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Purpose Determine associations between early residual fluid (ERF)-free status and improved long-term visual outcomes. Design Clinical cohort study from post hoc analysis of two phase 3 clinical trials’ data. Methods Independent of treatment allocation, patients from the multicenter, prospective, randomized, double-masked HAWK and HARRIER trials who received either brolucizumab 6 mg or aflibercept 2 mg were split into two cohorts dependent on presence or absence of ERF at week 12. Additionally, similar analyses were performed on presence or absence of early residual intraretinal fluid (IRF) and subretinal fluid (SRF) at week 12. The two groups, ERF-free (N=1051) and ERF (N=366) were compared. Changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST) were determined. Results From week 12 to 96, patients who were ERF-free had greater least square (LS) mean increases from baseline for BCVA and CST compared to ERF patients. Greater LS mean differences in BCVA from week 12 to 96 were noted between ERF-free and ERF patients. A greater proportion of patients in the ERF-free cohort reported a ≥5, ≥10, or ≥15 letter improvement and a higher proportion reported BCVA ≥70 letters from baseline to week 96 compared to those with fluid. Conclusions Improvements in visual outcomes in ERF-free patients were greater than in ERF patients occurring as early as 4 weeks (week 12) following the last loading dose and continued to week 96. Therefore, ERF status may be a useful indicator of anti-vascular endothelial growth factor treatment response.

Anti-vascular endothelial growth factor (anti-VEGF) therapies have become the standard of care in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), resulting in a remarkable decrease in disease-related vision loss. However, the need for regular injections places a significant burden on patients, caregivers, and the healthcare system and improvements in vision may not be maintained long term. As a result of its drying potency and duration of action, brolucizumab, an intravitreal anti-VEGF therapy approved for the treatment of nAMD and DME, could decrease injection frequency for patients and provide an efficacious treatment; however, balancing its benefits and risks can be challenging. There have been reports of intraocular inflammation (IOI) in patients treated with brolucizumab, which, if left untreated, may result in severe vision loss. Recent evidence, however, indicates that early recognition of IOI and prompt and aggressive systemic corticosteroid treatment in response to posterior segment involvement can lead to favorable outcomes in these relatively rare but severe cases. A series of consensus meetings were conducted in 2022 between Swiss medical retina experts and diabetologists, discussing the current data for brolucizumab and exploring various challenges to its use, including the associated risk of IOI. The outcome is a collation of practical insights and guidance for ophthalmologists on the use of brolucizumab in patients with nAMD and DME, including patient selection and assessment, treatment regimen and monitoring, and the recognition and management of adverse events.

Objective: we present a portable automatic kinetic perimeter based on a virtual reality (VR) headset device as innovative and alternative solution for the screening visual field clinical examination. We compared the performances of our solution with a gold standard perimeter, validating the test on healthy subjects. Methods: The system is composed by an Oculus Quest 2 as VR headset with a clicker for participant response feedback. An Android app was designed in Unity to generate moving stimuli along vectors, following a standard Goldmann kinetic perimetry approach. Sensitivity thresholds are obtained by moving centripetally three different targets (V/4e, IV/1e, III/1e) along 24 or 12 vectors from an area of non-seeing to an area of seeing and then transmitted wirelessly to a PC. A Python real-time algorithm processes the incoming kinetic results and displays the hill of vision in a two-dimensional map (isopter). We involved 21 subjects (5 males and 16, age range 22–73 years) for a total of 42 eyes tested with our proposed solution and results were compared with a Humphrey visual field analyzer to test reproducibility and efficacy. Results: isopters generated with the Oculus headset were in good agreement with those acquired with a commercial device (Pearson’s correlation values r > 0.83 for each target). Conclusions: we demonstrate feasibility of VR kinetic perimetry comparing performances between our system and a clinically used perimeter in healthy subjects. Significance: proposed device leads the way for a portable and more accessible visual field test, overcoming challenges in current kinetic perimetry practices.

To report the clinical features and treatment outcomes of patients with macular hole coexistent with rhegmatogenous retinal detachment surgically treated with pars plana vitrectomy and inverted internal limiting membrane flap technique.Eleven consecutive patients with rhegmatogenous retinal detachment and macular hole who underwent vitrectomy and internal limiting membrane peeling with the inverted flap technique between December 2017 and February 2021 were retrospectively evaluated. The main outcome measures were retinal reattachment rate, macular hole closure rate, and postoperative best-corrected visual acuity. A nonsystematic literature review was performed to compare the study outcomes with those previously reported.The primary retinal reattachment rate was 90% (10/11) with one surgery and 100% with 2 surgical procedures. Macular hole closure was achieved in all patients (11/11). All patients showed an improvement in visual acuity at the final postoperative visit, and the mean postoperative best-corrected visual acuity was 0.60 ± 0.32 logarithm of the minimum angle of resolution (20/80 Snellen equivalent).Vitrectomy with the inverted internal limiting membrane flap technique achieved not only favorable anatomical retinal reattachment rates but also an encouraging recovery of central macular anatomy and visual function in patients with macular hole coexistent with rhegmatogenous retinal detachment.

