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Diabetic retinopathy (DR) is a common complication of diabetes characterized by vascular pathology and neuroinflammation. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule that functions at the crossroads between innate immunity, inflammation, and tissue remodeling. DR is known to involve inflammatory pathways, although the potential relevance of PTX3 has not been explored. We found that PTX3 protein levels increased in the retina of diabetic mice. Similarly, evaluation of a publicly available transcriptomic human dataset revealed increased PTX3 expression in DR with diabetic macular edema and proliferative retinopathy, when compared to nondiabetic retinas or diabetic retinas without complications. To further understand the role of PTX3 within DR, we employed the streptozotocin-induced diabetes model in PTX3 knockout mice (PTX3 KO ), which were followed up for 9 mo to evaluate hallmarks of disease progression. In diabetic PTX3 KO mice, we observed decreased reactive gliosis, diminished microglia activation, and reduced vasodegeneration, when compared to diabetic PTX3 wild-type littermates. The decrease in DR-associated pathological features in PTX3 KO retinas translated into preserved visual function, as evidenced by improved optokinetic response, restored b-wave amplitude in electroretinograms, and attenuated neurodegeneration. We showed that PTX3 induced an inflammatory phenotype in human retinal macroglia, characterized by GFAP upregulation and increased secretion of IL6 and PAI-1. We confirmed that PTX3 was required for TNF-α-induced reactive gliosis, as PTX3 KO retinal explants did not up-regulate GFAP in response to TNF-α. This study reveals a unique role for PTX3 as an enhancer of sterile inflammation in DR, which drives pathogenesis and ultimately visual impairment., Competing Interests: Competing interests statement:The authors declare no competing interest.

Histopathologic studies of diabetic choroid suggest that diabetic choroidopathy is a key aspect secondary to diabetes. Recently, hyperreflective choroidal foci (HCF) have been introduced as novel optical coherence tomography (OCT) parameter. The aim of this study was to identify and quantify HCF in diabetic subjects with retinopathy, with or without diabetic macular edema (DME). Eighty-five diabetic subjects with different degrees of DR were enrolled: 37 without DME and 48 with DME. All subjects underwent full ophthalmologic examination including spectral domain optical coherence tomography (OCT). OCT images were analyzed to quantify and localize HCF. Each image was analyzed by two independent, masked examiners. OCT images showed that all subjects (100%) had HCF in the different layers of the choroid. The number of HCF was significantly higher in diabetics with DME versus those without DME (p < 0.0001). HCF showed variable size, shape and location inside the choroid. They were mainly located in choriocapillaris and Sattler's layer, on the edges of blood vessels. The intraobserver and interobserver agreement was almost perfect (ICC >0.9). This study suggests that hyperreflective foci in the choroid of subjects with DR may be accurately identified with structural OCT. Their number significantly increases with the progression of DME. These HCF may represent, as in the retina, a sign of infiltration of inflammatory cells (mainly migrating microglia) into the choroid, according to the hypothesis raised by Jerry Lutty. HCF may confirm in vivo the histopathologic findings suggesting that diabetic choroidopathy may be primarily a neuroinflammatory disorder., Competing Interests: Declaration of competing interest The authors declare no relevant conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study was intended to investigate the macular vascular and photoreceptor changes for diabetic macular edema (DME) at the early stage. A total of 255 eyes of 134 diabetes mellitus patients were enrolled and underwent an ophthalmological and systemic evaluation in this cross-sectional study. Early DME was characterized by central subfoveal thickness (CST) value between 250 and 325 μm, intact ellipsoid zone, and an external limiting membrane. While non-DME was characterized by CST < 250 μm with normal retinal morphology and structure. Foveal avascular zone (FAZ) area ≤ 0.3 mm 2 (P < 0.001, OR = 0.41, 95% CI 0.26-0.67 in the multivariate analysis) and HbA1c level ≤ 8% (P = 0.005, OR = 0.37, 95% CI 0.19-0.74 in multivariate analysis) were significantly associated with a higher risk of early DME. Meanwhile, no significant differences exist in cone parameters between non-DME and early DME eyes. Compared with non-DME eyes, vessel diameter, vessel wall thickness, wall-to-lumen ratio, the cross-sectional area of the vascular wall in the upper side were significantly decreased in the early DME eyes (P = 0.001, P < 0.001, P = 0.005, P = 0.003 respectively). This study suggested a vasospasm or vasoconstriction with limited further photoreceptor impairment at the early stage of DME formation. CST ≥ 250 μm and FAZ ≤ 0.3 mm 2 may be the indicator for early DME detection., (© 2024. The Author(s).)

Proliferative diabetic retinopathy (PDR) is a vision-threatening complication of diabetes mellitus (DM). Anterior chamber (AC) flare and intraocular cytokines are potent biomarkers reflecting the intraocular immune status in PDR. This study aimed to elucidate the complex interrelationship between AC flare and intraocular cytokines in PDR eyes. A retrospective observational study was conducted on 19 PDR eyes of 19 patients with type 2 DM, and on 19 eyes of 19 patients with idiopathic macular hole or epiretinal membrane as controls. AC flare was measured before pars plana vitrectomy (PPV). Aqueous humor (AH) and vitreous fluid (VF) samples were collected at the time of PPV, and the quantities of 27 cytokines in both intraocular fluids were analyzed. In the PDR and control groups, Spearman's rank correlation analysis revealed a positive correlation between AC flare and IL-8 level in both AH and VF. Additionally, IL-8 levels in AH correlated positively with IL-8 levels in VF. In the PDR group, receiver operating characteristic curve analysis identified IL-8 level in AH as a significant predictor for both diabetic macular edema (DME) and vitreous hemorrhage (VH) complications. The cut-off values of IL-8 were established at ≥26.6 pg/mL for DME and ≥7.96 pg/mL for VH. Given the positive correlation between AC flare and AH IL-8 level, the present findings suggest that AC flare value may potentially be a non-invasive biomarker for predicting DME.

Age-related macular degeneration (AMD) and diabetic macular edema (DME) are significant causes of blindness worldwide. The prevalence of these diseases is steadily increasing due to population aging. Therefore, early diagnosis and prevention are crucial for effective treatment. Classification of Macular Degeneration OCT Images is a widely used method for assessing retinal lesions. However, there are two main challenges in OCT image classification: incomplete image feature extraction and lack of prominence in important positional features. To address these challenges, we proposed a deep learning neural network model called MSA-Net, which incorporates our proposed multi-scale architecture and spatial attention mechanism. Our multi-scale architecture is based on depthwise separable convolution, which ensures comprehensive feature extraction from multiple scales while minimizing the growth of model parameters. The spatial attention mechanism is aim to highlight the important positional features in the images, which emphasizes the representation of macular region features in OCT images. We test MSA-NET on the NEH dataset and the UCSD dataset, performing three-class (CNV, DURSEN, and NORMAL) and four-class (CNV, DURSEN, DME, and NORMAL) classification tasks. On the NEH dataset, the accuracy, sensitivity, and specificity are 98.1%, 97.9%, and 98.0%, respectively. After fine-tuning on the UCSD dataset, the accuracy, sensitivity, and specificity are 96.7%, 96.7%, and 98.9%, respectively. Experimental results demonstrate the excellent classification performance and generalization ability of our model compared to previous models and recent well-known OCT classification models, establishing it as a highly competitive intelligence classification approach in the field of macular degeneration., (© 2024. The Author(s).)

The effect of diabetes mellitus (DM) on individual retinal layers remains incompletely understood. We evaluated the intra-retinal layer thickness alterations in 71 DM eyes with no diabetic retinopathy (DR), 90 with mild DR, and 63 with moderate DR without macular edema, using spectral-domain optical coherence tomography (SD-OCT) and the Iowa Reference Algorithm for automated retinal layer segmentation. The average thickness of 10 intra-retinal layers was then corrected for ocular magnification using axial length measurements, and pairwise comparisons were made using multivariable linear regression models adjusted for gender and race. In DM no DR eyes, significant thinning was evident in the ganglion cell layer (GCL; p < 0.001), inner nuclear layer (INL; p = 0.001), and retinal pigment epithelium (RPE; p = 0.014) compared to normal eyes. Additionally, mild DR eyes exhibited a thinner inner plexiform layer (IPL; p = 0.008) than DM no DR eyes. Conversely, moderate DR eyes displayed thickening in the INL, outer nuclear layer, IPL, and retinal nerve fiber layer (all p ≤ 0.002), with notably worse vision. These findings highlight distinctive patterns: early diabetic eyes experience thinning in specific retinal layers, while moderate DR eyes exhibit thickening of certain layers and slightly compromised visual acuity, despite the absence of macular edema. Understanding these structural changes is crucial for comprehending diabetic eye complications., (© 2024. The Author(s).)

