Search Results (231)

Background: North Carolina Macular Dystrophy (NCMD) is a non-progressive inherited macular dystrophy characterized by marked phenotypic variability. The genetic etiology of NCMD remains largely unknown, and only a limited number of families have been reported in Europe. Methods: We performed an in-depth investigation of an Italian family affected by NCMD using an integrated approach that combined SNP-array analysis, whole-exome sequencing, and long-read whole-genome sequencing. Additionally, we conducted a comprehensive review of NCMD-related literature. Results: We identified a novel 98 Kb duplication involving both PRDM13 and CCNC genes in a three-generation kindred, where the proband exhibited severe macular alterations, while all other affected family members presented with a milder clinical phenotype. A review of the literature suggests different genotype–phenotype correlations and similar penetrance for duplications and single-nucleotide variants (SNVs) in described families. Specifically, smaller duplications may be associated with more severe phenotypes, while SNVs exhibit high phenotypic variability. Conclusions: In this study, we describe the first NCMD Italian family, in which the integration of second- and third-generation sequencing methods enabled the identification of a novel pathogenic PRDM13 and CCNC duplication, thereby expanding the mutational spectrum of NCMD. Overall, these findings, together with the literature review, highlight the importance of selecting appropriate genetic testing approaches that allow the detection of non-coding variants and CNVs and thus enable accurate diagnosis and effective clinical management of patients and their families. Full article

Background: Retinal diseases are becoming an important public health issue, with early diagnosis and timely intervention playing a key role in preventing vision loss. Optical coherence tomography (OCT) remains the leading non-invasive imaging technique for identifying retinal conditions. However, distinguishing between diabetic macular edema (DME) and macular edema resulting from retinal vein occlusion (RVO) can be particularly challenging, especially for clinicians without specialized training in retinal disorders, as both conditions manifest through increased retinal thickness. Due to the limited research exploring the application of deep learning methods, particularly for RVO detection using OCT scans, this study proposes a novel diagnostic approach based on stacked convolutional neural networks. This architecture aims to enhance classification accuracy by integrating multiple neural network layers, enabling more robust feature extraction and improved differentiation between retinal pathologies. Methods: The VGG-16, VGG-19, and ResNet50 models were fine-tuned using the Kermany dataset to classify the OCT images and afterwards were trained using a private OCT dataset. Four stacked models were then developed using these models: a model using the VGG-16 and VGG-19 networks, a model using the VGG-16 and ResNet50 networks, a model using the VGG-19 and ResNet50 models, and finally a model using all three networks. The performance metrics of the model includes accuracy, precision, recall, $F_2$-score, and area under of the receiver operating characteristic curve (AUROC). Results: The stacked neural network using all three models achieved the best results, having an accuracy of 90.7%, precision of 99.2%, a recall of 90.7%, and an $F_2$-score of 92.3%. Conclusions: This study presents a novel method for distinguishing retinal disease by using stacked neural networks. This research aims to provide a reliable tool for ophthalmologists to improve diagnosis accuracy and speed. Full article

Recent findings highlight that Reelin, a glycoprotein involved in neural development, synaptic plasticity, and neuroinflammation, plays some specific roles in neurodegenerative disorders associated with aging, such as age-related macular degeneration (AMD) and Alzheimer’s disease (AD). Reelin modulates synaptic function and guarantees homeostasis in neuronal-associated organs/tissues (brain and retina). The expression of Reelin is dysregulated in these neurological disorders, showing common pathways depending on chronic neurogenic inflammation and/or dysregulation of the extracellular matrix in which Reelin plays outstanding roles. Recently, the relationship between AMD and AD has gained increasing attention as they share many common risk factors (aging, genetic/epigenetic background, smoking, and malnutrition) and histopathological lesions, supporting certain pathophysiological crosstalk between these two diseases, especially regarding neuroinflammation, oxidative stress, and vascular complications. Outside the nervous system, Reelin is largely produced at the gastrointestinal epithelial level, in close association with innervated regions. The expression of Reelin receptors inside the gut suggests interesting aspects in the field of the gut–brain–eye axis, as dysregulation of the intestinal microbiota has been frequently described in neurodegenerative and behavioral disorders (AD, autism, and anxiety and/or depression), most probably linked to inflammatory, neurogenic mediators, including Reelin. Herein we examined previous and recent findings on Reelin and neurodegenerative disorders, offering findings on Reelin’s potential relation with the gut–brain and gut–brain–eye axes and providing novel attractive hypotheses on the gut–brain–eye link through neuromodulator and microbiota interplay. Neurodegenerative disorders will represent the ground for a future starting point for linking the common neurodegenerative biomarkers (β-amyloid and tau) and the new proteins probably engaged in counteracting neurodegeneration and synaptic loss. Full article

