 4 days after intravitreal injection (aflibercept n = 5 and ranibizumab n = 2). These patients have some active neovascular condition: age related macular degeneration (n = 4), myopic choroidal neovascularization (n = 1) or macular edema: diabetic macular edema (n = 1), branch retinal vein occlusion (n = 1). Shared signs and symptoms included painless vision loss, anterior chamber and vitreous cell and lack of hypopyon. In all patients, visual acuity returned to within one line of baseline acuity. Conclusion Differentiating cases of sterile from infectious endophthalmitis may be challenging. It is crucial to differentiate both entities as a good diagnosis determines the visual prognosis. We should be aware of minimal inflammation after repeated intravitreal injections in order to establish the adequate treatment.

Diabetic macular edema is a relevant ocular disease associated with diabetes mellitus that constitutes a concerning global health issue. This disease is one of the main causes of reversible blindness in industrialized countries, despite the availability of effective health interventions. This macular disorder is a consequence of the appearance of abnormal fluid regions within the main tissues of the retina that significantly decrease the patient's visual acuity. These fluid accumulations are also known as macular edemas (MEs). In this chapter, we present a computational methodology for the identification and clinical classification of ME using optical coherence tomography (OCT) scans, following the clinical classification of reference in the ophthalmological field. The presented system was tested with a dataset composed of 170 OCT scans retrieved from different patients that were labeled by a clinical expert. The presented system obtained satisfactory results in the localization of the area affected by each type of ME, even when they are combined in the same region of the retina. This fully automatic tool has demonstrated to be very useful not only for patients (helping in the early diagnosis of diseases that, consequently, improve their quality of life and well-being), but also in clinical systems by reducing costs.

The assessment of vascular biomarkers and their correlation with visual acuity is one of the most important issues in the diagnosis and follow-up of retinal vein occlusions (RVOs). The high workloads of clinical practice make it necessary to have a fast, objective, and automatic method to analyze image features and correlate them with visual function. The aim of this study is to propose a fully automatic system which is capable of estimating visual acuity (VA) in RVO eyes, based only on information obtained from macular optical coherence tomography angiography (OCTA) images. We also propose an automatic methodology to rapidly measure the foveal avascular zone (FAZ) area and the vascular density (VD) in the superficial and deep capillary plexuses in swept-source OCTA images centered on the fovea. The proposed methodology is validated using a representative sample of 133 visits of 50 RVO patients. Our methodology estimates VA with very high precision and is even more accurate when we integrate depth information, providing a high correlation index of 0.869 with the real VA, which outperforms the correlation index of 0.855 obtained when estimating VA from the data obtained by the semiautomatic existing method. In conclusion, the proposed method is the first computational system able to estimate VA in RVO, with the additional benefits of being automatic, less time-consuming, objective and more accurate. Furthermore, the proposed method is able to integrate depth information, a feature which is lacking in the existing method This work has received partial financial support from the Mutua Madrileña project, Ref. 2017/365 SI

Combined central retinal artery and vein occlusion is an uncommon vascular pathology that can cause severe and permanent visual impairment. Optical coherence tomography angiography (OCTA) is a newly available, noninvasive imaging technique that can potentially improve understanding of the structural and vascular implications and prognosis of this infrequent pathology. The present report describes the principal clinical findings in a case of combined central retinal artery and vein occlusion, as detected by the different imaging modalities available in a tertiary referral hospital. OCTA wide-field montage images identified an extensive area of nonperfusion on the macula with involvement of the entire retina at nearly 360°. We observed the most severe nonperfusion in the deep capillary plexus, while perfusion of the choriocapillaris was unaffected. Meanwhile, fluorescein angiography (FA) findings revealed a delay in perfusion rate with marked nonperfusion areas in the peripheral retina at 360°. We identified that the wide-field OCTA montage permitted visualization of a similar or wider peripheral retinal area compared with FA. Therefore, OCTA is potentially useful for assessment of the global retinal nonperfusion status at baseline and during follow-up, with the added advantage of being a noninvasive technique This work was supported in part by the Mutua Madrileña project (Ref. 2017/365) SI