Aims: To evaluate the association between subfoveal choroidal thickness (SFCT) and diabetic macular edema (DME)., Design: A systematic review and meta-analysis., Methods: A retrospective or prospective study comparing SFCT in diabetic retinopathy (DR) patients with and without DME was included. The data were collected from published studies retrieved from PubMed, Web of Science, Embase, Ovid Medline, and Cochrane Library. The final search was conducted on July 2, 2023. Heterogeneity was assessed using I2 statistics, and a random-effects model was used for the meta analysis. This study calculated the weighted mean difference (WMD) and 95% confidence interval (CI) for SFCT., Results: A total of 26 relevant studies were identified, involving a combined sample size of 3201 eyes (1302 DR-DME eyes and 1899 DR-no DME eyes). The results showed no significance between DR-DME and DR-no DME (WMD = - 3.57 μm; 95% CI -26.54 to 19.41 μm; P = 0.76). Sub-analysis based on nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) subgroups showed that the SFCT of NPDR-DME was significantly thinner than that of NPDR-no DME eyes (WMD = - 19.80 μm; 95% CI - 34.55 to - 5.04 μm; P = 0.009), while there was no significance in SFCT between PDR-DME and PDR-no DME (WMD = - 26.45 μm; 95% CI - 104.00 to 51.11 μm; P = 0.50)., Conclusion: The SFCT was thinner in NPDR-DME eyes compared to NPDR-no DME eyes. Thinning SFCT might cause retinal hypoxia, and play an important role in DME occurrence. Additionally, this study highlights the importance of considering DR grades and treatment history when evaluating SFCT between DME and no DME., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

To improve the understanding of potential pathological mechanisms of macular edema (ME), we try to discover biomarker candidates related to ME caused by diabetic retinopathy (DR) and retinal vein occlusion (RVO) in spectral-domain optical coherence tomography images by means of deep learning (DL). 32 eyes of 26 subjects with non-proliferative DR (NPDR), 77 eyes of 61 subjects with proliferative DR (PDR), 120 eyes of 116 subjects with branch RVO (BRVO), and 17 eyes of 15 subjects with central RVO (CRVO) were collected. A DL model was implemented to guide biomarker candidate discovery. The disorganization of the retinal outer layers (DROL), i.e., the gray value of the retinal tissues between the external limiting membrane (ELM) and retinal pigment epithelium (RPE), the disrupted and obscured rate of the ELM, ellipsoid zone (EZ), and RPE, was measured. In addition, the occurrence, number, volume, and projected area of hyperreflective foci (HRF) were recorded. ELM, EZ, and RPE are more likely to be obscured in RVO group and HRFs are observed more frequently in DR group (all P ≤ 0.001). In conclusion, the features of DROL and HRF can be possible biomarkers related to ME caused by DR and RVO in OCT modality., (© 2024. The Author(s).)

We identified characteristics of patients with subretinal fluid (SRF) in macular edema (ME) secondary to branch retinal vein occlusion (BRVO) and determined their clinical outcomes after anti-vascular endothelial growth factor (VEGF) treatment. Fifty-seven eyes of BRVO patients with ME were divided into two groups according to the presence or absence of SRF at diagnosis. We compared the aqueous profiles, ocular and systemic characteristics at baseline, and the clinical outcomes. The SRF group had significantly greater central subfield thickness (CST) values and poorer best-corrected visual acuity (BCVA) at baseline compared to the non-SRF group. The former group had significantly higher aqueous levels of interleukin-8, VEGF, and placental growth factor. CST reduction and BCVA improvement during treatment were significantly greater in the SRF group than in the non-SRF group. Consequently, CST values were significantly lower in the SRF group than in the non-SRF group at 12 months, when BCVA did not differ significantly between the two groups. The SRF group required more frequent anti-VEGF treatment over 12 months and exhibited a higher rate of macular atrophy. Based on the aqueous profiles and the number of treatments required, the presence of SRF in BRVO patients appears to be associated with higher disease activity., (© 2024. The Author(s).)

Purpose: Both hypertension and diabetes are known to increase the wall-to-lumen ratio (WLR) of retinal arterioles, but the differential effects are unknown. Here, we study the timing and relative impact of hypertension versus diabetes on the WLR in diabetic retinopathy (DR) to address this unresolved question., Methods: This prospective cross-sectional study compared the retinal arteriolar WLR in 17 healthy eyes, 15 with diabetes but no apparent DR (DM no DR), and 8 with diabetic macular edema (DME) and either nonproliferative or proliferative DR. We imaged each arteriole using adaptive optics scanning laser ophthalmoscopy and measured the WLR using ImageJ. Multiple linear regression (MLR) was performed to estimate the effects of hypertension, diabetes, and age on the WLR., Results: Both subjects with DM no DR and subjects with DME had significantly higher WLR than healthy subjects (0.36 ± 0.08 and 0.42 ± 0.08 vs. 0.29 ± 0.07, 1-way ANOVA P = 0.0009). MLR in healthy subjects and subjects with DM no DR showed hypertension had the strongest effect (regression coefficient = 0.08, P = 0.009), whereas age and diabetes were not significantly correlated with WLR. MLR in all three groups together (healthy, DM no DR, and DME) showed diabetes had the strongest effect (regression coefficient = 0.05, P = 0.02), whereas age and hypertension were not significantly correlated with WLR., Conclusions: Hypertension may be an early driver of retinal arteriolar wall thickening in preclinical DR, independent of age or diabetes, whereas changes specific to DR may drive wall thickening in DME and later DR stages., Translational Relevance: We offer a framework for understanding the relative contributions of hypertension and diabetes on the vascular wall, and emphasize the importance of hypertension control early in diabetes even before DR onset.

Purpose: To investigate the effect of topical nonsteroidal anti-inflammatory drugs (NSAIDs,) bromfenac on the intraretinal cystic lesions (IRC) when performing simultaneous cataract and idiopathic epiretinal membrane (iERM) surgery., Methods: This study included patients with iERM who had been followed up for 6 months after vitrectomy, membrane removal, and concurrent cataract surgery. Eyes were treated with topical bromfenac or not. The baseline fluorescein angiography (FA) was obtained to assess the microvascular leakage (ML). Structural changes of macula, including IRC and central macular thickness (CMT) were assessed using optical coherence tomography (OCT). The main outcome measures were changes in IRCs and best-corrected visual acuity (BCVA) regarding FA findings., Results: One hundred eighteen eyes were included. IRC and ML were observed in 51 eyes (43.2%) and 63 eyes (53.4%), respectively. The IRC did not show any association with the ML. Of total, 29 eyes (24.6%) were treated with topical bromfenac (Group A). Compared to Group B, topical bromfenac did not show beneficial effects in aspect of preventions for the newly developed IRC and treatment for pre-existed IRC. Whether the ML existed or not, topical bromfenac did not show any different effect on the changes in BCVA and IRC., Conclusion: When performing simultaneous cataract and ERM surgery, topical NSAIDs, bromfenac did not show beneficial effects on the preventions and treatment of IRC in both eyes with and without the ML., (© 2024. The Author(s).)

Background: Vascular mural cells (VMCs) are integral components of the retinal vasculature with critical homeostatic functions such as maintaining the inner blood-retinal barrier and vascular tone, as well as supporting the endothelial cells. Histopathologic donor eye studies have shown widespread loss of pericytes and smooth muscle cells, the 2 main VMC types, suggesting these cells are critical to the pathogenesis of diabetic retinopathy (DR). There remain, however, critical gaps in our knowledge regarding the timeline of VMC demise in human DR., Methods: In this study, we address this gap using adaptive optics scanning laser ophthalmoscopy to quantify retinal VMC density in eyes with no retinal disease (healthy), subjects with diabetes without diabetic retinopathy, and those with clinical DR and diabetic macular edema. We also used optical coherence tomography angiography to quantify capillary density of the superficial and deep capillary plexuses in these eyes., Results: Our results indicate significant VMC loss in retinal arterioles before the appearance of classic clinical signs of DR (diabetes without diabetic retinopathy versus healthy, 5.0±2.0 versus 6.5±2.0 smooth muscle cells per 100 µm; P <0.05), while a significant reduction in capillary VMC density (5.1±2.3 in diabetic macular edema versus 14.9±6.0 pericytes per 100 µm in diabetes without diabetic retinopathy; P =0.01) and capillary density (superficial capillary plexus vessel density, 37.6±3.8 in diabetic macular edema versus 45.5±2.4 in diabetes without diabetic retinopathy; P <0.0001) is associated with more advanced stages of clinical DR, particularly diabetic macular edema., Conclusions: Our results offer a new framework for understanding the pathophysiologic course of VMC compromise in DR, which may facilitate the development and monitoring of therapeutic strategies aimed at VMC preservation and potentially the prevention of clinical DR and its associated morbidity. Imaging retinal VMCs provides an unparalleled opportunity to visualize these cells in vivo and may have wider implications in a range of diseases where these cells are disrupted., Competing Interests: Disclosures A.A. Fawzi is a consultant at Regeneron, Roche/Genentech, Boehringer Ingelheim, RegenXbio, 3Helix, and Optos, Inc, and reports grant support from Boehringer Ingelheim. The other authors report no conflicts.

