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Background With increasing experience using anti-VEGF therapy for the treatment of neovascular age-related macular degeneration (nAMD), ophthalmologists have shifted away from a “one size fits all” to an “individualised” approach based on disease activity with the aim of achieving a fluid-free retina. The FLUID study investigates the non-inferiority of a Treat and Extend (T&E) protocol of 0.5 mg ranibizumab, which allows treatment extension in the presence of incomplete resolution of sub-retinal fluid (SRF) ≤200 μm at the foveal centre relative to a T&E protocol that requires complete resolution of all retinal fluid (i.e., both SRF and intra-retinal fluid [IRF]) in patients with nAMD. Methods/Design This 24 month, randomised, phase IV trial has completed recruitment of treatment-naïve patients randomised 1:1 to ranibizumab “intensive” treatment (complete resolution of IRF and SRF) or ranibizumab “relaxed” treatment (resolution of IRF or >200 μm SRF only at foveal centre). Patients in both arms follow a T&E regimen where extension decisions are based upon assessment of lesion activity: loss of ≥5 letters of visual acuity, new haemorrhage, presence of IRF and SRF on an optical coherence tomography (OCT) scan. The determination of SRF is conducted at a reading centre while the assessment of IRF is physician-determined. The primary endpoint is the mean change in best-corrected visual acuity (BCVA) from baseline to 24 months. Secondary endpoints include the mean change in central retinal thickness (CRT) from baseline to 12 and 24 months, the number of ranibizumab injections administered at 12 and 24 months, and the pharmacogenomic assessment of AMD Gene Consortium-identified single-nucleotide polymorphisms (SNPs) and their association with treatment response. Three hundred and forty seven (347) patients have been recruited by 16 Australian sites within approximately 16 months. A protocol to adjudicate on SRF has been established by the central reading centre and is demonstrating good concordance with investigator assessment. Discussion This study will provide important insights into retreatment criteria for managing nAMD using a T&E regimen. The current paper describes the clinical rationale for using a less intensive treatment approach using ranibizumab and details of the treatment protocol. Trial registration Trial registration number: NCT01972789 . Date of registration: 24th October 2013.

Neovascular age-related macular degeneration (nAMD) is associated with considerable quality of life and economic burden. nAMD is characterized by pathological neovascularization, leading to the accumulation of retinal fluid. Intraretinal fluid (IRF) is a major contributor to vision loss and may predict response to treatment. In contrast, the role of subretinal fluid (SRF) is less clear. Nevertheless, complete resolution of retinal fluid accumulation is often stated to be a key goal of therapy for nAMD, even though some eyes may never achieve a fluid-free macula despite regular anti-vascular endothelial growth factor treatment. In this article, we review the current literature regarding the role of retinal fluid in nAMD disease outcomes and assess whether and when it may be beneficial to leave retinal fluid untreated. In this context, we highlight the importance of correctly identifying retinal fluid types in nAMD and avoiding confusion with other optical coherence tomography signs that may respond differently to therapy, such as subretinal pseudocysts. Current evidence shows that IRF is associated with poor outcomes and an increased risk of developing atrophy and fibrosis; resolution of this retinal fluid type should remain a treatment target. However, the literature around SRF indicates that low levels of this fluid type, potentially up to 150–200 µm in thickness, may be tolerated with minimal impact on vision, and that SRF could be protective against the development and progression of macular atrophy and fibrosis. Although mild SRF may be protective in nAMD, cause and effect between SRF and reduced or slowed atrophy has not yet been proven and requires further research. Treatment should be given for the most aggressive component; when both IRF and SRF are present, treatment should be given for IRF. Plain Language Summary Neovascular age-related macular degeneration (nAMD) is a progressive eye disease and a major cause of vision loss. In nAMD, new blood vessels grow into the light-sensitive layer at the back of the eye called the retina and can leak fluid. Fluid leaked into the retina is known as intraretinal fluid, and behind the retina is known as subretinal fluid. It is known that intraretinal fluid contributes to vision loss, but the impact of subretinal fluid is less clear. One aim of treatment for nAMD is to dry up retinal fluid, but in some eyes, this treatment is ineffective. This article summarizes previous research on identifying retinal fluid, the effect of retinal fluid on nAMD progression, and how the presence of retinal fluid impacts how patients respond to nAMD treatment. Findings from previous research showed that compared with eyes without intraretinal fluid, eyes with intraretinal fluid have worse vision, and this is more likely to decline further over time. Therefore, treatment should aim to dry up intraretinal fluid. Interestingly, the literature also suggested that a low level of subretinal fluid has little impact on vision and might even protect against nAMD worsening. The impact of mild subretinal fluid has not been proven yet and requires further study. Therefore, when both intraretinal fluid and subretinal fluid are present, treatment should be given for intraretinal fluid.