Visual field (VF) testing remains a cornerstone in assessing retinal function by measuring how well different parts of the retina detect light. It is essential for early detection, monitoring, and management of many retinal diseases. By mapping retinal sensitivity, VF exams can reveal functional loss before structural changes become visible. This review summarizes how VF testing is applied across key conditions: hydroxychloroquine (HCQ) retinopathy, age-related macular degeneration (AMD), diabetic retinopathy (DR) and macular edema (DME), and inherited disorders including inherited dystrophies such as retinitis pigmentosa (RP). Traditional methods like the Goldmann kinetic perimetry and simple tools such as the Amsler grid help identify large or central VF defects. Automated perimetry (e.g., Humphrey Field Analyzer) provides detailed, quantitative data critical for detecting subtle paracentral scotomas in HCQ retinopathy and central vision loss in AMD. Frequency-doubling technology (FDT) reveals early neural deficits in DR before blood vessel changes appear. Microperimetry offers precise, localized sensitivity maps for macular diseases. Despite its value, VF testing faces challenges including patient fatigue, variability in responses, and interpretation of unreliable results. Recent advances in artificial intelligence, virtual reality perimetry, and home-based perimetry systems are improving test accuracy, accessibility, and patient engagement. Integrating VF exams with these emerging technologies promises more personalized care, earlier intervention, and better long-term outcomes for patients with retinal disease. Full article

Gene therapy has emerged as a promising treatment for several eye diseases since it may restore vision and stop blindness. Many eye diseases, including retinitis pigmentosa and macular degeneration, have historically been rather difficult to treat and usually cause permanent vision loss. However, thanks to advances in gene therapy, many disorders can now be effectively targeted and genetically changed, providing a safer, more direct, maybe even curative approach. By introducing, altering, or repairing specific genes inside the eye, gene therapy seeks to fix the defective genes causing these disorders, thereby improving general eye health and visual ability. Voretigene neparvovec is one FDA- and EMA-approved treatment for RPE65 mutations. Retinitis pigmentosa, age-related macular degeneration, X-linked retinoschisis, choroideremia, and Stargardt disease are among the several eye disorders still under clinical trials, and experimental treatment is in progress. As research on gene therapy develops, it opens the path for groundbreaking treatments that could fundamentally change the ophthalmic care scene. Full article

Background: Age-related macular degeneration (AMD) is one of the leading causes of permanent vision loss in the elderly, particularly in higher-income countries. Fundus autofluorescence (FAF) imaging is a widely used, non-invasive technique that complements structural imaging in the assessment of retinal pigment epithelium (RPE) integrity. While optical coherence tomography (OCT) remains the gold standard for retinal imaging due to its high-resolution cross-sectional visualization, FAF offers unique metabolic insights. Among the FAF modalities, blue light FAF (B-FAF) is more commonly employed, whereas green light FAF (G-FAF) provides subtly different image characteristics, particularly improved visualization and contrast in the central macula. Despite identical acquisition times and nearly indistinguishable workflows, G-FAF is notably underutilized in clinical practice. Objectives: This narrative review critically compares green and blue FAF in terms of their diagnostic utility relative to OCT, with a focus on lesion detectability, macular pigment interference, and clinical decision-making in retinal disorders. Methods: A comprehensive literature search was performed using the PubMed database for studies published prior to February 2025. The search utilized the keywords fundus autofluorescence and age-related macular degeneration. The primary focus was on short-wavelength FAF and its clinical utility in AMD, considering three aspects: diagnosis, follow-up, and prognosis. The OCT findings served as the reference standard for anatomical correlation and diagnostic accuracy. Results: Both FAF modalities correlated well with OCT in detecting RPE abnormalities. G-FAF demonstrated improved visibility of central lesions due to reduced masking by macular pigment and enhanced contrast in the macula. However, clinical preference remained skewed toward B-FAF, driven more by tradition and device default settings than by evidence-based superiority. G-FAF’s diagnostic potential remains underrecognized despite its comparable practicality and subtle imaging advantages specifically for AMD patients. AMD stages were accurately characterized, and relevant images were used to highlight the significance of G-FAF and B-FAF in the examination of AMD patients. Conclusions: While OCT remains the gold standard, FAF provides complementary information that can guide management strategy. Since G-FAF is functionally equivalent in acquisition, it offers slight advantages. Broader awareness and more frequent integration of G-FAF that could optimize multimodal imaging strategies, particularly in the intermediate stage, should be developed. Full article