Background: Congenital simple hamartoma of the retinal pigment epithelium is often identified as an incidental finding. One important issue is the differentiation of these benign lesions from other lesions which could be potentially sight-threatening., Methods: This study describes 4 cases of congenital simple hamartoma of the retinal pigment epithelium that were referred to a university-based hospital. Multimodal imaging including fundus photo, multicolor fundus photo, fundus autofluorescence, optical coherence tomography (OCT), OCT angiography, fluorescein angiography and multifocal electroretinogram is provided., Results: The first case is a young man with an incidental finding of this lesion. The second and third cases are diabetic patients with congenital simple hamartoma of the retinal pigment epithelium and diabetic macular edema and the fourth one is a case of congenital simple hamartoma of the retinal pigment epithelium with a full-thickness macular hole., Conclusions: Differentiation of congenital simple hamartoma of the retinal pigment epithelium from other potentially sight-threatening lesions is important. Multimodal imaging can be helpful regarding this issue. Besides typical findings described in the literature, unique features in our cases include concurrent diabetic macular edema and association with a full-thickness macular hole.

Purpose: To study the systemic inflammatory mediator levels in non-proliferative diabetic retinopathy (NPDR) patients with diabetic macular edema (DME) and explore the correlation between systemic inflammatory mediators and DME., Methods: In this prospective study, we included 25 patients without diabetes (control group) and 75 patients with type 2 diabetes mellitus (diabetic group). According to fundus examination, the diabetic group patients were divided into: diabetic patients without diabetic retinopathy (DR) (Non-DR group), NPDR patients without DME (Non-DME group), and NPDR patients with DME (DME group). Serum levels of a broad panel of inflammatory mediators were analysed by multiplex protein quantitative detection technology based on a flow cytometry detection system., Results: The interferon-γ (IFN-γ) levels were significantly higher in DME group and Non-DME group as compared to control group ( p  = 0.023 and p  = 0.033) and Non-DR group ( p  = 0.009 and p  = 0.015). Significantly higher values were obtained in DME group and Non-DME group as compared to control group for the interleukin-8 (IL-8) ( p  = 0.003 and p  = 0.003). The IL-23 levels were significantly elevated in DME group and Non-DR group than in Non-DME group ( p  = 0.013 and p  = 0.004). The diabetic group had significantly higher serum levels of IL-8 and IL-33 ( p  = 0.001 and p  = 0.011), and lower serum levels of tumor necrosis factor-α (TNF-α) ( p  = 0.027) in comparison with control group., Conclusions: The changed levels of serum inflammatory mediators suggest that the systemic inflammatory mediators are involved in the pathogenesis of NPDR patients with DME. Such effects can guide clinical monitoring, diagnostic and therapeutic approaches for DME patients at an early stage.

Morphological changes in capillaries are one of major clinical signs in diabetic retinopathy (DR). In this study, we quantified the dilated deep capillaries on optical coherence tomography angiography (OCTA) images. Central 3 × 3 mm en face images were obtained using a swept source OCTA device in 105 eyes of 99 patients with DR. Capillaries with a greater diameter in the deep layers were defined as the dilated deep capillaries, using stepwise image processing. The relative areas of automatically selected capillaries with a great diameter were calculated as the index of the dilated deep capillaries. Most eyes with DR had string-like or dot-like dilated deep capillaries in the OCTA images, which appeared to be dilated capillary segments or microaneurysms histologically. They were distributed more densely in the parafovea than in the central sector, while there were no differences between individual quadrants. The index of the dilated deep capillaries was higher in eyes with DR than in nondiabetic eyes. The index in the central subfield was modestly associated with visual acuity, diabetic macular edema, and proliferative diabetic retinopathy. The quantitative dilated deep capillaries are designated as a biomarker of vision-threatening DR., (© 2023. Springer Nature Limited.)

Background: Numerous studies have demonstrated that retinal chronic inflammation plays a critical role in the pathogenesis of diabetic macular edema (DME). However, studies about the association between peripheral complete blood count, an inexpensive and easily measurable laboratory index, and DME are limited., Research Design and Methods: The current study was a hospital-based, cross-sectional study. The participants were inpatients with type 2 diabetes who underwent vitrectomy for PDR, and the contralateral eyes in these PDR patients meeting the criteria were included in the study. Central macular thickness (CMT) was measured automatically and the DME was characterized as CMT ≥ 300 μm., Results: A total of 239 PDR participants were enrolled. The average age was 55.46 ± 10.08 years old, and the average CMT was 284.23 ± 122.09 μm. In the fully adjusted model, for CMT, the results revealed a significantly negative association between CMT and both white blood cell (WBC) count and neutrophil count (β = -11.95, 95% CI: -22.08, -1.82; p = 0.0218; β = -14.96, 95% CI: -28.02, -1.90; p = 0.0259, respectively); for DME, the results showed an inverse association between DME and WBC count, monocyte count, and eosinophil count (OR = 0.75, 95% CI: 0.59, 0.95; p = 0.0153; OR = 0.07, 95% CI: 0.00, 0.92; p = 0.0431; OR = 0.03, 95% CI: 0.00, 0.88; p = 0.0420, respectively)., Conclusions: In conclusion, our results suggest that WBC and its subtypes in circulation may play an important role in the pathogenesis of DME in PDR patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lei, Gu, Liu, Zhang and Zhang.)

Diabetic macular edema (DME) is a common complication of diabetic retinopathy and is the leading cause of vision loss in diabetic patients. Various factors, such as metabolic disorders and inflammation caused by hyperglycemia, are involved in the occurrence and development of DME, but the specific mechanism is still unclear. Müller cells are a type of macroglial cell unique to the fundus, distributed throughout the retina, and they play a unique role in retinal homeostasis. This article reviews the role of Müller cells in the pathological process of DME and the research progress in the treatment of DME by targeting Müller cells through gene therapy.

Significance: Patient-based research plays a key role in probing basic visual mechanisms. Less-well recognized is the role of patient-based retinal imaging and visual function studies in elucidating disease mechanisms, which are accelerated by advances in imaging and function techniques and are most powerful when combined with the results from histology and animal models.A patient's visual complaints can be one key to patient management, but human data are also key to understanding disease mechanisms. Unfortunately, pathological changes can be difficult to detect. Before advanced retinal imaging, the measurement of visual function indicated the presence of pathological changes that were undetectable with existing clinical examination. Over the past few decades, advances in retinal imaging have increasingly revealed the unseen. This has led to great strides in the management of many diseases, particularly diabetic retinopathy and macular edema, and age-related macular degeneration. It is likely widely accepted that patient-based research, as in clinical trials, led to such positive outcomes. Both visual function measures and advanced retinal imaging have clearly demonstrated differences among retinal diseases. Contrary to initial thinking, sight-threatening damage in diabetes occurs to the outer retina and not only to the inner retina. This has been clearly indicated in patient results but has only gradually entered the clinical classifications and understanding of disease etiology. There is strikingly different pathophysiology for age-related macular degeneration compared with photoreceptor and retinal pigment epithelial genetic defects, yet research models and even some treatments confuse these. It is important to recognize the role that patient-based research plays in probing basic visual mechanisms and elucidating disease mechanisms, combining these findings with the concepts from histology and animal models. Thus, this article combines sample instrumentation from my laboratory and progress in the fields of retinal imaging and visual function., Competing Interests: Conflict of Interest Disclosure: AEE is an owner of Aeon Imaging, LLC, and is an inventor on patents related to some of the technologies in this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Optometry.)

The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic macular edema (DME) whose pathophysiology is still unclear. The aim of this study was to characterize in vivo, using retinal imaging and liquid biopsy, DRIL in eyes with DME. This was an observational cross-sectional study. Patients affected by center-involved DME were enrolled. All patients underwent spectral domain optical coherence tomography (SD-OCT) and proteomic analysis of aqueous humor (AH). The presence of DRIL at OCT was analyzed by two masked retinal experts. Fifty-seven biochemical biomarkers were analyzed from AH samples. Nineteen eyes of nineteen DME patients were enrolled. DRIL was present in 10 patients (52.63%). No statistically significant difference was found between DME eyes with and without DRIL, considering the AH concentration of all the analyzed biomarkers except for glial fibrillary acidic protein (GFAP), a biomarker of Müller cells dysfunction ( p = 0.02). In conclusion, DRIL, in DME eyes, seems to strictly depend on a major dysfunction of Müller cells, explaining its role not only as imaging biomarker, but also as visual function Müller cells-related parameter.