PurposeTo evaluate the relationship between retinal fluid location, amount/severity, and vision with ranibizumab-treated neovascular age-related macular degeneration (nAMD).MethodsIn the phase 3 HARBOR trial (NCT00891735), treatment-naive patients with nAMD received ranibizumab 0.5 or 2.0 mg through month 24. This post hoc analysis included eyes with subretinal fluid (SRF) and/or intraretinal fluid (IRF) at screening, baseline, or week 1, and optical coherence tomography data at months 12 and 24 (n = 917). Outcomes were best-corrected visual acuity (BCVA) change from baseline and proportion of eyes with 20/40 or better vision at months 12 and 24. Eyes were stratified by the location, amount, and/or severity of fluid.ResultsAt baseline, 86% and 63% of eyes had SRF and IRF, respectively. Among eyes with residual SRF, mean BCVA gains at each time point were greater in eyes with central versus noncentral SRF; location did not affect the odds of having 20/40 or better vision over 24 months. Eyes with 20/40 or better BCVA at month 12 had significantly lower SRF thickness versus eyes with worse vision; however, no difference was apparent at month 24. Vision was comparatively worse in eyes with residual IRF at months 12 and 24; location and severity did not appear to affect this outcome.ConclusionResidual IRF was associated with worse vision outcomes, regardless of location/severity, whereas, despite continued treatment, residual SRF was not associated with worse vision outcome at 24 months, regardless of location/thickness. These data suggest complex relationships between residual fluid, severity, and vision.

In an aging population, the prevalence and burden of diabetes mellitus, diabetic retinopathy, and vision-threatening diabetic macular edema (DME) are only expected to rise around the world. Similarly to other complications of diabetes mellitus, DME requires long-term management. This article aims to review the current challenges associated with the long-term management of DME, opportunities to improve outcomes for patients, and to develop a treat-to-target strategy based on macular morphology. At present, intravitreal anti–vascular endothelial growth factor (VEGF) therapy is the standard of care for the management of DME; however, best-achievable vision outcomes with treatment are reliant on frequent injections and close monitoring, which are difficult to maintain in current clinical practice because of the burden this imposes on patients. Achieving and maintaining good vision with treatment are the most important factors for patients with DME. Landmark trials have shown that vision gains with anti-VEGF therapy are typically accompanied by anatomical improvements (e.g., reductions in retinal thickness); therefore, multimodal imaging measures of macular morphology are often used in patients with DME to guide real-world treatment decisions. We would like to propose a hypothetical treat-to-target algorithm to guide physicians on treatment strategies for the long-term management of DME. Alternative measures of retinal fluid (e.g., persistence, stability, location) may be stronger predictors of visual acuity in DME, although further research is required to confirm whether alternate quantifiable biomarkers such as subretinal fluid and intraretinal fluid volumes can be used as a biomarker of clinical improvement. Identifying novel biomarkers and treatments that target neuroinflammation and neurodegeneration, improving patient-physician communication around treatment adherence, and using treat-to-target measures may help to ensure that the long-term benefits of treatment are realized. Key messages What is known: • Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for patients with diabetic macular edema (DME); however, the burden of frequent injections is a key reason why real-world vision outcomes are often inferior to those reported in clinical trials. • There is increasing evidence that the persistence, stability, and location of retinal fluid may be stronger predictors of visual acuity in DME; and that achieving rapid, stable, and sustained fluid control with anti-VEGF treatment could be an important treatment goal with the aim of improving longer-term outcomes. What is new : • A hypothetical treat-to-target algorithm to guide physicians on treatment paths for the long-term management of DME was proposed. • Introducing a treat-to-target strategy, which sets treatment targets based on factors such as intraretinal fluid volume, and involves selecting customized treatment regimens and conducting regular assessments, could improve the future management of DME.

