ABSTRACT
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and systems. Ocular involvement is estimated to manifest in one-third of individuals with SLE, of which lupus retinopathy and choroidopathy represent the severe subtype accompanied by vision impairment. Advancements in multimodal ophthalmic imaging have allowed ophthalmologists to reveal subclinical microvascular and structural changes in fundus of patients with SLE without ocular manifestations. Both ocular manifestations and subclinical fundus damage have been shown to correlate with SLE disease activity and, in some patients, even precede other systemic injuries as the first presentation of SLE. Moreover, ocular fundus might serve as a window into the state of systemic vasculitis in patients with SLE. Given the similarities of the anatomy, physiological and pathological processes shared among ocular fundus, and other vital organ damage in SLE, such as kidney and brain, it is assumed that ocular fundus involvement has implications in the diagnosis and evaluation of other systemic impairments. Therefore, evaluating the fundus characteristics of patients with SLE not only contributes to the early diagnosis and intervention of potential vision damage, but also holds considerate significance for the evaluation of SLE vasculitis state and prediction of other systemic injuries.
Subject(s)
Fundus Oculi , Lupus Erythematosus, Systemic , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , Retinal Diseases/etiology , Retinal Diseases/diagnosis , Retinal Diseases/pathology , Choroid Diseases/etiology , Choroid Diseases/diagnosisSubject(s)
Coloboma , Optic Disk , Humans , Coloboma/complications , Coloboma/diagnosis , Coloboma/diagnostic imaging , Optic Disk/abnormalities , Optic Disk/diagnostic imaging , Male , Tomography, Optical Coherence , Female , Retinal Diseases/complications , Retinal Diseases/diagnosis , Retinal Diseases/diagnostic imagingABSTRACT
BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare autosomal dominant systemic microvascular disorder attributed to TREX1 (three-prime repair exonuclease-1) gene mutations, often proned to misdiagnosed. METHODS: We reported a case of RVCL-S coexisting with systemic lupus erythematosus due to a mutation in the TREX1 gene. This study provided a summary and discussion of previously documented cases related to TREX1 mutations or RVCL-S. RESULTS: A 39-year-old female patient visited the clinic due to progressive memory loss and speech difficulties. Magnetic resonance imaging results showed corpus callosum atrophy and multiple subcortical calcifications in both brain hemispheres. Genetic testing revealed a TREX1 gene mutation (c.294dupA). Treatment with immunosuppressive therapy for 2 months led to improvements in communication and mobility. We also summarized previously reported cases providing an overview of TREX1 gene mutation or RCVL-S. CONCLUSION: Our case establishes a compelling foundation for future RVCL-S diagnosis and treatment paradigms. Notably, conducting systemic immunity screening in patients with RVCL-S emerges as a strategic approach to prevent potential diagnostic oversights.
Subject(s)
Exodeoxyribonucleases , Leukoencephalopathies , Lupus Erythematosus, Systemic , Mutation , Humans , Female , Adult , Exodeoxyribonucleases/genetics , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/genetics , Leukoencephalopathies/diagnosis , Leukoencephalopathies/genetics , Leukoencephalopathies/etiology , Phosphoproteins/genetics , Diagnostic Errors/prevention & control , Magnetic Resonance Imaging , Retinal Vasculitis/diagnosis , Retinal Vasculitis/etiology , Retinal Diseases , Vascular Diseases , Hereditary Central Nervous System Demyelinating DiseasesABSTRACT
Ischemic retinopathies including diabetic retinopathy are major causes of vision loss. Inner blood-retinal barrier (BRB) breakdown with retinal vascular hyperpermeability results in macular edema. Although dysfunction of the neurovascular unit including neurons, glia, and vascular cells is now understood to underlie this process, there is a need for fuller elucidation of the underlying events in BRB dysfunction in ischemic disease, including a systematic analysis of myeloid cells and exploration of cellular cross-talk. We used an approach for microglia depletion with the CSF-1R inhibitor PLX5622 (PLX) in the retinal ischemia-reperfusion (IR) model. Under non-IR conditions, PLX treatment successfully depleted microglia in the retina. PLX suppressed the microglial activation response following IR as well as infiltration of monocyte-derived macrophages. This occurred in association with reduction of retinal expression of chemokines including CCL2 and the inflammatory adhesion molecule ICAM-1. In addition, there was a marked suppression of retinal neuroinflammation with reduction in expression of IL-1b, IL-6, Ptgs2, TNF-a, and Angpt2, a protein that regulates BRB permeability. PLX treatment significantly suppressed inner BRB breakdown following IR, without an appreciable effect on neuronal dysfunction. A translatomic analysis of Müller glial-specific gene expression in vivo using the Ribotag approach demonstrated a strong suppression of Müller cell expression of multiple pro-inflammatory genes following PLX treatment. Co-culture studies of Müller cells and microglia demonstrated that activated microglia directly upregulates Müller cell-expression of these inflammatory genes, indicating Müller cells as a downstream effector of myeloid cells in retinal IR. Co-culture studies of these two cell types with endothelial cells demonstrated the ability of both activated microglia and Müller cells to compromise EC barrier function. Interestingly, quiescent Müller cells enhanced EC barrier function in this co-culture system. Together this demonstrates a pivotal role for myeloid cells in inner BRB breakdown in the setting of ischemia-associated disease and indicates that myeloid cells play a major role in iBRB dysregulation, through direct and indirect effects, while Müller glia participate in amplifying the neuroinflammatory effect of myeloid cells.