Introduction: Since July 2021, a worldwide shortage of verteporfin (Visudyne (R)) occurred: an essential medicine required for photodynamic therapy (PDT). PDT with verteporfin has a broad range of indications in ophthalmology, including chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy and choroidal haemangioma. For these disorders, PDT is either the first-choice treatment or regarded as a major treatment option. Materials and methods: A questionnaire was sent to key opinion leaders in the field of medical retina throughout the world, to assess the role of PDT in their country and the effects of the shortage of verteporfin. In addition, information on the application of alternative treatments during shortage of verteporfin was obtained, to further assess the impact of the shortage. Results: Our questionnaire indicated that the shortage of verteporfin had a major impact on ophthalmic care worldwide and was regarded to be a serious problem by most of our respondents. However, even though there is ample evidence to support the use of PDT in several chorioretinal diseases, we found notable differences in its use in normal patient care throughout the world. Various alternative management strategies were noted during the verteporfin shortage, including lowering the dose of verteporfin per patient, the use of alternative treatment strategies and the use of a centralized system for allocating the remaining ampoules of verteporfin in some countries. Conclusion: The shortage of verteporfin has had a large effect on the care of ophthalmic patients across the world and may have resulted in significant and irreversible vision loss. Mitigation strategies should be developed in consultation with all stakeholders to avoid future medication shortages of verteporfin and other unique ophthalmic medications. These strategies may include mandatory stock keeping, compulsory licensing to an alternative manufacturer or incentivizing the development of competition, for example through novel public-private partnerships.

To investigate the visual and anatomical impact of intravitreal injection treatment deferral because of the COVID-19 lockdown on patients affected by neovascular age-related macular degeneration. We retrospectively reviewed 314 patients (394 eyes) who were scheduled to receive the impact of intravitreal injections during the Swiss lockdown. We compared patients who continued to receive scheduled impact of intravitreal treatment without clinical consultation (Group Continue ‟C"; n = 215) and patients for whom the impact of intravitreal treatment was completely deferred (Group Stop, ‟S"; n = 179). Functional and anatomical parameters were collected at four time points before and after the lockdown. In Group C, the visual acuity at baseline and after the lockdown did not differ significantly. In Group S, the visual acuity deteriorated significantly compared with baseline and then improved slightly after the resumption of treatment, but it did not recover to baseline values. The mean central subfield thickness remained stable in Group C, whereas it increased in Group S and then returned to prelockdown values after the resumption of treatment. An "injection-only" approach was effective in managing patients with neovascular age-related macular degeneration during the pandemic lockdown, whereas patients who deferred their scheduled treatment showed partially irreversible deterioration of visual function. We recommend treatment continuation in patients with neovascular age-related macular degeneration during a lockdown.

Purpose To describe a unique unilateral association between an iris stromal tumor and a macular focal choroidal excavation. Case Description A 40-year old patient presented with a small iris tumor associated with a unilateral macular lesion disclosed during a routine ophthalmologic examination. The patient was asymptomatic and visual function was not affected. After clinical and instrumental evaluation, a diagnosis of nonmelanocytic undefined stromal tumor of the iris associated with macular focal choroidal excavation was made. The size and shape of the two lesions remained stable during a 7-year follow-up and the patient did not develop other signs. Conclusion The concurrent presence of a stromal iris tumor associated with focal choroidal excavation has never been reported. Further reports of this association are required in order to understand its exact pathogenesis.

To investigate the neuroprotective effect of brimonidine after retinal ischemia damage on mouse eye. Glaucoma is an optic neuropathy characterized by retinal ganglion cells (RGCs) death, irreversible peripheral and central visual field loss, and high intraocular pressure. Ischemia reperfusion (I/R) injury model was used in C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mouse eyes were treated topically with brimonidine and pattern electroretinogram were used to assess the retinal ganglion cells (RGCs) function. A wide range of inflammatory markers, as well as anti-inflammatory and neurotrophic molecules, were investigated to figure out the potential protective effects of brimonidine in mouse retina. In particular, brain-derived neurotrophic factor (BDNF), IL-6, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor DR-5, TNF-α, GFAP, Iba-1, NOS, IL-1β and IL-10 were assessed in mouse retina that underwent to I/R insult with or without brimonidine treatment. Brimonidine provided remarkable RGCs protection in our paradigm. PERG amplitude values were significantly (p < 0.05) higher in brimonidine-treated eyes in comparison to I/R retinas. Retinal BDNF mRNA levels in the I/R group dropped significantly (p < 0.05) compared to the control group (normal mice); brimonidine treatment counteracted the downregulation of retinal BDNF mRNA in I/R eyes. Retinal inflammatory markers increased significantly (p < 0.05) in the I/R group and brimonidine treatment was able to revert that. The anti-inflammatory IL-10 decreased significantly (p < 0.05) after retinal I/R insult and increased significantly (p < 0.05) in the group treated with brimonidine. In conclusion, brimonidine was effective in preventing loss of function of RGCs and in regulating inflammatory biomarkers elicited by retinal I/R injury.

