PURPOSE:To identify peripheral retinal vascular phenotypes in retinitis pigmentosa (RP) using ultra-widefield OCT angiography (UWF-OCTA), validate a quantitative vascular biomarker, and develop a clinically applicable severity grading system. DESIGN:Development and validation of a severity grading system. METHODS:We analyzed 544 eyes from 272 patients with primary RP from three tertiary centers. Peripheral vascular phenotypes were defined using UWF-OCTA. Structure-function correlations between the CNZ area and multimodal visual functions-including kinetic perimetry (KP), full-field stimulus threshold (FST), and static perimetry (SP)-were evaluated using linear mixed-effects models (LMMs) to account for inter-eye correlation. A four-stage severity grading system was developed using principal component analysis (PCA) to construct a composite functional score and regression tree analysis with cluster bootstrapping (1,000 resamples) to determine optimal CNZ cut-points; the system was then validated in internal and external datasets. Age-related severity distribution was evaluated through a Kaplan-Meier age-at-observation simulation. RESULTS:Two distinct peripheral vascular phenotypes were identified: Type 1 (Terminal Remodeling; 306 eyes, 56.2%) and Type 2 (Simple Atrophy; 238 eyes, 43.8%). Type 1 eyes showed greater disease severity than Type 2 eyes at comparable ages. The CNZ area demonstrated strong structure-function correlations, explaining substantial variance in KP (Marginal R2 up to 0.77) and FST (Marginal R2 up to 0.64). A CNZ-based 4-stage severity grading (Stage I, ≥ 260 mm²; Stage II, 200-260 mm²; Stage III, 150-200 mm²; Stage IV, < 150 mm²) effectively stratified disease severity, demonstrating high explanatory power for visual function (KP η² up to 0.75; FST η² up to 0.66) and maintaining discriminatory performance for best-corrected visual acuity (BCVA) in both internal (η² = 0.17) and external (η² = 0.28) validation cohorts. CONCLUSIONS:Peripheral retinal vascular alterations captured by UWF-OCTA define distinct RP phenotypes and identify the CNZ as a robust quantitative biomarker of disease severity. The CNZ-based severity grading system provides an objective framework for clinical severity assessment, disease monitoring, and patient stratification in future interventional trials.

Background To evaluate the central-field stimulus threshold (CST) values in patients with age-related macular degeneration (AMD) and investigate the relationship between CST values and conventional visual function assessments, as well as retinal anatomical parameters, thereby exploring the role of CST in assessing anti-vascular endothelial growth factor (VEGF) therapy. Methods Forty patients (80 eyes) with AMD were included in the analysis. All patients underwent complete ophthalmic examination, including slit-lamp examination, fundus examination, intraocular pressure measurement, Early Treatment Diabetic Retinopathy Study best-corrected visual acuity (BCVA), fundus photography, optical coherence tomography (OCT), OCT angiography, microperimetry (MP), and CST testing. Linear mixed-effects models and generalized linear mixed models were employed to analyze the correlations between CST and BCVA, MP, OCT features, and choroidal neovascularization (CNV) area, as well as changes in CST following anti-VEGF therapy. Results Compared to normal eyes, nAMD eyes exhibited higher CST values for white (-47.02 ± 9.02 vs. -51.09 ± 3.61 dB), blue (-52.50 ± 14.46 vs. -60.28 ± 8.60 dB), and red (-30.22 ± 8.21 vs. -36.24 ± 6.41 dB) stimuli. Approximately 39% of nAMD eyes exhibited cone-mediated vision under scotopic conditions. In nAMD eyes, BCVA was negatively correlated with blue and white CST, indicating that better BCVA was associated with higher central retinal light sensitivity. Red and blue CST were positively correlated with center retinal thickness (CRT) and CNV area (All P < 0.05). In the thicker CRT group, the blue-red CST difference decreased from -18.03 ± 10.01 dB to -22.85 ± 2.22 dB after 1 month of anti-VEGF treatment (P = 0.047), 9 of 14 eyes were cone-mediated at baseline, which decreased to 3 eyes after three months of treatment. Conclusions CST assessment revealed that both cone and rod were affected in nAMD eyes. CST was correlated with CRT and CNV area. In some nAMD patients, severe rod dysfunction leads to a shift to cone-mediated vision under scotopic conditions, but anti-VEGF therapy may ameliorate this phenomenon. These findings suggest that CST assesses the visual function of AMD patients from a more microscopic, cellular functional standpoint, which may be beneficial for monitoring AMD progression and evaluating the treatment efficacy.