Subject(s)
Blood-Retinal Barrier , Ependymoglial Cells , Myeloid Cells , Blood-Retinal Barrier/drug effects , Blood-Retinal Barrier/metabolism , Blood-Retinal Barrier/pathology , Animals , Mice , Ependymoglial Cells/metabolism , Ependymoglial Cells/drug effects , Ependymoglial Cells/pathology , Myeloid Cells/metabolism , Myeloid Cells/drug effects , Mice, Inbred C57BL , Retinal Diseases/pathology , Retinal Diseases/metabolism , Ischemia/metabolism , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Male , Microglia/metabolism , Microglia/drug effects , Organic ChemicalsABSTRACT
Purpose: High altitude retinopathy (HAR) is a retinal functional disorder caused by inadequate adaptation after exposure to high altitude. However, the cellular and molecular mechanisms underlying retinal dysfunction remain elusive. Retinal ganglion cell (RGC) injury is the most important pathological basis for most retinal and optic nerve diseases. Studies focusing on RGC injury after high-altitude exposure (HAE) are scanty. Therefore, the present study sought to explore both functional and morphological alterations of RGCs after HAE. Methods: A mouse model of acute hypobaric hypoxia was established by mimicking the conditions of a high altitude of 5000 m. After HAE for 2, 4, 6, 10, 24, and 72 hours, the functional and morphological alterations of RGCs were assessed using retinal hematoxylin and eosin (H&E) sections, retinal whole mounts, transmission electron microscopy (TEM), and the photopic negative response (PhNR) of the electroretinogram. Results: Compared with the control group, the thickness of the ganglion cell layer and retinal nerve fiber layer increased significantly, RGC loss remained significant, and the amplitudes of a-wave, b-wave, and PhNR were significantly reduced after HAE. In addition, RGCs and their axons exhibited an abnormal ultrastructure after HAE, including nuclear membrane abnormalities, uneven distribution of chromatin in the nucleus, decreased cytoplasmic electron density, widening and vacuolization of the gap between axons, loosening and disorder of myelin sheath structure, widening of the gap between myelin sheath and axon membrane, decreased axoplasmic density, unclear microtubule and nerve fiber structure, and abnormal mitochondrial structure (mostly swollen, with widened membrane gaps and reduced cristae and vacuolization). Conclusions: The study findings confirm that the morphology and function of RGCs are damaged after HAE. These findings lay the foundation for further study of the specific molecular mechanisms of HAR and promote the effective prevention.