We report a case of central retinal artery occlusion (CRAO) in a patient with a previous history of severe COVID-19 disease. This disease has been associated with inflammatory-induced homeostasis changes leading to endothelial dysfunction and a procoagulant state with multi-organ involvement, but the burden of thromboembolic complications in COVID-19 patients is currently unknown. The pathogenesis of retinal artery occlusions is a multifactorial process where inflammation and hypercoagulation state are established risk factors. Even if our experience may represent a coincidental relationship, it is likely that COVID-19 patients could be at risk of developing retinal vascular occlusions. A focused ophthalmological surveillance is advisable to prevent and manage this possible cause of severe vision loss that has an important impact in health care system.

Modern ophthalmic surgery has reached very high safety standards. Yet, given the large number of ophthalmic procedures, medical errors are common in eye care. This chapter presents general safety issues in ophthalmic surgery and focuses on the most common procedures: cataract surgery and intravitreal injection therapy. The literature on the translation of safety strategies to ophthalmology is summarized alongside with guidance elaborated by professional and regulatory bodies that are of greatest importance in eye care. The perspective adopted in this chapter is largely that of ophthalmology trainees, who are asked to guide the progression of ophthalmology toward safer care.

The study aims to analyze the changes produced by half-dose photodynamic therapy (HD-PDT) in the choroid of eyes with chronic central serous chorioretinopathy (CSC) applying the binarization method to spectral domain optical coherence tomography (SDOCT) and OCT Angiography (OCTA) images. SDOCT and OCTA were performed before, one hour, one week, and one month after HD-PDT. Binarization with a modified Niblack method and analysis by ImageJ were applied. An average ratio between luminal part and total structure was calculated. Twenty-two eyes of 21 patients (20 male and 1 female, mean age 54.8 years) were enrolled. A statistically significant reduction of the central choroidal thickness was observed one week (from 407 &micro, m to 362 &micro, m, p = 0.034) and one month (from 407 &micro, m to 341.5 &micro, m, p = 0.0004) after HD-PDT. The baseline average ratio between luminal part and total structure was 33.4% in SDOCT, and 61.1% in OCTA. These values were 35.3% and 61% one hour, 33.9% and 60.4% one week, and 34.5% and 60.6% one month after HD-PDT, respectively. Overall, PDT seems to produce short-term changes on the luminal component of both choriocapillaris and choroid, which return to baseline status after one month from treatment. However, choroid stays significantly thinner after one month, with both luminal and interstitial components significantly reduced.

Aims To evaluate the timing and spectral-domain optical coherence tomography (SD-OCT) features of diabetic macular oedema (DME) recurrence according to baseline OCT patterns in patients treated with dexamethasone implant (DEX-I). Methods This is a retrospective observational study (72 eyes/65 patients). Best-corrected visual acuity, timing of DME recurrence, and SD-OCT pattern [intraretinal cysts (IRC), IRC plus subretinal fluid (mixed), external limiting membrane (ELM), ellipsoid (IS/OS) layer integrity] were assessed at baseline and monthly until first DME recurrence. Results Forty-two (58.3%) and 30 (41.6%) DME eyes had an IRC and mixed DME pattern at baseline, respectively. Twenty-four out of thirty mixed eyes (80%) relapsed without subretinal fluid. At baseline, mixed eyes showed similar changes in ELM and IS/OS (60 and 76.6% of eyes, respectively) versus IRC eyes (42.8 and 80.9% of eyes). After DME recurrence, more mixed eyes at baseline showed ELM and IS/OS changes (63.3 and 86.6%) than IRC eyes (50 and 76.2%). 33.3% of mixed eyes had DME recurrence at ≥ 6 months from first DEX-I implant versus 19% of IRC eyes. Conclusions Mixed DME eyes were treated with DEX-I relapse later and more frequently without subretinal fluid than IRC eyes. SD-OCT characteristics of different DME patterns at baseline can predict morphological features and timing of DME recurrence.

Purpose: To report clinical outcomes of two different timings of intravitreal dexamethasone (DEX) implant administration for prevention of diabetic macular oedema (DME) worsening following cataract surgery. Methods: This multicentre, retrospective study included patients with DME who received an intravitreal DEX implant 1month before cataract surgery, ‘precataract DEX’ group, or at the time of cataract surgery, ‘concomitant treatments’ group. Inclusion criteria were a follow-up ≥3months and ophthalmological examination with optical coherence tomography (OCT) imaging at baseline (cataract surgery) and throughout follow-up. Anatomical improvement was considered to be a decrease in OCT central subfield (CSF) thickness ≥20% compared to baseline. The primary outcomes were anatomical and functional results at 3months. Results: Two hundred twenty-one patients were included: 136 in the ‘precataract DEX’ group and 85 in the ‘concomitant treatments’ group. At 3months, a reduction of CSF thickness≥20% was found in 7.3% of eyes in the ‘precataract DEX group’ and in 83.7% of eyes in the ‘concomitant treatments’ group (p&nbsp

The authors report the clinical course of two cases of autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV). One patient presenting with a novel BEST1 mutation (c.658 C>T, p.Gln220*) underwent anti-vascular endothelial growth factor therapy. Response to treatment was documented on optical coherence tomography angiography (OCTA). Despite initial response to treatment, recurrent CNV exudation with progressive subretinal fibrosis was observed. In the second patient, the CNV was not treated and spontaneous regression was observed. This report indicates that the clinical course of CNV in ARB may vary considerably, ranging from spontaneous regression to progressive subretinal fibrosis despite intervention. [ Ophthalmic Surg Lasers Imaging Retina. 2018;49:888–892.]