Retinal imaging has greatly expanded our understanding of various pathological conditions. This article presents a summary of the key points covered during the 2022 Ophthalmologica Lecture held at the Euretina Congress in Hamburg. The first part of the article focuses on the use of optical coherence tomography angiography to examine and comprehend the choroid in age-related macular degeneration (AMD). Subsequently, we delve into the discussion of the "postreceptor neuronal loss" theory in AMD, which was studied using en face structural optical coherence tomography (OCT). Following that, we explore pertinent findings obtained through cross-sectional OCT in retinal and optic nerve diseases, such as AMD, diabetic macular edema, pathologic myopia, central serous chorioretinopathy, and Leber's hereditary optic neuropathy., (© 2023 S. Karger AG, Basel.)

Purpose: The goal of the research was to determine the incidence of microstructural alterations in the macula and optic nerve head (ONH) occurred in eyes treated with peripheral laser photocoagulation retinopexy., Methods: Patients with retinal breaks, retinal holes, retinal dialysis, and lattice degenerations who required peripheral laser photocoagulation retinopexy were recruited in this prospective case series investigation. We performed preoperative and postoperative evaluations, including best corrected visual acuity (BCVA), slit lamp examination, intraocular pressure (IOP) measurement, funduscopic examination, and macular and ONH optical coherence tomography (OCT)., Results: Thirty-three eyes of the twenty-three patients enrolled in this study, 14 of which were female. The mean age of the sample was 45.12 ± 9.12 years. The mean refractive error was - 2.45 ± 1.12 Diopters (D). The most prevalent reason for peripheral laser photocoagulation retinopexy was retinal thinning with symptomatic lattice degeneration (90%), followed by retinal hole and break (7%) and retinal dialysis (3%). Between preoperative and postoperative (6-month) evaluation, there was no statistically significant difference in BCVA (P = 0.82), IOP (P = 0.54), central foveal thickness in macular OCT (P = 0.39), or global retinal nerve fiber layer (RNFL) thickness (P = 0.51). There was no association between changes in central foveal thickness and global RNFL thickness and total laser spot numbers (r = - 0.17 P = 0.21, r = 0.06 P = 0.60, respectively). None of patients developed cystoid macular edema (CME) or macular epiretinal membrane (ERM) ., Conclusion: We found that OCT parameters were not significantly affected by laser retinopexy in patients with high-risk peripheral retinal lesions, also none of our patients had developed ERM, vitromacular traction or CME at 6 months follow up periods., (© 2022. The Author(s).)

Purpose: To evaluate current practice patterns for Egyptian ophthalmologists in the diagnosis of diabetic retinopathy (DR) and explore potential implications of these approaches on management., Methods: Cross-sectional survey conducted in Egypt amongst practicing ophthalmologists., Results: The study had 203 responses (~6% of all Egyptian ophthalmologists). A majority of respondents were general ophthalmologists (78.2%), practicing for five to ten years (41.9%). In patients with DR and no diabetic macular edema (DME), 33.0% of respondents would use FA in patients with mild DR, 44.3% in patients with moderate DR and 51.2% in patients with severe non-proliferative diabetic retinopathy (NPDR). Color imaging (CI) was used by less than 1% as the sole imaging modality for any level of DR. Approximately 70% of respondents used fluorescein angiography (FA) to grade and base treatment decisions for DR, either alone or in conjunction with dilated eye exams and/or CI. Given the known more severe appearance of DR on FA than on standard color imaging upon which treatment guidelines are based, use of FA as the primary modality over a one-year period could result in PRP that would otherwise not be suggested in approximately 78,820 eyes at an additional cost of $10.1 million US dollars. These numbers are projected to double by 2045., Conclusion: Given that FA detects significantly greater pathology than CI, and that treatment and follow-up recommendations are based on CI, its use as the primary imaging modality in DR grading may result in apparently significantly higher DR severity, with subsequently increased procedures and associated costs., Competing Interests: None

Aim: To assess macular and optic nerve head characteristics in patients after kidney transplantation using noninvasive optical coherence tomography (OCT) imaging., Methods: The study had a prospective character and was performed during period from November 2019 to November 2020 at the University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina, and included 59 patients with renal graft who underwent OCT. The obtained OCT images, pathologic changes on the fundus, including macula and optic nerve, were analyzed by reviewing nonparametric measures such as scanning laser ophthalmoscope, B-scan, 3D display, as well as parametric measurements such as central macular thickness, optic nerve head excavation, and retinal nerve thickness fiber (RNFL)., Results: There is a statistically significant difference in RNFL values (P = 0.031) and cup to disc (P = 0.002) ratio in relation to duration of graft. The highest average values of RNFL was in patients with creatinine clearance <30 mL/min, while average cup to disc ratio was lowest in patients with creatinine clearance >60 mL/min. Optic nerve head edema was bilateral in 9 and unilateral in 5 patients. Fundus examination also revealed changes on posterior segment, including retinal detachment (1 patient), bilateral macular edema (9 patients), unilateral macular edema (3 patients), central serous chorioretinopathy (2 patients), and macular pseudo hole (3 patients)., Conclusions: Different retinal pathology is present in high incidence in patients secondary to renal transplant. Immunosuppressive therapy, older age, and comorbidities are the usual causes of these changes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Hyperreflective foci (HRF) features in macular edema associated with different etiologies may indicate the disease pathogenesis and help to choose proper treatment. The goal of this study is to investigate the retinal microstructural features of macular edema (ME) secondary to multiple etiologies with spectral-domain optical coherence tomography (SD-OCT) and analyze the origin of HRF in ME., Methods: This was a retrospective study. SD-OCT images were reviewed to investigate macular microstructural features such as the number and distribution of HRF and hard exudates and the internal reflectivity of the cysts. The differences in microstructural features between groups and the correlations between the number of HRF and other parameters were analyzed., Results: A total of 101 eyes with ME from 86 diabetic (diabetic macular edema, DME) patients, 51 eyes from 51 patients with ME secondary to branch retinal vein occlusion (branch retinal vein occlusion-macular edema, BRVO-ME), 59 eyes from 58 central retinal vein occlusion (central retinal vein occlusion-macular edema, CRVO-ME) patients, and 26 eyes from 22 uveitis (uveitic macular edema, UME) patients were included in this study. The number of HRF, the frequency of hard exudates and the enhanced internal reflectivity of the cysts were significantly different among the groups. The number of HRF in the DME group was significantly higher than that in the other groups (all P < 0.05). The frequency of hard exudates and enhanced internal reflectivity of the cysts in the DME group were significantly higher than ME secondary to other etiologies (all P < 0.001). Within the DME group, the number of HRF in the patients with hard exudates was significantly higher than that in the patients without hard exudates (P < 0.001)., Conclusion: HRF detected with SD-OCT were more frequent in DME patients than in BRVO-ME, CRVO-ME, or UME patients. The occurrence of HRF was correlated with the frequency of hard exudates. HRF may result from the deposition of macromolecular exudates in the retina, which is speculated to be a precursor of hard exudates., (© 2022. The Author(s).)

Background and Objectives: The presence of refractory cases resistant to anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME) is a problem in clinical practice. This study aimed to explore the less responsive area of optical coherence tomography (OCT) 3D map the characteristics of naïve DME cases after their first anti-VEGF. Materials and Methods: In 46 patients with DME who received an intravitreal injection of anti-VEGF agents, retinal thickness in 100 sections of the macular area was measured by 3D-mapping mode using OCT before and 1 month after injection. The density of the microaneurysm (MA) was calculated using merged images of the OCT map and fluorescein angiography. Results: One month after injection, the central retinal thickness significantly decreased (p < 0.0001). In severe edema (retinal thickness more than 500 µm), the area percentages with a reduction rate of the retinal thickness greater than 30% and less than 5% were 6.4 ± 6.6% and 10.1 ± 4.6%, respectively. The reduction rate of the retinal thickness varied from section to section. The mutual distance between the areas of maximum thickness before and after the injection averaged 1.22 ± 0.62 mm apart. The reduction rate of retinal thickness in the thickest region before injection was significantly higher (p = 0.02), and that in the thickest region after injection was lower (p = 0.001) than in the other regions. MA density in the residual edema was significantly higher than in the edema-absorbed area (p = 0.03). Conclusion: DME has areas that show low response to the reduction in retinal thickness with anti-VEGF therapy. A high density of MA may be associated with this pathogenesis.

Diabetic retinopathy (DR) is characterized by microvascular changes including ischemia. Degradation and metabolic changes of various retinal cells occur during ischemia. Ischemic region containing more cells will lead to greater metabolic impairment. We analyzed the non-perfusion region (NPR) by integrating histologic mapping with ultra-widefield fluorescein angiography (UWF FA) images. We also investigated the correlations of the weighted ischemic index (ISI) considering the regional distribution of retinal cells with cytokines, macular edema (ME), and neovascularization (NV). In this study, 32 patients with treatment-naïve DR and 21 age-matched control participants were included. The difference between the non-weighted and weighted ISI of NPR with leakage was greatest at the posterior region. The weighted ISI of NPR with leakage was correlated with MCP-1, IL-8, IL-6, PlGF, and VEGF-A levels, while the non-weighted ISI of NPR with leakage was correlated with IL-8 and IL-6 levels. The presence of baseline ME or NV in patients with DR was associated with the weighted ISI, with a stronger association when cones and rods were weighted. The weighted ISI reflecting both metabolic activity and cell distribution demonstrated a better correlation with clinical features and was more valuable in NPR with leakage than non-weighted ISI, which previous studies conventionally used., (© 2022. The Author(s).)