Subject(s)
Disease Models, Animal , Electroretinography , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Retinal Ganglion Cells , Animals , Retinal Ganglion Cells/pathology , Retinal Ganglion Cells/ultrastructure , Mice , Male , Altitude Sickness/physiopathology , Altitude Sickness/pathology , Retinal Diseases/physiopathology , Retinal Diseases/etiology , Retinal Diseases/pathology , Altitude , Acute DiseaseSubject(s)
Fluorescein Angiography , Retinal Artery Occlusion , Susac Syndrome , Tomography, Optical Coherence , Humans , Retinal Artery Occlusion/etiology , Retinal Artery Occlusion/diagnosis , Susac Syndrome/diagnosis , Susac Syndrome/complications , Tomography, Optical Coherence/methods , Fluorescein Angiography/methods , Female , Acute Disease , Retinal Diseases/etiology , Retinal Diseases/diagnosis , Adult , Macula Lutea/diagnostic imaging , Macula Lutea/pathology , Visual Acuity/physiology , MaleABSTRACT
PURPOSE: To determine the importance of optical coherence tomography (OCT) in patients scheduled for cataract surgery who present with no pathologies in biomicroscopic fundus examination. DESIGN: Retrospective study. METHODS: In this study, the routine ophthalmologic examination of patients who were recommended cataract surgery was performed.Occult retinal pathologies were evaluated using OCT in patients without any pathologies in biomicroscopic fundus examination.According to whether retinal pathologies were detected on OCT, the patients were divided into two groups: normal and abnormal OCT.The findings of patients with retinal pathologies on OCT and their distribution according to age were also evaluated. RESULTS: A total of 271 eyes from 271 patients were evaluated.The number of patients with retinal pathologies on OCT despite normal fundoscopic examination findings was 38(14.0%).Of these patients,15(39.4%) had an epiretinal membrane,10(26.3%) had age-related macular degeneration, eight(21%) had vitreomacular traction, two(5.2%) had a lamellar hole, and 1(2.6%) patient each had a full-thickness macular hole, an intraretinal cyst, and photoreceptor layer damage.The age distribution of the patients with retinal pathologies was as follows: two patients,<60 years; six patients,60-70 years;14 patients,70-80 years; and 16 patients,>80 years.The rate of patients aged > 70 years and above was 78.9%.There was no statistically significant difference between the normal and abnormal OCT groups in terms of age, gender, the presence of systemic diseases, visual acuity, central macular thickness, and cataract type or density(p > 0.05 for all). CONCLUSION: In one of seven patients evaluated, retinal pathologies were detected on OCT despite normal fundoscopic examination findings.OCT can be used to detect occult retinal pathologies that cannot be detected by biomicroscopic fundus examination before cataract surgery.
Subject(s)
Cataract Extraction , Retinal Diseases , Tomography, Optical Coherence , Humans , Tomography, Optical Coherence/methods , Retrospective Studies , Aged , Middle Aged , Male , Female , Aged, 80 and over , Retinal Diseases/diagnosis , Retinal Diseases/diagnostic imaging , Adult , Visual Acuity , Cataract/diagnosis , Cataract/complications , Cataract/diagnostic imaging , Preoperative Care/methodsABSTRACT
Retinal injury may be exacerbated by iron overload. Astragaloside IV (AS-IV) has potential applications in the food and healthcare industry to promote eye health. We sought to determine the mechanisms responsible for the protective effects of AS-IV on photoreceptor and retinal pigment epithelium cell death induced by iron overload. We conducted in vitro and in vivo experiments involving AS-IV pretreatment. We tested AS-IV for its ability to protect iron-overload mice from retinal injury. In particular, we analyzed the effects of AS-IV on iron overload-induced ferroptosis in 661W and ARPE-19 cells. AS-IV not only attenuated iron deposition and retinal injury in iron-overload mice but also effectively reduced iron overload-induced ferroptotic cell death in 661W and ARPE-19 cells. AS-IV effectively prevented ferroptosis by inhibiting iron accumulation and lipid peroxidation. In addition, inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) eliminated the protective effect of AS-IV against ferroptosis. The results suggest that ferroptosis might be a significant cause of retinal cell death associated with iron overload. AS-IV provides protection from iron overload-induced ferroptosis, partly by activating the Nrf2 signaling pathway.