Purpose To compare optical coherence tomography-angiography (OCT-A) performed during physical exercise (stress OCT-A) to the basal examination (rest OCT-A) in the imaging of choroidal neovascularization (CNV) in patients with chronic central serous chorioretinopathy (CSCR). Design Prospective, cohort study. Methods This multicenter study included 29 consecutive patients with chronic CSCR and flat irregular pigment epithelium detachments (FIPEDs). All patients underwent rest and stress OCT-A (i.e., hand-grip test [HGT]). Systemic hemodynamic data were recorded during the examinations. Rest and stress OCT-A in the en-face and cross-sectional views were qualitatively compared to establish the degree of evidence of flow signals due to CNVs. The en-face angiograms underwent additional automated quantitative analysis to assess the rate of change in neovascular parameters during the stress condition. Results Blood pressure significantly increased during the HGT (P = 0.001). Considering both the en-face and the cross-sectional images, CNV was identified in 13 eyes with the rest OCT-A and in 22 eyes with the stress OCT-A (P = 0.001). Cross-sectional imaging was more sensitive than en-face imaging in detecting neovascular blood flow signals under both rest (P = 0.125) and stress (P = 0.001) conditions. The quantitative analysis showed a significantly greater neovascular area and fractal dimension on the stress OCT-A (P = 0.002). Conclusions Performing OCT-A during HGT enhances the sensitivity of the examination in detecting CNV in chronic CSCR. The increased neovascular perfusion following the induced increase of blood pressure is consistent with choroidal blood flow dysregulation in patients with CSCR and indicates new areas of discussion about CNV in this disease.

Purpose: To compare efficacy of treat and extend (T&E) versus fixed regimen treatment protocols in neovascular age-related macular degeneration (nAMD). Methods: Randomized clinical trials (RCTs) comparing T&E versus fixed regimen protocols for nAMD were systematically searched. Primary outcome was to compare the mean best corrected visual acuity (BCVA) change in T&E regimen versus fixed regimen. Secondary outcomes were change in the mean optical coherence tomography (OCT) central retinal thickness (CRT) and mean number of injections. Standardized mean difference (SMD) along with 95% confidence intervals (CIs) were calculated. Random-effect models were used for meta-analyses. Results: Four RCTs were included, with a total of 649 and 621 eyes in the T&E and fixed regimen cohort at 12 months, and 267 and 249 eyes at 24 months. Pooled analysis of mean BCVA change included all four RCTs at 12 months and two RCTs at 24 months, showing no difference between the two groups (12-month: SMD = 0.08, 95% CI: −0.20 to 0.35, p = 0.55; 24-month: SMD = 0.04, 95% CI: −0.13 to 0.21, p = 0.64). Pooled analysis of OCT CRT change at 12 months included three studies, showing no difference between the two groups (SMD = 0.03, 95% CI: −0.46 to 0.51, p = 0.91). Pooled analysis of mean injection number included all four RCTs at 12 months and two RCTs at 24 months, showing significant difference between the two groups (12-month: SMD = −1.11, 95% CI: −1.67 to −0.56, p Conclusion: A T&E regimen proved as effective as a fixed dosage regimen throughout a 24-month follow-up and with a lower number of injections.

Purpose: We present the case of a 22-year-old woman, diagnosed as having atypical hemolytic uremic syndrome with a hypertensive crisis, who presented a bilateral serous retinal detachment. Case Description: A 22-year-old woman, diagnosed as having atypical hemolytic uremic syndrome, was referred for blurred vision in both eyes, evolving over 7 days. Treatment including hemodialysis, plasma exchange, systemic steroids, antihypertensive medications and eculizumab was started 1 month prior to referral. At presentation, best-corrected visual acuity was 20/40 in the right eye and 20/25 in the left eye. Retinal examination revealed bilateral serous retinal detachment in the posterior pole and some small, flat, variably pigmented lesions. Optical coherence tomography confirmed marked serous retinal detachment in both eyes. Fluorescein and indocyanine green angiography was performed. Treatment for systemic hypertension was changed. Seven days later, dilated fundus examination and optical coherence tomography demonstrated a significant regression of the serous retinal detachment. Her visual acuity improves in both eyes at the last control, showing at fundus examination a complete resolution of the exudative detachment but a persistence of variable flat pigmented lesion. Conclusion: Although multiple organ systems are commonly affected in hemolytic uremic syndrome, ocular involvement has only been described in very few cases. Ocular manifestations in atypical hemolytic uremic syndrome include retinal, choroidal and vitreal hemorrhages, retina and/or ischemic signs. Bilateral serous retinal detachment may also be a sign of atypical hemolytic uremic syndrome or even the first manifestation of a hypertensive event.