With non-invasive and high-resolution properties, optical coherence tomography (OCT) has been widely used as a retinal imaging modality for the effective diagnosis of ophthalmic diseases. The retinal fluid is often segmented by medical experts as a pivotal biomarker to assist in the clinical diagnosis of age-related macular diseases, diabetic macular edema, and retinal vein occlusion. In recent years, the advanced machine learning methods, such as deep learning paradigms, have attracted more and more attention from academia in the retinal fluid segmentation applications. The automatic retinal fluid segmentation based on deep learning can improve the semantic segmentation accuracy and efficiency of macular change analysis, which has potential clinical implications for ophthalmic pathology detection. This article summarizes several different deep learning paradigms reported in the up-to-date literature for the retinal fluid segmentation in OCT images. The deep learning architectures include the backbone of convolutional neural network (CNN), fully convolutional network (FCN), U-shape network (U-Net), and the other hybrid computational methods. The article also provides a survey on the prevailing OCT image datasets used in recent retinal segmentation investigations. The future perspectives and some potential retinal segmentation directions are discussed in the concluding context.

The accurate segmentation and quantification of retinal fluid in Optical Coherence Tomography (OCT) images are crucial for the diagnosis and treatment of ophthalmic diseases such as age-related macular degeneration. However, the accurate segmentation of retinal fluid is challenging due to significant variations in the size, position, and shape of fluid, as well as their complex, curved boundaries. To address these challenges, we propose a novel multi-scale feature fusion attention network (FNeXter), based on ConvNeXt and Transformer, for OCT fluid segmentation. In FNeXter, we introduce a novel global multi-scale hybrid encoder module that integrates ConvNeXt, Transformer, and region-aware spatial attention. This module can capture long-range dependencies and non-local similarities while also focusing on local features. Moreover, this module possesses the spatial region-aware capabilities, enabling it to adaptively focus on the lesions regions. Additionally, we propose a novel self-adaptive multi-scale feature fusion attention module to enhance the skip connections between the encoder and the decoder. The inclusion of this module elevates the model’s capacity to learn global features and multi-scale contextual information effectively. Finally, we conduct comprehensive experiments to evaluate the performance of the proposed FNeXter. Experimental results demonstrate that our proposed approach outperforms other state-of-the-art methods in the task of fluid segmentation.

Background Syphilis with ocular involvement has reemerged as a critical health problem. The aim of the present study was to explore the clinical manifestations and cerebrospinal fluid (CSF) status in ocular syphilis in human immunodeficiency virus (HIV)-negative patients. Methods The clinical records of patients with ocular syphilis presenting to the Shanghai Xuhui Central Hospital in the period from January 2011 to December 2012 were retrospectively reviewed. Results The median age of 25 HIV-negative patients with ocular syphilis was 53 years, 18 patients (72.0 %) were males and 7 (28.0 %) were females. None of them self-identified themselves as men who had sex with men (MSM). The ocular lesions included: uveitis (13 cases), optic neuropathy (6 cases), retinal vasculitis (5 cases), retinal detachment (3 cases), and neuroretinitis (4 cases). Serum toluidine red unheated serum test (TRUST) titer ranged from 1 to 512, with a median of 64. Overall, 18 (72.0 %) of the 25 patients had abnormal CSF results, 15 (60.0 %) CSF samples had elevated white blood cell counts, 13 (52.0 %) had elevated protein levels, and 9 (36.0 %) had reactive CSF Venereal Disease Research Laboratory (VDRL) test, respectively. Mann–Whitney U tests showed higher serum TRUST titer (>32) correlated with the abnormal CSF results. Conclusions The demographic characteristics of patients with ocular syphilis in this study were different from previous reports. The study showed a high CSF abnormal rate in HIV-negative patients. The recommendation for CSF examination from all patients with ocular syphilis, including HIV-negative cases, is strongly supported by the present data.