This pilot study explored whether the ceruloplasmin (CP) and ferritin (FT) levels in ocular fluids could serve as biomarkers for early neurodegenerative diseases (Alzheimer’s, Parkinson’s, and other dementias). CP and FT are known to modulate neurodegenerative tissue responses. We analysed aqueous and vitreous samples from 26 patients (8M/18F, aged 60–85) who were undergoing elective vitreoretinal (VR) surgery. Of these, 14 had idiopathic epiretinal membranes (ERMs), 6 had idiopathic macular holes (MH), and 6 were patients with Alzheimer’s disease (AD) who presented with VR disorders (VRDs). CP, FT, and selected neuroinflammatory mediators such as interferon γ (IFN-γ), interleukin (IL-6), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) were quantified. Odds ratio analysis was applied to assess the CP/FT ratio’s association with subretinal drusen. We found distinct CP and FT profiles in VRD samples. In aqueous fluid, the CP increased and the FT decreased in early-stage ERM, which reduced the CP/FT ratio. Similar patterns were observed in vitreous fluid. The CP levels correlated with the VEGF (aqueous), IL-4 (vitreous), NGF, and BDNF levels; FT correlated with IL-6 and NGF. A higher CP/FT ratio was associated with increased risk for neurodegenerative conditions. Our findings support the quantification of CP and FT in ocular fluids as a promising approach for identifying early neurodegenerative changes and suggest that the CP/FT ratio may be linked to drusen imaging and clinical neurodegenerative history. Full article

Purpose: To evaluate the cost-effectiveness of alternative treatment strategies for subretinal macular hemorrhage (SRMH), a condition often associated with neovascular age-related macular degeneration (AMD) and other retinal vascular disorders, leading to severe visual impairment. Methods: A retrospective cross-sectional study conducted at Oslo University Hospital assessed the cost and utility of various SRMH treatment modalities. These included intravitreal anti-VEGF monotherapy, intravitreal tissue plasminogen activator (tPA) with gas displacement (alone and in combination with anti-VEGF), and pars plana vitrectomy (PPV) with subretinal tPA and gas displacement (with and without anti-VEGF). Costs were analyzed from a healthcare perspective, encompassing direct and indirect costs. Effectiveness was measured using median best-corrected visual acuity (BCVA) improvements. Sensitivity analyses were performed to account for complications and variations in follow-up. Results: Anti-VEGF monotherapy was the most cost-effective treatment, with the lowest cost per unit of BCVA improvement (NOK 44,717) in outpatient settings. Intravitreal tPA with gas displacement emerged as a cost-effective alternative but exhibited higher costs when combined with anti-VEGF or performed as an inpatient procedure. PPV with subretinal tPA and gas displacement, with or without anti-VEGF, was the least cost-effective modality, particularly in inpatient settings. Sensitivity analyses indicated that anti-VEGF therapy remained cost-effective even with increased follow-up requirements and complications, while tPA-based therapies required significant BCVA improvements to match anti-VEGF’s cost–utility. Conclusions: Outpatient intravitreal anti-VEGF monotherapy followed by tPA with gas displacement are the most cost-effective strategies for SRMH management. Subretinal tPA-based treatments are associated with higher costs and limited economic viability, highlighting the importance of tailored treatment selection. These findings support strategic resource allocation in managing SRMH while optimizing patient outcomes. Full article

Age-related macular degeneration (AMD) is a progressive retinal disorder and a leading cause of irreversible blindness among elderly individuals, impacting millions of people globally. This review synthesizes the current understanding of the cellular and molecular signaling mechanisms driving AMD, with a focus on the distinct pathophysiological features of dry and wet AMD subtypes. Key mechanisms include oxidative stress, inflammation, lipid metabolism dysregulation, and immune dysregulation, all of which converge on the retinal pigment epithelium (RPE) as a central player in disease initiation and progression. In dry AMD, oxidative damage, mitochondrial dysfunction, and lipofuscin accumulation impair RPE function, contributing to drusen formation and geographic atrophy. In wet AMD, vascular endothelial growth factor-mediated angiogenesis, coupled with inflammation and endothelial metabolic reprogramming, drives choroidal neovascularization. This article integrates findings from multiomics approaches and highlights the potential of artificial intelligence in elucidating AMD pathogenesis and advancing personalized therapies. Future research directions emphasize targeting these molecular pathways to develop innovative treatments, offering hope for improved management of this debilitating condition. Full article