Subject(s)
Ferroptosis , Iron Overload , Mice, Inbred C57BL , Retinal Pigment Epithelium , Saponins , Triterpenes , Ferroptosis/drug effects , Animals , Triterpenes/pharmacology , Triterpenes/therapeutic use , Saponins/pharmacology , Iron Overload/metabolism , Iron Overload/drug therapy , Mice , Retinal Pigment Epithelium/drug effects , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/pathology , Disease Models, Animal , Lipid Peroxidation/drug effects , Humans , Retinal Diseases/prevention & control , Retinal Diseases/metabolism , Retinal Diseases/pathology , Retinal Diseases/drug therapy , NF-E2-Related Factor 2/metabolism , Blotting, Western , Male , Iron/metabolismABSTRACT
PURPOSE: To investigate the pathophysiology and prognostic significance of acute Henle fiber layer (HFL) hyperreflectivity in placoid diseases by examining its relationship with impaired choroidal flow and persistent photoreceptor disruption. METHODS: Retrospective-prospective observational study on patients with placoid diseases. Indocyanine green angiography and optical coherence tomography were performed during the acute phase and follow-up. Impaired choroidal flow, HFL hyperreflectivity, and persistent ellipsoid zone disruption, their colocalization index, and their associations with initial and final visual acuity were explored. RESULTS: Sixteen eyes from eight patients (mean age, 25.3 ± 6.44 years) were included (median follow-up, 13.5 months). Quantitative analysis revealed significant correlations between areas of impaired choroidal flow, HFL hyperreflectivity, and persistent ellipsoid zone disruption (correlation coefficients of 0.69, 0.63, and 0.46, respectively). Impaired choroidal flow area exceeded HFL hyperreflectivity (P = 0.002) and ellipsoid zone disruption (P = 0.003). A noteworthy 94% nonrandom overlap between HFL hyperreflectivity and ellipsoid zone disruption was observed. Worse initial visual acuity correlated with foveal involvement (P = 0.0002), thicker choroid (P = 0.001), larger impaired choroidal flow areas (P = 0.02), and thinner outer retina post lesion inactivation (P = 0.04). CONCLUSION: Henle fiber layer hyperreflectivity predicted photoreceptor recovery potential in placoid diseases. If HFL hyperreflectivity corresponds to acute HFL damage, it may suggest more severe involvement of the entire photoreceptor length.
Subject(s)
Choroid , Fluorescein Angiography , Tomography, Optical Coherence , Visual Acuity , Humans , Tomography, Optical Coherence/methods , Female , Male , Adult , Retrospective Studies , Visual Acuity/physiology , Fluorescein Angiography/methods , Prospective Studies , Prognosis , Young Adult , Choroid/pathology , Choroid/diagnostic imaging , Choroid/blood supply , Adolescent , Follow-Up Studies , Retinal Diseases/physiopathology , Retinal Diseases/diagnosis , Fundus Oculi , Acute DiseaseABSTRACT
PURPOSE: Evaluating the presence of class 3, 4, and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO). METHODS: Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmologic history, complete ophthalmologic examination, antiretinal antibodies, and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: nonparaneoplastic autoimmune retinopathy, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy. RESULTS: The authors included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20-68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, two also demonstrated class 5 variants in other IRD genes. The remaining five patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) nonparaneoplastic autoimmune retinopathy patient in the RUO cohort. When considering the nonparaneoplastic autoimmune retinopathy subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved. CONCLUSION: Every suspected nonparaneoplastic autoimmune retinopathy patient should benefit from gene panel testing to not overlook undiagnosed IRDs. By contrast, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy subpopulations did not benefit from genetic testing in this study.
Subject(s)
Retinal Diseases , Humans , Female , Retrospective Studies , Male , Middle Aged , Adult , Retinal Diseases/genetics , Retinal Diseases/diagnosis , Aged , Young Adult , Genetic Testing/methods , Mutation , Eye Proteins/geneticsABSTRACT
BACKGROUND: Topical non-steroidal anti-inflammatory drugs have the potential to reduce treatment burden and improve outcomes of anti-VEGF therapy for a number of retinal disorders, including neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. In this review, we focused on the advantages of topical bromfenac as an adjunct to intravitreal anti-VEGF therapy in VEGF-driven maculopathies. METHODS: Cochrane Library, PubMed, and EMBASE were systematically reviewed to identify the relevant studies of neovascular age-related macular degeneration, diabetic macular edema, macular edema associated with retinal vein occlusion, myopic choroidal neovascularization, and radiation maculopathy which reported changes in central retinal thickness, visual acuity, and the number of anti-VEGF injections needed when anti-VEGF therapy was combined with topical bromfenac. RESULTS: In total, ten studies evaluating bromfenac as an adjunct to anti-VEGF therapy were identified. Five studies were included in meta-analysis of the number of injections and five studies were included in the analysis of changes in central retinal thickness. A statistically significantly lower number of intravitreal injections (p = 0.005) was required when bromfenac was used as an adjunct to anti-VEGF therapy compared to anti-VEGF monotherapy with pro re nata regimen. At the same time, eyes receiving bromfenac as an adjunct to anti-VEGF therapy demonstrated non-inferior outcomes in central retinal thickness (p = 0.07). Except for one study which reported better visual outcomes with combined treatment, no difference in visual acuity or clinically significant adverse effects were reported. CONCLUSIONS: This literature review and meta-analysis showed that topical bromfenac can be considered as a safe adjunct to anti-VEGF therapy with a potential to reduce the treatment burden with anti-VEGF drugs requiring frequent injections without compromising improvement of central retinal thickness or visual acuity.