Angiography by Optical Coherence Tomography (OCT-A) is a non-invasive retinal imaging modality of recent appearance that allows the visualization of the vascular structure at predefined depths based on the detection of the blood movement through the retinal vasculature. In this way, OCT-A images constitute a suitable scenario to analyze the retinal vascular properties of regions of interest as is the case of the macular area, measuring the characteristics of the foveal vascular and avascular zones. Extracted parameters of this region can be used as prognostic factors that determine if the patient suffers from certain pathologies (such as diabetic retinopathy or retinal vein occlusion, among others), indicating the associated pathological degree. The manual extraction of these biomedical parameters is a long, tedious and subjective process, introducing a significant intra and inter-expert variability, which penalizes the utility of the measurements. In addition, the absence of tools that automatically facilitate these calculations encourages the creation of computer-aided diagnosis frameworks that ease the doctor's work, increasing their productivity and making viable the use of this type of vascular biomarkers. In this work we propose a fully automatic system that identifies and precisely segments the region of the foveal avascular zone (FAZ) using a novel ophthalmological image modality as is OCT-A. The system combines different image processing techniques to firstly identify the region where the FAZ is contained and, secondly, proceed with the extraction of its precise contour. The system was validated using a representative set of 213 healthy and diabetic OCT-A images, providing accurate results with the best correlation with the manual measurements of two experts clinician of 0.93 as well as a Jaccard's index of 0.82 of the best experimental case in the experiments with healthy OCT-A images. The method also provided satisfactory results in diabetic OCT-A images, with a best correlation coefficient with the manual labeling of an expert clinician of 0.93 and a Jaccard's index of 0.83. This tool provides an accurate FAZ measurement with the desired objectivity and reproducibility, being very useful for the analysis of relevant vascular diseases through the study of the retinal micro-circulation.

A formulation of aflibercept for intravitreal injection (Eylea) is approved for the treatment of patients with exudative age-related macular degeneration (AMD). Aflibercept has a significantly higher affinity for Vascular endothelial growth factor (VEGF)-A compared with other monoclonal anti-VEGF antibodies. In addition to binding all VEGF-A isoforms, aflibercept also blocks other proangiogenic factors such as VEGF-B and placental growth factor. The VIEW 1 and 2 trials showed this drug achieves improved results in patients with exudative AMD similar to those obtained with monthly ranibizumab, using a bimonthly treatment regimen after a loading dose of three intravitreal injections, which translates to less use of healthcare resources. There is a subgroup of patients that present with persistent fluid after the loading dose that could benefit from monthly injections or personalized proactive treatment after the first year. In the second year of treatment, the Treat and Extend patterns can permit even more lengthening of the time between injections. More data are needed to confirm the optimal monitoring and retreatment dosing, to maintain long-term efficacy. Other preliminary data suggest that patients that do not respond to other anti-angiogenics and patients with special pathologies such as polypoidal choroidopathy or retinal angiomatous proliferation can improve upon switching to aflibercept. To date, the safety profile of aflibercept is excellent and is comparable to other anti-angiogenic treatments.

Objectives. To evaluate efficacy and safety of an aflibercept treat-and-extend (TAE) regimen in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO). Design, Setting, and Patients. Phase IV, prospective, open-label, single-arm trial in 11 Spanish hospitals. Treatment-naïve patients with Intervention. Intravitreal aflibercept 2 mg monthly (3 months) followed by proactive individualized dosing. Main Outcomes. Mean change in BCVA after 12 months. Results. 24 eyes (24 patients) were included; mean (SD) age: 62.8 (15.0) years; 54.2% male; median (IQR) time since diagnosis: 7.6 (3.0, 15.2) days. Mean BCVA scores significantly improved between baseline (56.0 (16.5)) and Month 12 (74.1 (17.6)); mean (95% CI) change: 14.8 (8.2, 21.4); P=0.0001. Twelve (50.0%) patients gained ≥15 ETDRS letters. Foveal thickness improved between baseline (mean: 569.4 (216.8) µm) and Month 12 (mean 257.4 (48.4) µm); P<0.0001. At Month 12, 8.3% patients had MO. The mean (SD) number of injections: 8.3 (3.0). No treatment-related AEs were reported. Five (20.8%) patients experienced ocular AEs. Two nonocular serious AEs were reported. Conclusions. An aflibercept TAE regimen improves visual acuity in patients with MO secondary to CRVO over 12 months with good tolerability.