Purpose: To investigate the correlation of volumetric measurements of intraretinal (IRF) and subretinal fluid obtained by deep learning and central retinal subfield thickness (CSFT) based on optical coherence tomography in retinal vein occlusion, diabetic macular edema, and neovascular age-related macular degeneration., Methods: A previously validated deep learning-based approach was used for automated segmentation of IRF and subretinal fluid in spectral domain optical coherence tomography images. Optical coherence tomography volumes of 2.433 patients obtained from multicenter studies were analyzed. Fluid volumes were measured at baseline and under antivascular endothelial growth factor therapy in the central 1, 3, and 6 mm., Results: Patients with neovascular age-related macular degeneration generally demonstrated the weakest association between CSFT and fluid volume measurements in the central 1 mm (0.107-0.569). In patients with diabetic macular edema, IRF correlated moderately with CSFT (0.668-0.797). In patients with retinal vein occlusion, IRF volumes showed a moderate correlation with CSFT (0.603-0.704)., Conclusion: The correlation of CSFT and fluid volumes depends on the underlying pathology. Although the amount of central IRF seems to partly drive CSFT in diabetic macular edema and retinal vein occlusion, it has only a limited impact on patients with neovascular age-related macular degeneration. Our findings do not support the use of CSFT as a primary or secondary outcome measure for the quantification of exudative activity or treatment guidance.

Purpose: Age-related macular degeneration (AMD) and retinal vein occlusion (RVO) are irreversible chorioretinal diseases, which might induce severe damage in visual function. The metabolic factor and inflammatory factors might play important roles in the pathogenesis of AMD and RVO. The levels of irisin and 14 cytokines were analyzed in aqueous humor of AMD and RVO eyes to evaluate the roles of irisin and inflammatory factors., Methods: We collected aqueous humor samples from patients with AMD ( n = 27), RVO ( n = 30), and cataract (as control, n = 23) eyes. Samples were assayed using ELISA kit for irisin and a multiplex immunoassay kit for 14 cytokines. The macular thickness (MT) was measured with OCT in all included eyes., Results: MT in the RVO group is significantly higher than that in the AMD or control group. Irisin levels in the aqueous samples of AMD and RVO eyes were both significantly lower than that in the control. Furthermore, a positive correlation was found between irisin and MT in the RVO. Compared with the controls, AMD eyes had significantly higher levels of BDNF, VEGF-A, VEGF-R1, VEGF-R2, IL-10, TNF-α, VCAM-1, IP-10, and MCP-1. Similarly, RVO eyes had significantly higher levels of BDNF, VEGF-A, VEGF-R1, VEGF-R2, IL-6, IL-8, IL-10, TNF-α, ICAM-1, VCAM-1, IP-10, and MCP-1. However, there was no significant difference between the levels of PDGF-BB or TNF-β in these three groups. A negative correlation was found between VEGF-A and MT in AMD, as well as in control. Furthermore, a positive correlation was found between IL-6 and MT in the 80 included eyes, as well as in RVO. A positive correlation was found between ICAM-1 and MT in the 80 included eyes, as well as in RVO., Conclusions: The metabolic factor, irisin levels in the aqueous humor are decreased in AMD and RVO eyes and show a positive correlation between irisin and MT in RVO eyes, prompting researchers to explore the relationship between irisin and macular edema. We also identified the higher expression of vascular growth factors (VEGF-A, VEGF-R1, and PDGF-BB), inflammatory cytokines (IL-6, IL-8, IL-10, and TNF-α), and chemokines (ICAM-1, VCAM-1, IP-10, and MCP-1) in AMD and RVO eyes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Cao, Zhao and Bao.)

Purpose: To evaluate the effect of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection on central choroidal thickness (CCT), central macular thickness (CMT) and best-corrected visual acuity (BCVA) in diabetic macular edema (DME)., Methods: Retrospective, cohort analysis of 90 eyes of 90 patients receiving anti-VEGF therapy for DME. In patients' records, measurements of CCT, CMT, and BCVA before treatment and at 2 years after treatment were recorded. Using enhanced-depth imaging optical coherence tomography (EDI-OCT) images, choroidal thickness and macular thickness measurements were recorded in the subfoveal area and 1 mm nasal to 1 mm temporal to the central foveal area. The baseline and final CMT and CCT values measured from all three quadrants were analyzed statistically., Results: Mean age of the patients was 59.60 ± 9.78 (range, 40-77) years. Mean baseline nasal-CT 226.4 ± 52.5 µm, central-CT 243.2 ± 51.1 μm and temporal-CT 224.6 ± 47.9 μm. Mean final nasal-CT 220.0 ± 50.2 µm, central-CT 235.3 ± 53.6 μm, temporal-CT 220.5 ± 48.1 μm ( p  = 0.122, p  = 0.056, p  = 0.184, respectively). Mean baseline nasal- MT 385.3 ± 67.7, central-MT 345.5 ± 119.7 μm and temporal-MT 365.0 ± 64.9 μm. Mean final nasal-MT 359.6 ± 59.2 µm, central-MT 306.2 ± 98.4 μm and temporal-MT 353.4 ± 63.3 μm ( p  = 0.001, p  = 0.002, p  = 0.234, respectively). The BCVA improved from 0.52 ± 0.44 logMAR at baseline to 0.38 ± 0.33 at final ( p  = 0.002)., Conclusion: After treatment of diabetic macular edema with intravitreal anti-VEGF injection, CMT and BCVA improved significantly, but CCT did not decrease significantly.

Purpose: To assess the repeatability of multiple automatic vessel density (VD) measurements and the effect of image averaging on vessel detection by optical coherence tomography angiography (OCTA)., Methods: An observational study was conducted in a series of healthy volunteers and patients with macular oedema. Five sequential OCTA images were acquired for each eye using the OptoVue HD device. The effect of the averaging of the 5 acquisitions on vessel detection was analysed quantitatively using a pixel-by-pixel automated analysis. In addition, two independent retina experts qualitatively assessed the change in vessel detection in averaged images segmented in 9 boxes and compared to the first non-averaged image., Results: The automatic VD measurement in OCTA images showed a good repeatability with an overall mean intra-class correlation coefficient (ICC) of 0.924. The mean ICC was higher in healthy eyes compared to eyes with macular oedema (0.877 versus 0.960; p < 0.001) and in the superficial vascular plexus versus the deep vascular complex (0.967 versus 0.888; p = 0.001). The quantitative analysis of the effect of the averaging showed that averaged images had a mean gain of 790.4 pixels/box, located around or completing interruptions in the vessel walls, and a mean loss of 727.2 pixels/box. The qualitative analysis of the averaged images showed that 99.6% of boxes in the averaged images had a gain in vessel detection (i.e., vessels detected in the averaged image but not in the non-averaged image). The loss of pixels was due to a reduction in background noise and motion artifacts in all cases and no case of loss of vessel detection was observed., Conclusion: The automatic VD measurement using the OptoVue HD device showed a good repeatability in 5 acquisitions in a row setting. Averaging images increased vessel detection, and in about a third of boxes, decreased the background noise, both in healthy eyes and, in a greater proportion, in eyes with macular oedema., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. LE BOITE, Dr. CHETRIT, Dr ERGINAY and Dr LAVIA have nothing to disclose. Dr BONNIN reports personal fees from Allergan, outside of the submitted work. Dr. COUTURIER reports personal fees from Allergan, Bayer, Horus and Novartis, outside of the submitted work. Dr. TADAYONI reports personal fees from Novartis, Bayer, Roche, Genentech, Allergan, Zeiss, Alcon and Oculis, outside of the submitted work. All authors attest that they meet the current ICMJE criteria for authorship.