Purpose To assess the safety and efficacy of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, administered in combination with the anti–vascular endothelial growth factor (VEGF) agent ranibizumab (Lucentis; Roche, Basel, Switzerland) compared with ranibizumab monotherapy in patients with neovascular age-related macular degeneration (nAMD). Design Phase IIb global, multicenter, randomized, prospective, double-masked, controlled superiority trial. Participants Four hundred forty-nine patients with treatment-naive nAMD. Methods Participants were randomized in a 1:1:1 ratio to 1 of the following 3 intravitreal treatment groups: E10030 0.3 mg in combination with ranibizumab 0.5 mg, E10030 1.5 mg in combination with ranibizumab 0.5 mg, and sham in combination with ranibizumab 0.5 mg (anti-VEGF monotherapy). Drugs were administered monthly in each of the groups for a total duration of 24 weeks. Main Outcome Measures The prespecified primary end point was the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy [ETDRS] letters) from baseline to 24 weeks. Results No significant safety issues were observed in any treatment group. The E10030 (1.5 mg) combination therapy regimen met the prespecified primary end point of superiority in mean VA gain compared with anti-VEGF monotherapy (10.6 compared with 6.5 ETDRS letters at week 24; P = 0.019). A dose-response relationship was evident at each measured time point commencing at 4 weeks. Visual acuity outcomes favored the E10030 1.5 mg combination therapy group regardless of baseline VA, lesion size, or central subfield thickness on optical coherence tomography. All clinically relevant treatment end points of visual benefit (≥15 ETDRS letter gain, final VA ≥20/40 or ≥20/25) and visual loss (≥1 ETDRS line loss, ≥2 ETDRS line loss, final VA ≤20/125 or ≤20/200) favored the E10030 1.5 mg combination group. Conclusions In this phase IIb clinical trial, a 62% relative benefit from baseline was noted in the E10030 1.5 mg combination therapy group compared with the anti-VEGF monotherapy group. A favorable safety and efficacy profile of E10030 combination therapy for nAMD was evident across multiple clinically relevant end points. This highly powered study provides strong rationale for a confirmatory phase III clinical trial.

Technological advances in ophthalmology are becoming more and more important. New imaging instruments and software analysis allow ultra-wide field visualization of the retina non-invasively. This creates important clinical advantages for an aging population affected by chronic pathologies such as cataract, age related macular degeneration, and diabetic retinopathy. In particular, it will be possible to organize screening programs and an individualized approach and follow up of the patients. While new retinal implants are under development a new drug is now available for the treatment of corneal scars.La technologie devient de plus en plus présente dans l’ophtalmologie. Les nouvelles modalités d’imagerie ainsi que les analyses automatisées permettent une visualisation de la rétine à haute résolution et à grand champ de façon non invasive. Les avantages du point de vue clinique pour la population qui vieillit et qui présente des pathologies chroniques (cataracte, dégénérescence maculaire liée à l’âge, rétinopathie diabétique) sont immédiats : organisation de dépistage et prise en charge individualisée des patients. Les développements des implants rétiniens progressent et un nouveau traitement pour les cicatrices cornéennes est désormais disponible.

Diabetic retinopathy (DR) is a secondary complication of diabetes. DR can cause irreversible blindness, and its pathogenesis is considered multifactorial. DR can progress from non-proliferative DR to proliferative DR, characterized by retinal neovascularization. The main cause of vision loss in diabetic patients is diabetic macular edema, caused by vessel leakage and blood retinal barrier breakdown. Currently, aflibercept is an anti-VEGF approved for diabetic macular edema. Aflibercept can bind several members of vascular permeability factors, namely VEGF-A, B, and PlGF. We analyzed the aflibercept-PlGF complex at molecular level, through an in silico approach. In order to explore the role of PlGF in DR, we treated primary human retinal endothelial cells (HRECs) and mouse retinal epithelial cells (RPEs) with aflibercept and an anti-PlGF antibody. We explored the hypothesis that aflibercept has anti-inflammatory action through blocking of PlGF signaling and the ERK axis in an in vitro and in vivo model of DR. Both aflibercept and the anti-PlGF antibody exerted protective effects on retinal cells, by inhibition of the ERK pathway. Moreover, aflibercept significantly decreased (p < 0.05) the expression of TNF-? in an in vitro and in vivo model of DR. Therefore, our data suggest that inhibition of PlGF signaling, or a selective blocking, may be useful in the management of early phases of DR when the inflammatory process is largely involved.

To evaluate criteria driving retreatment with ranibizumab in Italian patients with myopic choroidal neovascularization (mCNV). OLIMPIC was a 12-month, phase IIIb, open-label study. Patients with active mCNV were treated with ranibizumab 0.5 mg according to the European label. The study assessed local criteria in Italy driving retreatment decisions with ranibizumab; and the efficacy, safety, and tolerability of ranibizumab. The mean (standard deviation [SD]) age of treated patients (N = 200) was 61.8 (12.7) years; range 22–85 years. The multivariate regression model indicated that presence of active leakage (odds ratio [OR] 95% confidence interval [CI]: 11.30 [1.03–124.14]), presence of intraretinal fluid (OR [95%CI]: 28.21 [1.55–513.73]), and an improvement in best-corrected visual acuity (BCVA) from baseline