We performed a systematic review and meta-analysis to determine whether the use of local antibiotics is a beneficial prophylactic treatment for endophthalmitis in patients treated with anti-VEGF agents. We searched the MEDLINE and EMBASE databases, and the Cochrane Library over the period January 2007 to December 2016. The search terms used included “Endophthalmitis”, “Antibiotic” and “Intravitreal injection”. Studies in which the patients were treated exclusively with intravitreal injections of anti-VEGF were selected. Eight studies fit the inclusion criteria, which included a total of 276,774 injections; 109,178 (39.45%) were associated with the use of antibiotics and 114,821 (60.55%) were not associated with the use of antibiotics. Our meta-analysis indicated a significant risk for endophthalmitis that was 1.70 times greater with the use of antibiotics than that without antibiotics, with a confidence interval of 1.08 to 2.66 (p = 0.02). A meta-regression indicated that the location (operating rooms versus outpatient clinics) of injection did not have a significant effect on the incidence of endophthalmitis. The prophylactic use of antibiotics when administering anti-VEGF intravitreal injections may contribute to a greater incidence of endophthalmitis. This finding, in addition to reducing costs, would eliminate a treatment that has been shown to be unnecessary and even harmful to patients.

Purpose To analyze the changes in retinal nerve fiber layer (RNFL) in eyes with and without prior history of optic neuritis (ON) of patients with multiple sclerosis (MS) after a 5-year time period (2010–2015) using optical coherence tomography. Methods The RNFL thickness of 114 eyes of 57 MS patients and 40 eyes of 20 healthy subjects were measured in year 2010 and year 2015. Measurements were made separately in twelve sectors around the optic nerve head. Statistical comparisons were made with the obtained data. Results Progressive RNFL thinning occurs with time in both MS patients (regardless the eye had history of ON or not) and in normal subjects. The baseline mean RNFL thickness in ON eyes of MS patients (year 2010) was 74.2 ± 15.7 µm and five years later was 68.7 ± 12.2 µm. The baseline mean RNFL thickness in eyes without ON of MS patients was 90.0 ± 11.1 µm and 84.7 ± 10.3 µm five years later. The median RNFL thickness reduction was 3.5 µm for ON eyes, 4.7 µm for eyes without ON, and 2.2 µm for control eyes. The RNFL thickness reduction rate was similar in eyes with history of ON that in those with no history of ON. On the contrary, the MS group had a significantly higher rate of reduction than the control group. Conclusions MS patients have thinner RNFL than normal controls, regardless their eyes had past episodes of ON or not. Eyes of MS patients lose their axons in a similar fashion regardless they had history of ON or not. Although ON causes RNFL loss, once resolved it does not influence the rate of RNFL loss in MS patients.

This work aimed at describing the time course of vitreous clearance through the use of positron emission tomography (PET) as a noninvasive tool for pharmacokinetic studies of intravitreal injection.The pharmacokinetic profile of intravitreal injections of molecules labeled with 18Fluorine (18F) was evaluated in adult Sprague Dawley rats by using a dedicated small-animal PET/computed tomography scanner. Different conditions were studied: three molecules radiolabeled with 18F (18F-FDG, 18F-NaF, and 18F-Choline), three volumes of intravitreal injections (7, 4, and 2 μL), and absence or presence of eye inflammation (uveitis).Our results showed that there are significant pharmacokinetic differences among the radiolabeled molecules studied but not among the injected volumes. The presence or absence of uveitis was an important factor in vitreous clearance, since the elimination of the drug was clearly increased when this condition is present.Intravitreal pharmacokinetic studies based on the use of dedicated PET imaging can be of potential interest as noninvasive tools in ophthalmic drug development in small animals.