Purpose: To assess choroidal vasculature changes in eyes with branch retinal vein occlusion (BRVO) and macular edema (ME) using the choroidal vascularity index (CVI) and evaluate the effectiveness of CVI as a prognostic biomarker., Methods: 35 patients with monocular BRVO and ME were analyzed retrospectively. Luminal and stromal areas in choroids of swept-source optical coherence tomography were calculated using the image binarization technique. The CVI was calculated as the ratio of the luminal to total choroidal area. The CVI of BRVO and ME eyes were compared with that of the unaffected fellow and post anti-vascular endothelial growth factor (VEGF) injected eyes. A regression analysis was performed on the choroidal parameters, logMAR visual acuity (VA) two years post disease onset and central macula thickness (CMT)., Results: The CVI of BRVO and ME eyes was significantly lower than the fellow and post-injected eyes (p<0.05). The regression analysis showed a strong association between two years after logMAR VA and the CVI of fellow eyes (R2 = 0.433, p<0.001). Remarkable correlations were observed in the CVI and subfoveal choroidal thickness of BRVO and ME eyes (R2 = 0.189, 0.155, respectively, p<0.05). The CMT of diseased eyes were also significantly associated with the CVI of unaffected fellow eyes (R2 = 0.113, p<0.05)., Conclusions: The alteration of CVI in BRVO and ME suggests that choroidal vasculature might be affected by extracellular fluid shift and VEGF changes. The fellow eye CVI could be a useful supplementary prognostic biomarker., Competing Interests: The authors have declared that no competing interests exist.

To investigate the visual/anatomical outcome of diabetic macular edema (DME) patients lost to follow-up (LTFU) for more than 1 year during intravitreal anti-VEGF treatment. A retrospective review of 182 treatment-naïve DME patients was performed. Among them, we identified patients LTFU for more than 1 year during anti-VEGF treatment. Visual acuity and anatomic outcomes at the first visit, last visit before being LTFU, return visit, and after re-treatment were analyzed and compared with those of DME patients with regular follow-up. Patients who had continuous follow-up visits were assigned to the control group. Sixty patients (33%) with DME were LTFU for more than 1 year during anti-VEGF treatment. Multivariate analysis revealed that the ratio of male (p = 0.004), diabetes mellitus (DM) duration less than 5 years (p = 0.015), and poor early anatomic response (p = 0.012) were higher compared to the control group. Eighteen patients returned to the clinic and received re-treatment. After re-treatment with anti-VEGF, central subfield thickness (CST) was significantly improved to the CST of before LTFU. However, visual acuity did not recover to the level before LTFU (0.63 ± 0.26 vs. 0.45 ± 0.28, p = 0.003). About thirty percent of DME patients were LTFU for more than 1 year. Permanent visual loss was observed in these LTFU patients. Patients with a high risk of LTFU such as male, early DM, and poor response after initial injections should be treated more aggressively to improve the visual outcomes., (© 2021. The Author(s).)

Purpose: To investigate the dynamics of the healing process after therapeutic subthreshold micropulse laser (SMPL) for diabetic macular edema (DME) using polarization-sensitive optical coherence tomography (PS-OCT)., Methods: Patients with treatment-native or previously-treated DME were prospectively imaged using PS-OCT at baseline, 1, 2, 3, and 6 months. The following outcomes were evaluated: changes in the entropy value per unit area (pixel2) in the retinal pigment epithelium (RPE) on the B-scan image; changes in the entropy value in each stratified layer (retina, RPE, choroid) based on the ETDRS grid circle overlaid with en face entropy mapping, not only the whole ETDRS grid area but also a sector irradiated by the SMPL; and the relationship between edema reduction and entropy changes., Results: A total of 11 eyes of 11 consecutive DME patients were enrolled. No visible signs of SMPL treatment were detected on PS-OCT images. The entropy value per unit area (pixel2) in the RPE tended to decrease at 3 and 6 months from baseline (35.8 ± 17.0 vs 26.1 ± 9.8, P = 0.14; vs 28.2 ± 18.3, P = 0.14). Based on the en face entropy mapping, the overall entropy value did not change in each layer in the whole ETDRS grid; however, decrease of entropy in the RPE was observed at 2, 3, and 6 months post-treatment within the SMPL-irradiated sectors (P < 0.01, each). There was a positive correlation between the change rate of retinal thickness and that of entropy in the RPE within the SMPL-irradiated sector at 6 months (r2 = 0.19, P = 0.039)., Conclusion: Entropy measured using PS-OCT may be a new parameter that facilitates objective monitoring of SMPL-induced functional changes in the RPE that could not previously be assessed directly. This may contribute to a more promising therapeutic evaluation of DME., Clinical Trial: This clinical study was registered in UMIN-CTR (ID: UMIN000042420)., Competing Interests: MY is an inventor of patents, whose applicant and assignee are Tomey Corporation, in the following; JP 6463051 B2, US 9593936 B2, and EP 2995245 B1, which partly cover the interferometer of PS-OCT; JP 6542178 B2, US 2018/0035894 A1, and EP 3278720 B1, which partly cover the signal processing of PS-OCT. PS-OCT used in this study is related to products in development by Tomey Corporation. Tomey Corporation is a sales distributor of the micropulse laser (IQ 577; Iridex Corporation, Mountain View, CA, USA) in Japan. Three TOMEY staff members were only involved in confirming the content of this paper on the principle of PS-OCT, and were not involved in any funding or other activities. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: To evaluate inflammation biomarkers in diabetic macular edema (DME) treated with intravitreal dexamethasone implant (Ozurdex ® ). Methods: This retrospective single-center study investigated 64 eyes of 64 patients with DME who were nonresponsive to prior antivascular endothelial growth factor and treated with intravitreal Ozurdex. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio were calculated. Visual acuity and optical coherence tomography markers, including hyper-reflective dots and subretinal fluid (SRF), were determined, and central retinal thickness was also evaluated monthly for 3 months. Results: The average age was 64.06 ± 7.81 (48-84) years. The baseline NLR and MLR were significantly higher in patients with better visual outcomes ( P  = 0.029 and P  = 0.048, respectively). Better anatomical outcomes were observed in the presence of SRF ( P  = 0.027). No significant differences were observed in the rates of the presence of SRF and hyper-reflective points about the better functional outcome ( P  > 0.05). Conclusions: SRF as an imaging biomarker, and NLR and MLR as blood biomarkers, stand out as markers of inflammation and were found to be associated with better response to Ozurdex implantation in DME.

Purpose: To investigate the potential association between peripheral blood biomarkers and morphological characteristics of retinal imaging in patients with diabetic macular edema (DME)., Methods: Participants in this cross-sectional study were 36 consecutive patients (36 eyes) with treatment-naïve DME, who underwent spectral domain-optical coherence tomography (SD-OCT), fundus photography, and fundus fluorescein angiography (FFA). In addition, peripheral blood samples were taken to evaluate full blood count and biochemical parameters. Correlation between imaging characteristics and laboratory parameters was examined., Results: Eyes with central subfield thickness greater than 405  μ m presented significantly higher neutrophils/lymphocytes ( p = 0.043) and higher lipoprotein (a) compared to eyes with CST < 405  μ m ( p = 0.003). Presence of hyperreflective foci on SD-OCT was associated with significantly higher white blood cell count ( p = 0.028). Ellipsoid zone disruption was associated with significantly lower hematocrit ( p = 0.012), hemoglobin ( p = 0.009), and red blood cell count ( p = 0.026), as well as with higher lipoprotein (a) ( p = 0.015). Macular ischemia on FFA was associated with significantly higher monocytes ( p = 0.027) and monocytes/HDL ( p = 0.019). No significant associations were found between laboratory parameters and subretinal fluid, intraretinal fluid, exudates, cysts, disorganization of inner retinal layers, epiretinal membrane, and external limiting membrane condition., Conclusion: Specific imaging morphological characteristics were found to be associated with laboratory parameters in patients with DME. These findings may shed light on the pathophysiology of DME and its correlation with the development of specific clinical signs., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Eleni Dimitriou et al.)

Cohen syndrome (CS) is a rare syndromic form of rod-cone dystrophy. Recent case reports have suggested that cystoid maculopathy (CM) could affect CS patients with an early onset and high prevalence. Our study aims at improving our understanding and management of CM in CS patients through a retrospective case series of ten CS patients with identified pathogenic variants in VPS13B. Longitudinal optical coherence tomography (OCT) imaging was performed and treatment with carbonic anhydrase inhibitors (CAI) was provided to reduce the volume of cystoid spaces. CM affected eight out of ten patients in our cohort. The youngest patient showed a strong progression of macular cysts from the age of 4.5 to 5 years despite oral CAI medication. Other teenage and young adult patients showed stable macular cysts with and without treatment. One patient showed a moderate decrease of cystoid spaces in the absence of treatment at 22 years of age. Through a correlative analysis we found that the volume of cystoid spaces was positively correlated to the thickness of peripheral and macular photoreceptor-related layers. This study suggests that CAI treatments may not suffice to improve CM in CS patients, and that CM may resolve spontaneously during adulthood as photoreceptor dystrophy progresses., (© 2021. The Author(s).)