Background Microglia-associated inflammation is closely related to the pathogenesis of various retinal diseases such as uveitis and diabetic retinopathy, which are associated with increased vascular permeability. In this study, we investigated the effect of systemic lipopolysaccharide (LPS) exposure to activation and proliferation of retinal microglia /macrophages. Methods Balb/c and Cx3cr1 gfp/+ mice were challenged with LPS (1 mg/kg) daily for four consecutive days. For microglia depletion, mice were treated with colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 1 week before the first LPS challenge and until the end of the experiment. In vivo imaging of the retina was performed on days 4 and 7 after the first LPS challenge, using optical coherence tomography and fluorescein angiography. Flow cytometry analysis, retinal whole mount, and retinal sections were used to investigate microglia and macrophage infiltration and proliferation after LPS challenge. Cytokines were analyzed in the blood as well as in the retina. Data analysis was performed using unpaired t tests, repeated measures one-way ANOVA, or ordinary one-way ANOVA followed by Tukey’s post hoc analysis. Kruskal-Wallis test followed by Dunn’s multiple comparison tests was used for the analysis of non-normally distributed data. Results Repeated LPS challenge led to activation and proliferation of retinal microglia, infiltration of monocyte-derived macrophages into the retina, and breakdown of the blood-retina barrier (BRB) accompanied by accumulation of sub-retinal fluid. Using in vivo imaging, we show that the breakdown of the BRB is highly reproducible but transitory. Acute but not chronic systemic exposure to LPS triggered a robust release of inflammatory mediators in the retina with minimal effects in the blood plasma. Inhibition of the CSF-1R by PLX5622 resulted in depletion of retinal microglia, suppression of cytokine production in the retina, and prevention of BRB breakdown. Conclusions These findings suggest that microglia/macrophages play an important role in the pathology of retinal disorders characterized by breakdown of the BRB, and suppression of their activation may be a potential therapeutic target for such retinopathies.

To evaluate the anatomical and functional outcomes and treatment burden of intravitreal brolucizumab in chronic central serous chorioretinopathy (cCSCR) over 12 months in a real-world setting. In this retrospective, single-center cohort, 29 eyes with cCSCR received pro re nata intravitreal brolucizumab. Baseline OCT angiography excluded macular neovascularization. Patients were seen monthly for three months, then as needed through month 12. At each visit, best-corrected visual acuity (BCVA), central retinal thickness (CRT), and presence of SRF, intraretinal fluid (IRF), and pigment epithelium detachment (PED; including PED height) were recorded. Total injections per eye were tallied. Twenty-nine eyes (mean age 55.2±11.0 years; 72% male) with cCSCR received 1.72 ± 0.62 intravitreal brolucizumab injections over 12 months. Vision improved from BCVA 0.59 ± 0.23 logMAR at baseline to 0.46 ± 0.22 at one month ( =0.002), 0.40 ± 0.20 at three months ( <0.001), and 0.39 ± 0.20 at month 12 ( <0.001). Mean CRT reduced from 340 ± 140 µm to 260 ± 110 µm at one month and stabilized at 230 ± 98 µm by month 12 ( <0.001). Mean PED height decreased from 48 ± 55 µm at baseline to 13 ± 17 µm at month 12 ( <0.001). Fluid resolution was rapid and sustained; SRF cleared in 63% at one month ( <0.001) and 88.9% at 12 months ( <0.001), IRF in 85.7% by month 3 ( =0.016) and 71.4% by month 12 ( =0.063), and PEDs in 43.8% at one month ( =0.021) rising to 68.8% at month 12 ( =0.001). No ocular or systemic adverse events occurred. Intravitreal brolucizumab provided significant and sustained visual and anatomical improvements in cCSCR with a low injection burden over 12 months. Given the off‑label use and absence of a control group, findings should be interpreted cautiously and confirmed in prospective controlled studies.

Background: The art of scleral buckle (SB) surgery is being largely forgotten. However, it still remains a good option for selected cases of rhegmatogenous retinal detachment. Drainage of subretinal fluid (SRF) is one of the most crucial steps of the surgery. When performed correctly, it gives the advantage of immediate retinal reattachment, and it hastens recovery. However, it has its own set of complications. Purpose: To demonstrate, step by step, the scleral cut-down technique of SRF drainage in SB surgery for rhegmatogenous retinal detachment (RRD) and to discuss its indications, contraindications, and complications. Synopsis: Longstanding RRDs with bullous detachments, old age, inferior breaks, or multiple breaks are indications of SRF drainage. In shallow RDs or young patients, a non-drainage procedure may be preferred. It is safer to drain at the bed of the buckle. After the sclera is cut and dissected, it is essential to inspect the choroid for the presence of large vessels. Choroidal vessels are avoided from getting injured while perforating. The release of pigments indicates the end of the drainage. Various possible complications can be prevented by being careful in the surgical technique. Highlights: Diagrammatic illustrations explain the steps of the surgical technique. Intraoperative complications have been explained in an easy-to-understand manner with tips to manage such conditions and their prevention. The video highlights the correct way of performing SRF drainage. Online Video Link: https://youtu.be/L0TrdkCwk20 Key words: Scleral buckle, scleral cut-down technique, sub-retinal fluid drainage