Subject(s)
Angiogenesis Inhibitors , Anti-Inflammatory Agents, Non-Steroidal , Benzophenones , Bromobenzenes , Vascular Endothelial Growth Factor A , Humans , Administration, Topical , Angiogenesis Inhibitors/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Benzophenones/administration & dosage , Bromobenzenes/administration & dosage , Intravitreal Injections , Macular Edema/drug therapy , Ophthalmic Solutions/administration & dosage , Retinal Diseases/drug therapy , Retinal Diseases/physiopathology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Visual AcuityABSTRACT
BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is a rare autosomal dominant disease caused by mutations in KIF11 which disrupt EG5 protein function, impacting the development and maintenance of retinal and lymphatic structures due to its expression in the retinal photoreceptor cilia. The primary ocular finding in MCLMR is chorioretinopathy. Additional features can include microphthalmia, angle-closure glaucoma, persistent hyperplastic primary vitreous, cataract, pseudo-coloboma, persistent hyaloid artery, and myopic or hypermetropic astigmatism. The appearance of the chorioretinal lesions as white to pinkish, round, non-elevated atrophic areas devoid of blood vessels resembles the lacunae in Aicardy syndrome. Due to the lack of systematic description of the lesions and significant phenotypical variability, there is an impending need for a detailed report of each case. CASE PRESENTATION: A child with microcephaly detected in the third trimester of gestation began her following in the ophthalmology department due to a non-visually significant cataract. Shortly after, she developed nystagmus and large-angle alternating esotropia with cross-fixation. Her fundus initially showed a pallid optic disc and pigmentary changes, developing thereafter retinal lacunae and a retinal fold. Her differential diagnosis accompanied the dynamic changes in her fundus, which included congenital infections, Leber´s Congenital Amaurosis and Aicardy syndrome. At 19 months old, genetic testing identified a heterozygous mutation (c.1159 C > T, p.Arg387*) in the KIF11 gene. The patient underwent bilateral medial rectus muscle recession surgery at 2 years old for persistent esotropia, with significant improvement. Refraction revealed a hyperopic astigmatism in both eyes (+ 0.25 -2.50 × 180 OD and + 0.75 -2.00 × 170 OS). She continues to require right eye patching for 2 hours daily. CONCLUSIONS: This case report expands the phenotypic spectrum of MCLMR by demonstrating a unique combination of retinal features which sheds new light on differential diagnosis from Aicardy syndrome. Our findings emphasize the significant phenotypic variability associated with MCLMR, particularly regarding ocular involvement. This underscores the importance of detailed clinical evaluation and comprehensive reporting of cases to improve our understanding of the disease spectrum and genotype-phenotype correlations.
Subject(s)
Intellectual Disability , Lymphedema , Microcephaly , Humans , Microcephaly/genetics , Microcephaly/diagnosis , Female , Lymphedema/genetics , Lymphedema/diagnosis , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Retinal Diseases/diagnosis , Retinal Diseases/genetics , Retinal Dysplasia , Kinesins , FaciesABSTRACT
In ophthalmology, Optical Coherence Tomography (OCT) has become a daily used tool in the diagnostics and therapeutic planning of various diseases. Publicly available datasets play a crucial role in advancing research by providing access to diverse imaging data for algorithm development. The accessibility, data format, annotations, and metadata are not consistent across OCT datasets, making it challenging to efficiently use the available resources. This article provides a comprehensive analysis of different OCT datasets, with particular attention to dataset properties, disease representation, accessibility, and aims to create a catalog of all publicly available OCT datasets. The goal is to improve accessibility to OCT data, increase openness about the availability, and give important new perspectives on the state of OCT imaging resources. Our findings reveal the need for improved data-sharing practices and standardized documentation.