Controversy still exists regarding the role of the TGF-β in neovascular age-related macular degeneration (nAMD), a major cause of severe visual loss in the elderly in developed countries. Here, we measured the concentrations of active TGF-β1, TGF-β2, and TGF-β3 by ELISA in the aqueous humor of 20 patients affected by nAMD, who received 3 consecutive monthly intravitreal injections of anti-VEGF-A antibody. Samples were collected at baseline (before the first injection), month 1 (before the second injection), and month 2 (before the third injection). The same samples were used in a luciferase-based reporter assay to test the TGF-β pathway activation. Active TGF-β1 concentrations in the aqueous humor were below the minimum detectable dose. Active TGF-β2 concentrations were significantly lower at baseline and at month 1, compared to controls. No significant differences in active TGF-β3 concentration were found among the sample groups. Moreover, TGF-β pathway activation was significantly lower at baseline compared to controls. Our data corroborate an anti-angiogenic role for TGF-β2 in nAMD. This should be considered from the perspective of a therapy using TGF-β inhibitors.

Age-related Macular Degeneration (AMD) represents one of the most sight-threatening diseases in developed countries that substantially impacts the patients' lifestyle by compromising everyday activities, such as reading and driving. In this context, understanding the prevalence, burden, and population-specific risk/protective factors of AMD is essential for adequate health care planning and provision. Our work aimed to characterize exudative AMD in Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking and dietary habits) which are specific for the onset of disease. Our study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects. In particular, the sample cohort has been subjected to a large genotyping analysis of 20 genetic variants which are known to be associated with AMD among European and Asiatic populations. This analysis revealed that 8 genetic variants (CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA and COL8A1) were significantly associated with AMD susceptibility. Successively, we performed a multivariate analysis, considering both genetic and non-genetic data available for our sample cohort. The multivariate analysis showed that age, smoking, dietary habits and sex, together with the genetic variants, were significantly associated with AMD in our population. Altogether, these data represent a starting point for the set-up of adequate preventive and personalized strategies aimed to decrease the burden of disease and improve the patients' quality of life.

Purpose To investigate the retinal vascular response to the isometric exercise in patients with central serous chorioretinopathy (CSCR) by using optical coherence tomography angiography (OCT-A). Methods This was a multicenter case-control study including 35 CSCR patients and 25 age-matched healthy controls. All subjects underwent macular OCT-A scans in resting conditions and during a handgrip isometric exercise. Hemodynamic data, such as systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and ocular perfusion pressure (OPP), were recorded at baseline and during the stress test. Qualitative and quantitative assessments of the retinal superficial capillary plexus (SCP) and deep capillary plexus (DCP) were performed on OCT angiograms. The results obtained in CSCR patients were then compared with those of healthy subjects. Results At baseline and during the isometric exercise, SBP, DBP, MAP, and OPP were significantly higher (P < 0.05) in CSCR patients than controls. Under stress conditions, the hemodynamic values significantly increased both in patients and controls. The qualitative and quantitative analyses of OCT angiograms evidenced an increased blood flow during exercise only in CSCR patients. Baseline vascular perfusion density (VPD) values of SCP and DCP were significantly lower (P < 0.05) in CSCR cases than in healthy subjects. A significant increase (P < 0.05) of VPD values was obtained during the exercise in CSCR patients and not in controls. Conclusions Unlike healthy subjects, retinal blood flow in patients with CSCR seems affected by rapid increases in BP and OPP. Our study suggests that the autoregulatory mechanisms controlling retinal microcirculation are not entirely able to counteract overperfusion in patients with CSCR.

International audience; Here we report novel mutations in ABCA4 with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment (p = 0.002) and an earlier age of onset (p = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of ABCA4 underlying Stargardt disease.

We report results of DNA analysis with next generation sequencing (NGS) of 21 consecutive Italian patients from 17 unrelated families with clinical diagnosis of Usher syndrome (4 USH1 and 17 USH2) searching for mutations in 11 genes: MYO7A, CDH23, PCDH15, USH1C, USH1G, USH2A, ADGVR1, DFNB31, CLRN1, PDZD7, HARS. Likely causative mutations were found in all patients: 25 pathogenic variants, 18 previously reported and 7 novel, were identified in three genes (USH2A, MYO7A, ADGRV1). All USH1 presented biallelic MYO7A mutations, one USH2 exhibited ADGRV1 mutations, whereas 16 USH2 displayed USH2A mutations. USH1 patients experienced hearing problems very early in life, followed by visual impairment at 1, 4 and 6 years. Visual symptoms were noticed at age 20 in a patient with homozygous novel MYO7A missense mutation c.849G > A. USH2 patients’ auditory symptoms, instead, arose between 11 months and 14 years, while visual impairment occurred later on. A homozygous c.5933_5940del;5950_5960dup in USH2A was detected in one patient with early deafness. One patient with homozygous deletion from exon 23 to 32 in USH2A suffered early visual symptoms. Therefore, the type of mutation in USH2A and MYO7A genes seems to affect the age at which both auditory and visual impairment occur in patients with USH.

Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies. Anti-VEGFs currently used to treat AMD included a monoclonal antibody (bevacizumab), an antibody fragments (ranibizumab), a fusion protein (aflibercept), and an aptamer (pegaptanib). The wide introduction of anti-VEGF therapy has led to an improvement in the prognosis of patients affected by AMD, with a consequent effects on the burden of care due to highly priced drugs, increasing patient numbers, and long-term disease chronicity. Aim of this review is to present an overview of available therapeutic strategies in AMD in term of clinical efficacy and economic sustainability.