The foveal avascular zone (FAZ) is the capillary-free area in the central macula with high photoreceptor density and metabolic activity. In the present study we measured the superficial and deep macular foveal avascular zone (sFAZ, dFAZ) in the eyes of healthy adults of both sexes of various ages ranging from 10 to 69 years using optical coherence tomography angiography (OCT-A) in order to evaluate the influence of gender and age on FAZ size. A cross-sectional study was carried out in 240 eyes of 120 healthy subjects, OCT-A was performed by means of a Topcon swept source OCT. sFAZ and dFAZ areas were measured using the IMAGEnet6 software package. Subjects were grouped by age (six groups) and gender. The mean ± sd age of the subjects was 39.2 ± 17.4 years (50% women, 50% men), ranging from 10 to 69 years. The overall mean sFAZ size in women (0.297 ± 0.110 mm2) was significantly larger (p = 0.002) than in men (0.254 ± 0.098 mm2). Similarly, the overall mean dFAZ in women (0.322 ± 0.111 mm2) was significantly larger (p In conclusion for both sFAZ and dFAZ, women have larger areas than men, but this occurs only in the young and old age groups. In men, age does not seem to influence the size of the FAZ, but in women, both sFAZ and dFAZ were significantly smaller in younger than in older ages. These results suggest that retinal changes in retinal structure caused by aging may be different in woman than in men, probably reflecting the more hormonal variations known to exist with age in women.

Ocriplasmin is a human plasmin fragment indicated for vitreomacular traction treatment. With its increasing use, several reported cases have suggested possible toxicity to the retina.We describe a case of a 55-year-old woman with symptomatic vitreomacular traction and a macular hole in the right eye who showed an acute decrease in visual acuity after an intravitreal ocriplasmin injection. Spectral-domain optical coherence tomography showed an alteration in the ellipsoid layer. Significant retinal vessel constriction was observed by angiography. The visual acuity improved to 20/100, and the electroretinogram progressively improved after the 1-year follow-up and following pars plana vitrectomy.A decrease in visual acuity and an enlargement of the macular hole were observed while studying this patient. This study shows the recovery of adverse effects caused by intravitreal injection of ocriplasmin for 1-year follow-up.

Luis Arias,1–3 Francisco Gómez-Ulla,2–4 José M Ruiz-Moreno2,3,51Ophthalmology Department, Bellvitge University Hospital, C/Feixa Llarga, L’Hospitalet de Llobregat, Barcelona, 2Spanish Vitreoretinal Society (SERV), C/Xosé Chao Rego, Santiago de Compostela, 3RETICS OFTARED, Institute of Health Carlos III, C/Sinesio Delgado, Madrid, 4Gómez-Ulla Eye Institute, Santiago de Compostela, 5Department of Ophthalmology, Albacete University Hospital, Avenida de Almansa s/n, Albacete, Spain Purpose: To compare the effects of intravitreal ranibizumab in monotherapy (group A) and combined with photodynamic therapy (PDT) with verteporfin (group B) in retinal angiomatous proliferation (RAP) treatment.Methods: This was a multicentric, prospective, randomized clinical study conducted with parallel groups. The study eye in both groups received ranibizumab on days 1, 30, and 60 (loading dose); group B received PDT additionally on day 1. Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) testing and optical coherence tomography were performed monthly, and fluorescein angiography and indocyanine green angiography were performed quarterly. Retreatment criteria were leakage in fluorescein angiography or indocyanine green angiography, mean foveal thickness increase≥100 µm, or VA decrease ≥5 letters.Results: Twenty patients were recruited (ten patients in each group). Six eyes had previous treatment (three eyes in group A and three eyes in group B), so only 14 eyes were naïve. At 12-month follow-up, mean VA improved +1.5 letters in group A and +5.6 letters in group B (analysis of variance test; P>0.05). Two patients (20%) in both groups gained ≥15 letters (chi-square test; P>0.05). Mean changes in greatest linear dimension and in foveal thickness were not statistically significant between groups of treatment (analysis of variance test; P>0.05). Mean retreatments per patient were 1.8 (group A) and 0.9 (group B) (Mann–Whitney U-test; P>0.05). One patient died due to underlying disease not related to study medication.Conclusion: Intravitreal ranibizumab administered in monotherapy or combined with PDT was efficacious in terms of VA stabilization in patients with RAP.Keywords: age-related macular degeneration, intravitreal injection, photodynamic therapy, ranibizumab, retinal angiomatous proliferation, verteporfin