Subject(s)
Tomography, Optical Coherence , Humans , Retinal Diseases/diagnostic imaging , Databases, Factual , Retina/diagnostic imaging , Information DisseminationABSTRACT
The retina is one of the highest metabolically active tissues with a high oxygen consumption, so insufficient blood supply leads to visual impairment. The incidence of related conditions is increasing; however, no effective treatment without side effects is available. Furthermore, the pathomechanism of these diseases is not fully understood. Our aim was to develop an optimal ischemic retinopathy mouse model to investigate the retinal damage in a time-dependent manner. Retinal ischemia was induced by bilateral common carotid artery occlusion (BCCAO) for 10, 13, 15 or 20 min, or by right permanent unilateral common carotid artery occlusion (UCCAO). Optical coherence tomography was used to follow the changes in retinal thickness 3, 7, 14, 21 and 28 days after surgery. The number of ganglion cells was evaluated in the central and peripheral regions on whole-mount retina preparations. Expression of glial fibrillary acidic protein (GFAP) was analyzed with immunohistochemistry and Western blot. Retinal degeneration and ganglion cell loss was observed in multiple groups. Our results suggest that the 20 min BCCAO is a good model to investigate the consequences of ischemia and reperfusion in the retina in a time-dependent manner, while the UCCAO causes more severe damage in a short time, so it can be used for testing new drugs.
Subject(s)
Disease Models, Animal , Glial Fibrillary Acidic Protein , Hypoxia , Ischemia , Retina , Tomography, Optical Coherence , Animals , Mice , Ischemia/metabolism , Ischemia/pathology , Glial Fibrillary Acidic Protein/metabolism , Retina/metabolism , Retina/pathology , Hypoxia/metabolism , Retinal Diseases/metabolism , Retinal Diseases/pathology , Retinal Diseases/etiology , Male , Retinal Ganglion Cells/pathology , Retinal Ganglion Cells/metabolism , Mice, Inbred C57BL , Time FactorsABSTRACT
Patient-specific induced pluripotent stem cell-derived (iPSC-derived) cell lines allow for therapies to be tailored to individual patients, increasing therapeutic precision and efficiency. Bietti crystalline dystrophy (BCD) is a rare blinding disease estimated to affect about 67,000 individuals worldwide. Here, we used iPSC-derived retinal pigment epithelium (iRPE) cells from patients with BCD to evaluate adeno-associated virus-mediated (AAV-mediated) gene augmentation therapy strategies. We found that BCD iRPE cells were vulnerable to blue light-induced oxidative stress and that cellular phenotype can be quantified using 3 robust biomarkers: reactive oxygen species (ROS), 4-hydroxy 2-nonenal (4-HNE) levels, and cell death rate. Additionally, we demonstrated that AAV-mediated gene therapy can significantly reduce light-induced cell death in BCD iRPE cells. This is the first proof-of-concept study to our knowledge to show that AAV-CYP4V2 gene therapy can be used to treat light-induced RPE damage in BCD. Furthermore, we observed significant variability in cellular phenotypes among iRPE from patients with BCD of divergent mutations, which outlined genotype-phenotype correlations in BCD patient-specific cell disease models. Our results reveal that patient-specific iRPE cells retained personalized responses to AAV-mediated gene therapy. Therefore, this approach can advance BCD therapy and set a precedent for precision medicine in other diseases, emphasizing the necessity for personalization in healthcare to accommodate individual diversity.