Background/Objectives: Inherited retinal diseases (IRDs) are a heterogeneous group of rare eye disorders characterized by progressive photoreceptor degeneration, leading to severe visual impairment or even blindness. This study aims to investigate the prevalence, types, and clinical significance of ophthalmic comorbidities in Portuguese patients with IRDs. Methods: This nationwide Portuguese population-based retrospective study was based on the IRD-PT registry (retina.com.pt). Statistical analysis was conducted using Microsoft^® Excel^® for Microsoft 365 and IBM SPSS Statistics version 29.0.2.0. Informed consent was obtained from all participants. Results: A total of 1531 patients (1254 families) from six centers were enrolled. The cohort consisted of 51% males, with a mean age of 45.8 ± 19.3 years and a mean age at diagnosis of 39.4 ± 19.5 years. Overall, ocular comorbidities were reported in 644 patients (42.1%). In 176 individuals (11.5%), multiple concurrent comorbidities were found. Cataract was the most common comorbidity (21.3%), followed by amblyopia (6.3%) and high myopia (5.9%). Statistically significant associations with ocular comorbidities were observed in isolated progressive IRDs. Specifically, AR RP was associated with cataract (p < 0.001), and gene analysis revealed several significant associations. CRB1 was statistically linked to epiretinal membrane (ERM) (p = 0.003), EYS with cataract (p = 0.001), PROM1 with choroidal neovascularization (CNV) (p = 0.0026), and USH2A with macular hole (p = 0.01). Patients with the RPE65 mutation in Leber congenital amaurosis were associated with ERM (p = 0.019). There was also a significant association between X-linked RP and high myopia (p < 0.001) and CNV in Best disease (p < 0.001); in syndromic IRDs, cataract, cystoid macular edema, and ERM were observed in Usher syndrome, p = 0.002, p = 0.002, and p = 0.005, respectively, and the MYO7A gene was linked to cataract (p = 0.041) and strabismus (p = 0.013); pseudoxanthoma elasticum was significantly associated with CNV (p = 0.002); and foveal hypoplasia was associated with anterior segment dysgenesis (p < 0.001). Conclusions: This study enhances the current understanding of ocular comorbidities in IRDs in Portuguese patients. Common findings were cataract, refractive error, and CME. Stationary IRDs and pattern dystrophies showed fewer concomitant comorbidities, supporting their classification as non-progressive or benign conditions. The significance of registries like IRD-PT cannot be overstated, particularly in the context of rare diseases. These databases serve multiple crucial functions in enabling detailed documentation of disease characteristics and long-term monitoring of disease progression. Full article

Pericytes, specialized mural cells surrounding microvessels, play a crucial role in maintaining vascular homeostasis and function across various organs, including the eye. These versatile cells regulate blood flow, support the integrity of the blood–retinal barrier, and contribute to angiogenesis. Recent advancements in molecular and cellular biology have revealed the heterogeneity of pericytes and their critical involvement in ocular physiology and pathology. This review provides a comprehensive analysis of pericyte functions in ocular health and their implications in diseases such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinal vein occlusion. Pericyte dysfunction is implicated in vascular instability, neurovascular coupling failure, inflammation, and pathological neovascularization, contributing to vision-threatening disorders. The review further explores recent findings on pericyte-targeted therapies, including pharmacological agents, gene therapy, and cell-based approaches, aiming to restore pericyte function and preserve ocular health. Full article

Current evidence indicates that most types of autophagy represent a pivot in promoting retinal integrity. In healthy conditions, autophagy acts on multiple pathways, which are fundamental for the biochemistry and the fine structure of the retina. Autophagy is essential in granting visual processes. On the other hand, autophagy dysfunction characterizes several retinal disorders. This is mostly evident in age-related macular degeneration (AMD), which represents the most common degenerative disease leading to blindness. The involvement of autophagy in AMD is documented in vitro and in vivo experiments, and it is strongly suggested by clinical findings in humans. The present manuscript provides an overview of the specific types of autophagy, which prevail in the retina and their alterations in retinal degeneration with an emphasis on AMD. The dysfunction of specific autophagy steps was analyzed in relation to hallmarks of AMD pathology and symptoms. An extended session of the manuscript analyzes the connection between altered autophagy and cell pathology within retinal pigment epithelium, as well as the site and structure of extracellular aggregates named drusen. The significance of the drusen in relation to visual function is discussed in the light of the role of autophagy in regulating key steps of phototransduction. Full article