We hypothesized the smoothness of the border between the inner nuclear layer (INL) and outer plexiform layer (OPL) associates with the frequency of macular edema (ME) recurrences secondary to branch retinal vein occlusion (BRVO). Thirty-seven consecutive eyes with BRVO treated with anti-vascular endothelial growth factor (VEGF) injections at 1-year follow-up were included. We manually traced the border between the INL and OPL within the 1.5-mm vertical line from the fovea on optical coherence tomography (OCT) images at the initial visit. The jagged ratio (JR), the border length divided by the spline curve length, was calculated. We performed univariate and multivariate regression analyses, including JR, patient characteristics, number of cystoid spaces in the INL, INL area, and outer retina area. Multivariate regression analysis showed JR significantly correlates with the total number of anti-VEGF injections (P < 0.0001). Moreover, the mean JR was significantly lower in the nine eyes receiving two or fewer injections than in the 28 eyes receiving three or more injections (1.02 ± 0.01 vs. 1.13 ± 0.06, P < 0.0001). A smooth border between the INL and the OPL on OCT images at the initial visit may be a biomarker for fewer ME recurrences in eyes with BRVO., (© 2021. The Author(s).)

Given the capacity of Optical Coherence Tomography (OCT) imaging to display structural changes in a wide variety of eye diseases and neurological disorders, the need for OCT image segmentation and the corresponding data interpretation is latterly felt more than ever before. In this paper, we wish to address this need by designing a semi-automatic software program for applying reliable segmentation of 8 different macular layers as well as outlining retinal pathologies such as diabetic macular edema. The software accommodates a novel graph-based semi-automatic method, called "Livelayer" which is designed for straightforward segmentation of retinal layers and fluids. This method is chiefly based on Dijkstra's Shortest Path First (SPF) algorithm and the Live-wire function together with some preprocessing operations on the to-be-segmented images. The software is indeed suitable for obtaining detailed segmentation of layers, exact localization of clear or unclear fluid objects and the ground truth, demanding far less endeavor in comparison to a common manual segmentation method. It is also valuable as a tool for calculating the irregularity index in deformed OCT images. The amount of time (seconds) that Livelayer required for segmentation of Inner Limiting Membrane, Inner Plexiform Layer-Inner Nuclear Layer, Outer Plexiform Layer-Outer Nuclear Layer was much less than that for the manual segmentation, 5 s for the ILM (minimum) and 15.57 s for the OPL-ONL (maximum). The unsigned errors (pixels) between the semi-automatically labeled and gold standard data was on average 2.7, 1.9, 2.1 for ILM, IPL-INL, OPL-ONL, respectively. The Bland-Altman plots indicated perfect concordance between the Livelayer and the manual algorithm and that they could be used interchangeably. The repeatability error was around one pixel for the OPL-ONL and < 1 for the other two. The unsigned errors between the Livelayer and the manual algorithm was 1.33 for ILM and 1.53 for Nerve Fiber Layer-Ganglion Cell Layer in peripapillary B-Scans. The Dice scores for comparing the two algorithms and for obtaining the repeatability on segmentation of fluid objects were at acceptable levels.

Background: Diabetic macular edema (DME) is a major cause of vision loss in diabetics that is currently mainly treated by antivascular endothelial growth factor (VEGF) agents. The effect of these agents on macular perfusion (MP) is a current concern. Optical coherence tomography angiography (OCTA) is an imaging modality that allows noninvasive high-resolution retinal microvasculature imaging. Several recent studies evaluated the effect of anti-VEGF agents on the MP of DME patients using OCTA. Our aim is to provide a systematic review of these studies., Methods: Multiple databases were searched including PubMed, Ovid Medline, EMBASE, and Google Scholar for relevant studies published between January 2016 and November 2020 which were included in this review. Studies were compared regarding their design, the number of included patients, the machine and scanning protocol used, the inclusion and exclusion criteria, the number of injections given, the type of anti-VEGF agent used, the outcome measures assessed, and the effect of injections on different MP parameters., Results: A total of 16 studies were included. The studies assessed various OCTA parameters that define MP including the foveal avascular zone area and superficial and deep vascular density and yielded conflicting results. Seven studies showed stable or improved MP following treatment, while 7 studies showed worsening MP following treatment, and 2 studies showed inconclusive results. This could have been due to differences in study design, inclusion criteria, type of anti-VEGF agents used, treatment duration, and methods of image analysis and vascular density quantification. All identified studies were noncomparative case series, and 14 of them (87.5%) used the RTVue XR Avanti OCTA machine. Only one study compared OCTA to fluorescein angiography findings., Conclusion: Analysis of MP changes following VEGF inhibition for DME could benefit from a unified scanning protocol and analysis approach that uses similar study designs to eliminate potential sources of bias. This may provide more definitive conclusions regarding the effect of treatment on MP., Competing Interests: Ayman G. Elnahry declares that he has no conflict of interest. Gehad A. Elnahry declares that he has no conflict of interest., (Copyright © 2021 Ayman G. Elnahry and Gehad A. Elnahry.)

Protein S (PS) is a multifunctional glycoprotein that ameliorates the detrimental effects of diabetes mellitus (DM). The aim of this study was to evaluate the distribution of PS in diabetic retinopathy (DR) and diabetic macular edema (DME). This was a study of 50 eyes with DM (37 with DME, 6 with proliferative DR, and 7 with no DR) and 19 eyes without DM. The level of PS was measured by enzyme immunoassay and was compared between eyes with or without DM, with or without DME, and with severe DME (≥ 350 μm) or mild DME (< 350 μm). We also performed immunohistopathologic evaluations of post-mortem eyes and the cystoid lesions excised during surgery. The aqueous free PS was significantly higher with DM (7.9 ± 1.2 ng/ml, P < 0.01) than without DM (6.1 ± 0.7). The aqueous free PS was significantly elevated with DME (8.2 ± 1.2, P < 0.05) compared to proliferative DR (7.0 ± 1.0) and no DR (7.0 ± 0.7). Eyes with severe DME had significantly higher aqueous free PS than mild DME (8.5 ± 1.3 vs. 7.7 ± 1.0, P < 0.05). Immunohistochemistry showed PS in the outer plexiform layer of the retina and cystoid lesion. The higher expression of PS with DR and DME suggests that PS is involved in their pathogenesis.

To demonstrate the long-term effect of cystotomy with or without fibrinogen clot removal for treatment-resistant cystoid macular edema (CME) secondary to branch retinal vein occlusion (BRVO). Retrospective clinical study. We retrospectively analyzed medical records of 22 eyes of 22 patients with treatment-resistant CME secondary to BRVO with 12 months observation after cystotomy with or without fibrinogen clot removal. Patients included 11 women and 11 men. The mean ± SD age was 72.7 ± 10.2 years. LogMAR-converted best corrected visual acuity (BCVA) was statistically better at 12 months after surgery (0.30 ± 0.30) than preoperative BCVA (0.39 ± 0.27) (p = 0.01). The central sensitivity of microperimetry (dB) was maintained during follow-up (preoperative sensitivity: 25.4 ± 4.1, postoperative sensitivity at 12 months after the surgery: 25.9 ± 4.2, p = 0.69). Twelve months after surgery, there was a significant improvement in the central retinal thickness (CRT) on optical coherence tomography (OCT) (303.7 ± 80.1) (μm) compared with the preoperative CRT (524.2 ± 114.8) (p < 0.01). In 12 months, CME recurred in 3 of 22 eyes. The preoperative reflectivity in cystoid cavity on OCT was significantly higher in patients with fibrinogen clot removal (n = 5) than in patients without fibrinogen clot removal (n = 17) (p < 0.01). For treatment-resistant CME secondary to BRVO, Cystotomy with or without fibrinogen clot removal may be one of the treatment options.

Rationale: The best treatment protocol for radiation maculopathy in children has not been determined. The purpose of this study was to determine the effect of photodynamic therapy (PDT) on radiation maculopathy., Patient Concerns: An 11-year-old boy who was originally diagnosed with orbital rhabdomyosarcoma when he was 1 year old, in October 2008. The lesion improved after peripheral blood stem cell transplantation, chemotherapy and radiation therapy. A cataract was detected in his right eye in May 2011, and he underwent cataract surgery in July 2011. Continuous amblyopia training maintained his visual acuity in his right eye. In January 2017, his visual acuity was reduced and macular edema was detected with optical coherence tomography., Diagnoses: We diagnosed radiation maculopathy, from the history of radiation therapy, macular edema by optical coherence tomography, and hyperfluorescent site by fluorescein angiography., Interventions: We performed PDT in June 2017., Outcomes: Treatment with PDT improved macular edema and his visual acuity., Lessons: Radiation retinopathy is progressive disorder with poor prognosis. PDT could be considered to treat radiation maculopathy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To evaluate microstructural changes in cystoid macular edema in retinitis pigmentosa after intravitreal dexamethasone implant injection., Methods: In an extended cohort of a randomized trial of intravitreal dexamethasone implant for the management of retinitis pigmentosa-associated cystoid macular edema, microstructural changes during six months after the treatment were evaluated using spectral-domain optical coherence tomography., Results: Forty-two eyes were included, and all had cystoid space in the inner nuclear layer (INL) at baseline. No eyes showed subretinal fluid, and 28.6% showed hyperreflective foci. Among 38 eyes with cystoid space both in the INL and outer nuclear layer/Henle's layer, 13 (34.2%) showed complete resolution and 12 (31.6%) showed cystoid space only in the INL at 2 months after injection, whereas others showed persistent cystoid space in both layers. After complete resolution, cystoid space recurrence was earlier in the INL than in the outer nuclear layer/Henle's layer. Multivariable analysis showed that greater cystoid space area in the INL and outer nuclear layer/Henle's layer, presence of macular leakage, and longer intact external limiting membrane at baseline were associated with greater cystoid space area decrease after the treatment., Conclusion: Resolution and recurrence pattern of retinitis pigmentosa-associated cystoid macular edema after dexamethasone treatment showed that the INL is the primary layer of cystic change, and this suggests its pathogenesis is most likely caused by Müller cell dysfunction.