Subject(s)
Corneal Dystrophies, Hereditary , Dependovirus , Genetic Therapy , Induced Pluripotent Stem Cells , Precision Medicine , Retinal Pigment Epithelium , Humans , Precision Medicine/methods , Genetic Therapy/methods , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/pathology , Induced Pluripotent Stem Cells/metabolism , Corneal Dystrophies, Hereditary/therapy , Corneal Dystrophies, Hereditary/genetics , Corneal Dystrophies, Hereditary/metabolism , Corneal Dystrophies, Hereditary/pathology , Dependovirus/genetics , Oxidative Stress/genetics , Cytochrome P450 Family 4/genetics , Cytochrome P450 Family 4/metabolism , Reactive Oxygen Species/metabolism , Retinal Diseases/therapy , Retinal Diseases/genetics , Retinal Diseases/pathology , Aldehydes/metabolism , MaleABSTRACT
PURPOSE: The aim of this study was to explore the potential benefits of retinal pigment epithelium replacement therapy in patients with Bietti crystalline dystrophy (BCD) by assessing the disease pathology with the distinctive relationship between fundus autofluorescence (FAF) abnormality and visual field defect. METHODS: Sixteen eyes from 16 patients with BCD and 16 eyes from 16 patients with RHO-associated retinitis pigmentosa were included. Fundus autofluorescence, optical coherence tomography, and Goldmann perimetry results were retrospectively reviewed and assessed using image analyses. RESULTS: In patients with BCD, the FAF abnormality area was not correlated with the overall visual field defect area and median overall visual field defect area (57.5%) was smaller than FAF abnormality area (98.5%). By contrast, the ellipsoid zone width was significantly correlated with the central visual field area (r = 0.806, P < 0.001). In patients with RHO-associated retinitis pigmentosa, the FAF abnormality area and ellipsoid zone width were significantly correlated with the overall visual field defect area (r = 0.833, P < 0.001) and central visual field area (r = 0.887, P < 0.001), respectively. CONCLUSION: The FAF abnormality shown in patients with BCD involves retinal pigment epithelium degeneration without complete loss of photoreceptors or visual function. These results suggest that patients with BCD are good candidates for retinal pigment epithelium replacement therapy for preservation of residual visual function.
Subject(s)
Corneal Dystrophies, Hereditary , Fluorescein Angiography , Fundus Oculi , Retinal Pigment Epithelium , Tomography, Optical Coherence , Visual Acuity , Visual Field Tests , Visual Fields , Humans , Visual Fields/physiology , Female , Male , Retrospective Studies , Middle Aged , Tomography, Optical Coherence/methods , Corneal Dystrophies, Hereditary/diagnosis , Corneal Dystrophies, Hereditary/physiopathology , Fluorescein Angiography/methods , Adult , Retinal Pigment Epithelium/pathology , Aged , Visual Acuity/physiology , Retinal Diseases/diagnosis , Retinal Diseases/physiopathology , Vision Disorders/physiopathology , Vision Disorders/diagnosis , Optical Imaging , Retinitis Pigmentosa/physiopathology , Retinitis Pigmentosa/diagnosis , Young AdultABSTRACT
PURPOSE: To provide a genotype and phenotype characterization of the BEST1 mutation in Chinese patients with autosomal recessive bestrophinopathy (ARB) through multimodal imaging and next-generation sequencing (NGS). METHODS: Seventeen patients from 17 unrelated families of Chinese origin with ARB were included in a retrospective cohort study. Phenotypic characteristics, including anterior segment features, were assessed by multimodal imaging. Multigene panel testing, involving 586 ophthalmic disease-associated genes, and Sanger sequencing were performed to identify disease-causing variants. RESULTS: Among 17 ARB patients, the mean follow-up was 15.65 months and average onset age was 30.53 years (range: 9-68). Best corrected visual acuity ranged from light perception to 0.8. EOG recordings showed a typically decreased Arden ratio in 12 patients, and a normal or slightly decreased Arden ratio in two patients. Anterior features included shallow anterior chambers (16/17), ciliary pronation (16/17), iris bombe (13/17), iridoschisis (2/17), iris plateau (1/17), narrow angles (16/17) and reduced axial lengths (16/17). Sixteen patients had multiple bilateral small, round, yellow vitelliform deposits distributed throughout the posterior pole, surrounding the optic disc. Initial diagnoses included angle-closure glaucoma (four patients), Best disease (three patients), and central serous chorioretinopathy secondary to choroidal neovascularization (CNV) (one patient), with the remainder diagnosed with ARB. Fourteen patients underwent preventive laser peripheral iridotomy, four of whom also received combined trabeculectomy and iridotomy in both eyes for uncontrolled intraocular pressure. One patient received intravitreal conbercept for CNV. Overall, 15 distinct disease-causing variants of BEST1 were identified, with 14 (82.35%) patients having missense mutations. Common mutations included p. Arg255-256 and p. Ala195Val (both 23.68%), with the most frequent sites in exons 7 and 5. CONCLUSIONS: This study provides a comprehensive characterization of anterior segment and genetic features in ARB, with a wide array of morphological abnormalities. Findings are relevant for refining clinical practices and genetic counseling and advancing pathogenesis research.