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International audience; Age related macular degeneration (AMD) is a complex multifactorial disease caused by the interplay of age and genetic and environmental risk factors. A common feature observed in early and both forms of late AMD is the breakdown of the physiologically immunosuppressive subretinal environment and the protracted accumulation of mononuclear phagocytes (MP). We here discuss the origin and nature of subretinal MPs, the mechanisms that lead to their accumulation, the inflammatory mediators they produce as well as the consequences of their chronic presence on photoreceptors, retinal pigment epithelium and choroid. Recent advances highlight how both genetic and environmental risk factors directly promote subretinal inflammation and tip the balance from a beneficial inflammation that helps control debris accumulation to detrimental chronic inflammation and destructive late AMD. Finally, we discuss how changes in life style or pharmacological intervention can help to break the vicious cycle of inflammation and degeneration, restore the immunosuppressive properties of the subretinal space, and reestablish homeostasis.

ClC-2 is a plasma membrane chloride channel with widespread expression in the human body, including the brain. Its function is still being studied, although it is thought to have a role in ion and water homoeostasis in the brain. ClC-2 is part of a complex containing GlialCAM and MLC1. Both these genes are associated with autosomal recessive human leukodystrophies with intramyelinic oedema. Biallelic mutations in CLCN2 , encoding the ClC-2 channel, have been reported in patients with a rare form of leukoencephalopathy with ataxia (LKPAT; MIM #615651). No peculiar neurological features have been reported for this disease, although slight visual impairment due to chorioretinopathy or optic atrophy, mild ataxia, learning disabilities, and headaches are recurrent symptoms in patients. However, MRI shows a typical diagnostic pattern that consists of white matter signal abnormalities in the posterior limbs of the internal capsules, cerebral peduncles, pontine pyramidal tracts and in the middle cerebellar peduncles, associated with lower apparent diffusion coefficient values in most cases. Specific anomalies of brainstem auditory evoked potentials (BAEP) have also been described.1–3 Here, we report on a 52-year-old Moroccan woman presenting with mild and asymptomatic bilateral optic atrophy detected at a routine ophthalmological examination for presbyopia. Best-corrected high-contrast visual acuity was 20/20 in both eyes. Anterior segment and intraocular pressures were normal, and pupillary reflexes were present. On fundus biomicroscopy, mild pallor and excavation of the optic …

Recent developments in vitreoretinal surgery have increased the need for suitable vitreous substitutes. A successful substitute should maintain all the physical and biochemical properties of the original vitreous, be easy to manipulate, and be long lasting. Substitutes can be gaseous or liquid, both of which have associated advantages and disadvantages related to their physical properties and use. Furthermore, new surgical techniques with smaller vitreoretinal instruments have driven the use of more viscous substitutes. In this review, we analyze and discuss the most frequently used vitreous substitutes and look ahead to future alternatives. We classify these compounds based on their composition and structure, discuss their clinical use with respect to their associated advantages and disadvantages, and analyze how new vitreoretinal surgical techniques have modified their use.

Purpose To measure macular pigment (MP) and find possible correlation between heterochromatic flicker photometry (HFP) and quantitative autofluorescence (qAF) in young healthy subjects. Methods We enrolled 80 eyes of 40 young healthy subjects. Macular pigment optical density (MPOD) was automatically calculated with a macular pigment screener (MPS; MPODHFP). We calculated qAF comparing gray levels (GL) of qAF images with GL of internal reference of a confocal scanning laser ophthalmoscopy. A raster of concentric rings was used to automatically calculate foveal qAF (qAFF) values (0°-1.2°); inner ring (1.3°-4.3°; qAF3); middle ring (4.5°-7°; qAF6); and outer ring (7.2°-9.7°; qAF8). The test-retest coefficient of repeatability was calculated with Bland-Altman method. The between-eyes coefficient of agreement and correlation between the two techniques were calculated. Finally, an estimation of MPOD from qAF was performed (MPOD-AF), to find possible direct correlations with MPODHFP obtained with the MPS II. Results Paired data sets of repeated measurements were not statistically different for MPS II (P = 0.66); log qAFF (P = 0.95); log qAF3 (P = 0.48); log qAF6 (P = 0.4); and log qAF8 (P = 0.56). Stepwise regression analysis showed negative correlation between MPS II and log qAFF values (R2 = 0.35) with Spearman coefficient (ρ) of -0.60 (P < 0.01) and log qAF3 (R2 = 0.18; ρ = -0.38.; P < 0.01). No correlation was found between MPS II and log qAF6 (ρ = 0.01, P = 0.93), neither with log qAF8 (ρ = -0.05, P = 0.66). Conclusions In young healthy subjects, a negative correlation between qAF values and MPODHFP was found in the central degrees. However, qAF and HFP do not seem to be interchangeable: they represent two opposite ways of estimating MP.