Advanced glycation end-products (AGEs) and oxidative stress are recognized as central contributors to the pathogenesis of age-related or diabetic cataracts, diabetic retinopathy (DR), and age-related macular degeneration (AMD). These glycation-related diseases are characterized by impaired redox balance and decreased glutathione (GSH) levels. This review aims to examine the mechanistic links between AGEs and GSH depletion across ocular tissues by integrating in vitro, ex vivo, in vivo, and clinical studies relevant to this topic. The multiple levels of evidence highlight GSH homeostasis as both a biomarker and therapeutic target in glycation-related ocular disorders. Therapeutic strategies aimed at restoring GSH homeostasis under glycation stress are categorized into four mechanistic domains: (I) promoting GSH supply and synthesis, (II) enhancing GSH recycling, (III) mitigating glycation stress, and (IV) reducing oxidative and nitrosative stress. Most of these strategies have been explored via different approaches, and experimental findings with various interventions have shown promise in restoring GSH balance and mitigating AGE-induced damage. A pathological link between GSH depletion and vascular endothelial growth factor (VEGF) overexpression is observed in DR and wet AMD. GSH-centered interventions act upstream to modulate redox homeostasis while anti-VEGF therapies target downstream angiogenesis. This study supports the rationale for a dual-targeting strategy that combines redox-based interventions with VEGF inhibition in glycation-related ocular diseases. Full article

Ocular drug delivery presents a persistent clinical challenge due to the protective anatomical structure of the eye, physiological barriers such as reflex blinking, and continuous tear fluid turnover. These factors significantly limit the bioavailability of topically applied medications, reducing the therapeutic effectiveness of conventional formulations, such as eye drops, ointments, and suspensions, particularly in the management of chronic ocular disorders, including dry eye syndrome, diabetic retinopathy, and age-related macular degeneration. Drug-eluting contact lenses (DECLs) offer a promising alternative, enabling sustained, localized, and controlled drug release directly at the ocular surface. While several reviews have addressed contact lenses as drug delivery platforms, this work provides a distinct perspective by focusing specifically on biodegradable polymer-based systems. Emphasis is placed on recent advances in the design and fabrication of DECLs using natural and synthetic biodegradable polymers, which offer superior biocompatibility, customizable degradation kinetics, and the capacity for programmable drug release. This review discusses the selection criteria for polymer matrices, strategies for drug incorporation, and key factors influencing release profiles. Moreover, this study highlights innovative methodologies and therapeutic approaches that differentiate it from the existing literature, providing a timely and comprehensive resource for researchers developing next-generation polymeric ocular drug delivery systems. Full article

Background/Objectives: The retinal microvasculature may reflect systemic vascular health and can be non-invasively imaged using optical coherence tomography angiography (OCTA). Investigation of the capillary plexuses in the macula and the peripapillary area could potentially provide insights into the pathophysiology of ocular manifestations in preeclampsia. We aimed to review the literature on OCTA metrics in preeclampsia to evaluate its use in this condition. Methods: A literature search was performed using the PubMed database, and studies published up to December 2024 were included. Results: We summarized the current evidence on chorioretinal microvascular changes in pregnancy and the ocular manifestations of preeclampsia. We reported findings from seven published studies characterizing the chorioretinal capillary plexuses in preeclampsia using OCTA. These revealed changes in microvasculature characteristics, such as foveal avascular zone size and vessel density in the macula and the peripapillary area; however, there was variability in reported parameters. Conclusions: Microvascular changes in the chorioretinal capillary plexus in preeclampsia were reported by several studies; however, results were inconsistent and may have been affected by multiple factors. Nevertheless, OCTA may have diagnostic and prognostic value, by providing evidence of microcirculation sequalae and aiding our understanding of ocular manifestations in this condition. Further studies are warranted to establish appropriate OCTA acquisition protocols and metrics, and whether these could guide clinical practice in preeclampsia. Full article