Subject(s)
Bestrophins , Eye Diseases, Hereditary , Visual Acuity , Adolescent , Adult , Aged , Child , Female , Humans , Male , Middle Aged , Young Adult , Bestrophins/genetics , China/epidemiology , DNA Mutational Analysis , East Asian People , Electrooculography , Electroretinography , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/diagnosis , Follow-Up Studies , Genotype , High-Throughput Nucleotide Sequencing , Multimodal Imaging , Mutation , Pedigree , Phenotype , Retinal Diseases/genetics , Retinal Diseases/diagnosis , Retrospective Studies , Tomography, Optical Coherence , Visual Acuity/physiologyABSTRACT
Lycium ruthenicum Murray (LR) is a medicine and edible plant in Northwest China, and L. ruthenicum Murray anthocyanins (LRA) are green antioxidants with various pharmacological activities, such as antioxidant and anti-inflammatory activities. However, the protective effect and mechanism of LRA against retinal damage induced by blue light exposure are poorly understood. This study explored the protective effects and potential mechanisms of LRA on retinal damage induced by blue light exposure in vitro and in vivo. The results showed that LRA could ameliorate oxidative stress injury by activating the antioxidant stress nuclear factor-related factor 2 pathway, promoting the expression of phase II detoxification enzymes (HO-1, NQO1) and endogenous antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase), and reducing reactive oxygen species and malondialdehyde levels. Additionally, LRA could inhibit inflammatory response by decreasing the expression of blue light exposure-induced nuclear factor-κB (NF-κB) pathway-related proteins (NF-κB and p-IκBα), as well as interleukin (IL)-6, tumor necrosis factor-α, IL-1ß pro-inflammatory factors and pro-inflammatory chemokine VEGF, and increasing the expression of anti-inflammatory factor IL-10. Furthermore, LRA could ameliorate oxidative stress-induced apoptosis by upregulating Bcl-2 and downregulating Bax and Caspase-3 protein expression. All these results indicate that LRA can be used as an antioxidant dietary supplement for the treatment or prevention of retinal diseases.
Subject(s)
Anthocyanins , Antioxidants , Apoptosis , Light , Lycium , Oxidative Stress , Retina , Lycium/chemistry , Animals , Anthocyanins/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/radiation effects , Retina/radiation effects , Retina/drug effects , Retina/metabolism , Light/adverse effects , Antioxidants/pharmacology , Mice , Apoptosis/drug effects , Apoptosis/radiation effects , Male , Plant Extracts/pharmacology , Reactive Oxygen Species/metabolism , NF-kappa B/metabolism , Protective Agents/pharmacology , Malondialdehyde/metabolism , Anti-Inflammatory Agents/pharmacology , Superoxide Dismutase/metabolism , Retinal Diseases/prevention & control , Retinal Diseases/etiology , Blue LightABSTRACT
PURPOSE: To report optical coherence tomography findings of presumed veterinary anthelmintic drugs (VADs)-induced retinal toxicity that may aid in understanding potential pathogenic mechanisms. METHODS: This is a retrospective observational case series analysis of patients with vision abnormalities following the accidental or intentional consumption of veterinary anthelmintic drugs. All cases underwent a thorough ophthalmological examination. Moreover, medical records, as well as the initial and follow-up optical coherence tomography images, were thoroughly scrutinized. RESULTS: Four patients were identified (3 men; mean [range] age, 36.5 [22-52] years). Each patient overdosed on one or two of the following VADs: closantel, triclabendazole, praziquantel, pyrantel pamoate, and niclofolan. The most characteristic optical coherence tomography finding was diffuse, granular, hyperreflective lesions throughout the outer retina, which were initially identified in the ellipsoid zone in two cases. At follow-up, optical coherence tomography exhibited regression of hyperreflective lesions and extensive loss of the outer retinal elements in two patients. In addition, the subfoveal outer retinal layers may be partially preserved. CONCLUSION: Some veterinary anthelmintic drugs could be detrimental to the human retina if overdosed, resulting in visual disturbances. Optical coherence tomography revealed the mitochondria-enriched ellipsoid zone where outer retinal damage first appeared on, implying that these medications may harm the retina by inhibiting mitochondrial energy metabolism, as they do to eliminate parasites.