Retinal vein occlusion (RVO) is a vascular disease that represents characteristic retinal hemorrhage and dilated retinal veins. Despite its clinical importance, its pathogenesis remains largely unknown because of limited opportunities to acquire human retinal samples. Therefore, an animal model that reproduces the clinical features of RVO patients is required for further investigation. In this study, we established a pigmented murine RVO model that reproduced characteristic fundus appearances similar to human RVO findings. Retinal edema in this model was observed in both optical coherence tomography and histological analysis, which is a clinically important outcome. With quantitative real-time PCR analysis on retinal samples, we revealed that the mRNA level of vascular endothelial growth factor (VEGF) increased in the retina induced RVO. Moreover, this retinal edema was reduced by intravitreal injection of anti-VEGF antibody. These results were consistent with human clinical knowledge and suggested that this model could be a useful tool for research into new therapeutic approaches., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Intravitreal antivascular endothelial growth factor (VEGF) drugs represent the first-line treatment option for wet age-related macular degeneration (w-AMD) and diabetic macular edema (DME); however, the frequent injection intervals have illuminated to the necessity for new molecules allowing a more prolonged treatment regimen. Faricimab is a promising bispecific drug targeting VEGF-A and the Ang-Tie/pathway. Phase II STAIRWAY and AVENUE Trials showed its clinical efficacy for the treatment of w-AMD, while the phase II BOULEVARD Trial revealed its superiority to monthly ranibizumab in the management of DME with a monthly treatment regimen. The agents are awaiting approval for the treatment of w-AMD and DME., Areas Covered: This article presents an overview of w-AMD and diabetic retinopathy and examines the progress of Faricimab through clinical trials. It offers insights on where Faricimab may be placed in the future market of anti-VEGF treatments and discusses the role of Ang/Tie pathway as a potential additive weapon for the treatment of w-AMD, DME, and retinal vein occlusion (RVO)., Expert Opinion: The possibility of administering faricimab with more prolonged treatment intervals represents an important advantage to decrease the treatment burden and improve patient compliance. Further phase III trials should provide more evidence on clinical efficacy.

To analyze functional and anatomical response patterns to dexamethasone (DEX) implant in diabetic macular edema (DME), to describe proportion of responders and non-responders, and to propose a new DME grading system. Retrospective, multicenter, observational cohort study. Naïve and non-naïve DME patients were treated with DEX, with visual acuity (VA) ≥ 0.2 logMAR and central subfield thickness (CST) of ≥ 300 µm. Functional and anatomical responses were graded after 2 and 4 months, and categorized as early and stable improvement, early and progressive improvement, pendular response, delayed improvement, and persistent non-response. 417 eyes were included (175 treatment naïve eyes). Compared to non-naïve eyes, naïve eyes showed a very good functional response (VA gain ≥ 10 letters) more frequently after 2 and 4 months (56% and 57% [naïve] vs. 33% and 28% [non-naïve], p < 0.001). A VA gain < 5 letters (non-response) after 2 and 4 months was seen in 18% and 16% of naïve eyes, and in 49% and 53% of non-naïve eyes (p < 0.001). A lack of anatomical response was rare in both groups, but more frequently in non-naïve eyes (12% vs. 4%, p = 0.003). Functionally and anatomically, naïve eyes showed most frequently an early and stable improvement (functionally: 77/175 44%; anatomically: 123/175 eyes, 70%). Most non-naïve eyes experienced no significant improvement functionally (97/242 eyes, 40%), despite a mostly early and stable improvement anatomical response pattern (102/242 eyes, 42%). Functional but not anatomical response patterns were influenced by baseline VA. Naïve and non-naïve eyes show different functional and anatomical response patterns to DEX implant. Functional non-responders are rare in naïve eyes, whereas anatomical non-response is unusual in both groups.

The aim of this study is to evaluate the relationship between retinal structures and visual acuity in diabetic patients using optical coherence tomography (OCT) and OCT angiography (OCTA). This study was a retrospective observational study conducted at a single medical center in Japan. Evaluation of retinal images was analyzed using spectral domain OCT. Twelve factors including central retinal thickness, length of disorganization of retinal inner layer (DRIL), number of inner hyperreflective foci, number of outer hyperreflective foci, height of intraretinal fluid, height of subretinal fluid, length of external limiting membrane disruption, length of external ellipsoid zone (EZ) disruption, vessel density of superficial capillary plexus (SCP), foveal avascular zone (FAZ) area, and FAZ circularity were analyzed based on OCT/OCTA findings. Multivariate analysis was used to investigate the OCT-based factors that could be correlated with poor visual acuity in treatment-naïve diabetic eyes. A total of 183 eyes of 123 diabetic patients with type 2 diabetes (mean age 61.9 ± 12.3 years, 66 men and 57 women) and 62 eyes of 55 control subjects (mean age 64.4 ± 12.5 years, 15 men and 40 women) was enrolled in this study. Multiple regression analysis showed that OCT-based factors correlated with visual acuity were length of DRIL (β = 0.24, P < 0.01), length of EZ disruption (β = 0.35, P < 0.001), and FAZ circularity (β =  - 0.14, P < 0.05). The other factors showed no significant correlation. In conclusion, the length of DRIL, length of EZ disruption, and FAZ circularity measured by OCT were identified as related factors for visual impairment in treatment-naïve diabetic eyes.

Purpose: To evaluate the retinal vessel density (VD) in the macular region and the foveal avascular zone (FAZ) area using optical coherence tomography angiography (OCTA) in patients with and without disorganization of retinal inner layers (DRILs) after resolution of diabetic macular edema., Methods: Thirty-seven eyes of 37 DRIL patients (mean age 63 ± 13.97 years), 30 eyes of 30 no DRIL patients and 35 eyes of 35 controls were enrolled in this study. We evaluated the VD in the macular region of superficial capillary plexus (SCP), deep capillary plexus (DCP) and FAZ area., Results: DRIL and no DRIL groups showed decreased VD in SCP and DCP (p<0.05) and a larger FAZ area (p<0.001) compared to controls. However, DRIL patients revealed a statistically significant reduction in VD of SCP (p = 0.041) and a greater FAZ area (p<0.001) with respect to no DRIL patients. We found a significant negative correlation between the VD of the foveal SCP (r = -0.414, p = 0.011), foveal DCP (r = -0.358, p = 0.025) and best corrected visual acuity (BCVA) in DRIL group. Moreover there was a significant positive correlation between the FAZ area (r = 0.425, p = 0.034) and BCVA. Therefore, in presence of DRILs lower VD values of SCP and DCP and a larger FAZ area correlated with a worse visual acuity. In no DRILs group, there was a significant negative correlation between the VD of the foveal DCP and BCVA., Conclusion: OCTA highlights the role of retinal vascular ischemia in the pathogenesis of DRILs. This parameter could represent an important functional predictive factor in diabetic patients., Competing Interests: The authors have declared that no competing interests exist.

We investigated the relationship between aqueous cytokine levels, changes in ocular blood flow, and morphological and functional improvements after intravitreal ranibizumab injection (IRI) in treatment-naïve eyes with center-involving diabetic macular edema (DME). Thirty-three eligible patients with DME (33 eyes) were recruited. At the first IRI, we collected a sample of aqueous humor from each eye and measured levels of the cytokines/chemokines. Mean blur rate (MBR) was used to evaluate retinal and choroidal flow by laser speckle flowgraphy at the time of the first IRI and 1 month later. One month after IRI, both retinal and choroidal MBR had significantly decreased from baseline. The reduction ratio of the retinal MBR was significantly correlated with aqueous levels of monocyte chemotactic protein (MCP)-1 and interleukin-8, and with reduction of central macular thickness, but not with improvement of best corrected visual acuity. The reduction ratio of choroidal MBR showed no statistical correlation with any cytokine levels or changes in clinical parameters. We conclude that IRI reduces both retinal and choroidal blood flow in treatment-naïve DME. Reduction of retinal blood flow correlated with regression of morphological pathology, which is regulated by the initial aqueous levels of some cytokines.