Diabetic retinopathy is characterized by the breakdown of endothelial blood-retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE2 pathway, by blocking the effect of advanced glycation end-products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60μg/ml) or aflibercept (AFL, 40μg/ml), a VEGF-trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA2, an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE2 release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFκB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE2 pathway by reducing AGE-related signaling and downstream NFκB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX.

Purpose To compare the capability of indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCTA) in detecting choroidal neovascularization (CNV). Methods In this prospective study, patients with CNV detected with fluorescein angiography (FA) underwent ICGA and OCTA, spectral domain OCT (SD-OCT), and infrared or fundus color photographs. CNV lesions were outlined on ICGA and OCTA images, and the composition and size of the CNV was documented. Results One hundred eighty-two eyes were included. With ICGA, well-defined lesions were observed in 37.9%, partly defined in 44.5%, and undefined in 17% of eyes. On OCTA, well-defined, partly defined, and undefined vessels were observed in 53.8%, 27.5%, and 18.7% of eyes, respectively. There was a good correlation between CNV size measured with the two instruments (r = 0.84). However, OCTA underestimated CNV area by about 4.5% (slope coefficient with linear regression: 0.55, 95% confidence interval [CI]: 0.46 to 0.65; intercept: 0.27, 95% CI: -0.2 to 0.56). On ICGA, CNV composition was capillary in 28%, mature in 14.3%, and mixed (capillary and major neovascular complex) in 57.7% of eyes. Similarly, OCTA revealed capillary, mature, and mixed CNV in 28.9%, 15.9%, and 55.5% of eyes, respectively. Conclusions OCTA provides the clinician the ability to perform precise structural and vascular assessment of CNV noninvasively. Our study is, to our knowledge, the largest OCTA analysis to date of CNV secondary to neovascular AMD analyzed simultaneously by ICGA and OCTA.

Purpose To compare corneal astigmatism derived from total corneal refractive power (CA TCRP ), a ray-tracing method, with that derived from simulated keratometry (CA SimK ), an anterior surface–based method, in candidates for toric intraocular lens (IOL) implantation. Design Reliability analysis. Methods In 1 eye of 200 consecutive patients (mean age 71 ± 9 years) with cataract, a Pentacam HR (Oculus) was used to measure CA TCRP and CA SimK . Eyes with CA TCRP >1 diopter (D) were defined as candidates for toric IOL implantation. The estimation difference between CA TCRP and CA SimK was analyzed by calculating the arithmetic, absolute, and vector differences between the 2 methods. Results Seventy-seven candidates were identified. In the candidates, CA SimK was TCRP and CA SimK was 0.31 ± 0.29 D and 0.30 ± 0.29 D × 180 degrees, respectively. The absolute and vector differences between the 2 methods were >0.50 D in 21 of 77 (27.2%) and 25 of 77 (32.5%) eyes, respectively; the proportions were significantly ( P TCRP ≤1 D (0.8% and 9.8%, respectively). The difference in steep meridian alignment between CA TCRP and CA SimK was >5 degrees in 22.1% and >10 degrees in 2.6% of cases. Conclusion The difference between CA TCRP and CA SimK , as calculated by Pentacam HR, is greater in candidates for toric IOL implantation than in the general population. That difference considerably influences the candidate and toric IOL power selection in a large proportion of cases.

To assess the safety and efficacy of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, administered in combination with the anti-vascular endothelial growth factor (VEGF) agent ranibizumab (Lucentis; Roche, Basel, Switzerland) compared with ranibizumab monotherapy in patients with neovascular age-related macular degeneration (nAMD).Phase IIb global, multicenter, randomized, prospective, double-masked, controlled superiority trial.Four hundred forty-nine patients with treatment-naïve nAMD.Participants were randomized in a 1:1:1 ratio to 1 of the following 3 intravitreal treatment groups: E10030 0.3 mg in combination with ranibizumab 0.5 mg, E10030 1.5 mg in combination with ranibizumab 0.5 mg, and sham in combination with ranibizumab 0.5 mg (anti-VEGF monotherapy). Drugs were administered monthly in each of the groups for a total duration of 24 weeks.The prespecified primary end point was the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy [ETDRS] letters) from baseline to 24 weeks.No significant safety issues were observed in any treatment group. The E10030 (1.5 mg) combination therapy regimen met the prespecified primary end point of superiority in mean VA gain compared with anti-VEGF monotherapy (10.6 compared with 6.5 ETDRS letters at week 24; P = 0.019). A dose-response relationship was evident at each measured time point commencing at 4 weeks. Visual acuity outcomes favored the E10030 1.5 mg combination therapy group regardless of baseline VA, lesion size, or central subfield thickness on optical coherence tomography. All clinically relevant treatment end points of visual benefit (≥15 ETDRS letter gain, final VA ≥20/40 or ≥20/25) and visual loss (≥1 ETDRS line loss, ≥2 ETDRS line loss, final VA ≤20/125 or ≤20/200) favored the E10030 1.5 mg combination group.In this phase IIb clinical trial, a 62% relative benefit from baseline was noted in the E10030 1.5 mg combination therapy group compared with the anti-VEGF monotherapy group. A favorable safety and efficacy profile of E10030 combination therapy for nAMD was evident across multiple clinically relevant end points. This highly powered study provides strong rationale for a confirmatory phase III clinical trial.