Purpose:To assess the safety, tolerability, and preliminary efficacy of a single intravitreal injection of LX102-C01 in eyes with neovascular age-related macular degeneration (nAMD) followed up to 52 weeks. Design:Open-label, single-center, dose-escalation investigator-initiated trial (NCT05831007) with 2 cohorts (3E10 vector genome [vg] and 1E11 vg per eye). Subjects:Eyes with choroidal neovascularization secondary to nAMD, subretinal or intraretinal fluid, and a history of >2 anti-VEGF treatments in the past 6 months with a good response. Methods:All patients received 1 injection of aflibercept 2 weeks before LX102-C01. Dose escalation started with 3E10 vg and increased to 1E11 vg per eye. Visual acuity, anatomy, and adverse events (AEs) were assessed. Macular choroidal thickness (CT) and vascularity were measured using a 6 × 6 mm scan on swept-source OCT angiography imaging. Main Outcome Measures:The primary endpoint was AEs at 1 year. The secondary endpoints were best-corrected visual acuity (BCVA), central subfield thickness (CST), and incidence of rescue treatment. Exploratory endpoints included the macular hypoautofluorescent area, CT, and choroidal vascularity index (CVI). Results:Six eyes of 6 patients were included. There were no LX102-C01-related nonocular AEs. All LX102-C01-related ocular AEs were mild, predominantly anterior inflammation. There was no evidence of vasculitis, retinitis, choroiditis, vascular occlusions, or endophthalmitis. Two eyes from 2 patients developed recurrent subretinal fluid or hemorrhages that did not meet rescue criteria and resolved spontaneously after 1 to 2 months. All patients were free of rescue anti-VEGF treatments till the latest visit. Compared to baseline, BCVA maintained and CST decreased up to 12 months in both cohorts. The area of hypo-autofluorescence remained stable in both groups. The mean choroidal thickness (MCT) decreased from 162.1 μm to 147.1 μm (P = 0.03), but the CVI measurement showed no significant change (P = 0.6) up to 12 months. Changes in the MCT and CVI showed no statistically significant differences compared with the control group receiving standard aflibercept treatment. Conclusions:LX102-C01 showed a favorable safety profile and potential efficacy in this preliminary 52-week study, with no observed macular atrophy, suggesting short-term tolerability of gene therapy associated anti-VEGF expression. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PURPOSE:To investigate the genotype-phenotype correlation in RHO-associated retinopathy, with a focus on delineating an ethnic-specific variant spectrum and comparing clinical severity across biological classes and common variants. DESIGN:Retrospective cohort study and literature review. METHODS:We systematically reviewed all published cases of RHO-associated retinal diseases (2196 patients, 1278 probands) and analyzed clinical, genetic, and imaging data from our institutional cohort (80 probands). Variants were categorized by type and by biological class (Class 1-7), and phenotypes were compared across different biological classes and three common variants. RESULTS:A marked geographic divergence was observed: P23H was common in North America but rare in other populations, whereas P347L and R135W were major common variants in European and Asian populations. Genotype-phenotype analysis revealed that Class 2 variants were associated with later onset and slower visual decline, whereas Class 1 and Class 3 variants correlated with earlier onset (P < .0001) and more aggressive phenotypes. Notably, R135W (Class 3) emerged as an under-recognized but highly aggressive variant, with earlier onset (P < .01) and potentially earlier macular involvement. CONCLUSIONS:Our study represents the largest study integrating ethnic, genotypic, and clinical data in RHO-associated retinopathy. The findings highlight substantial inter-ethnic differences in common variants and underscore the clinical relevance of biological classification in predicting disease course. In particular, R135W and P347L warrants closer clinical attention due to their aggressive trajectory, which may inform prioritization in gene therapy trials and individualized patient management.

PURPOSE:To devise a novel and objective staging strategy of Bietti crystalline dystrophy (BCD) for gene therapy. DESIGN:Development and validation of severity and staging assessments. METHODS:We screened out 127 BCD patients from a cohort of 2146 patients with inherited retinal diseases (IRDs). Our study analyzed 6 critical indicators: age, LogMAR BCVA, absent autofluorescence (AF) area, mottled AF area, and average retinal thickness in ETDRS 1 mm circle and 3 mm ring. Using Principal Component Regression (PCR), we developed a quantitative model termed the Bietti Crystalline Dystrophy Score for Severity Assessment (BCD-SA Score), integrating indicators for disease severity. Additionally, a corresponding staging system (BCD-SA Stage) was derived from this model. We assessed the efficacy of the BCD-SA Stage, comparing it to the traditional staging strategy through a paired-sample t-test and Cohen's Kappa (κ) for agreement evaluation. RESULTS:The patients' mean age was 47.96 ± 10.1 years. Spearman correlation analysis and univariate linear regression demonstrated a strong correlation between all indicators and the disease stages defined by the traditional method (P < .001). Principal Component Analysis (PCA) addressed the multicollinearity among indicators, extracting 2 linear uncorrelated principal components (PCs, Factor 1 and Factor 2). These PCs were then used in a multiple linear regression model to develop the BCD-SA Score. Subsequently, a novel and objective staging system (BCD-SA Stage) was created, providing a more precise disease delineation. CONCLUSIONS:We developed an innovative and objective scoring and staging strategy for BCD by integrating 6 variables and utilizing the PCR approach. This strategy advances BCD assessment and serves as a benchmark for the natural history evaluation and staging of other IRDs.

Purpose To assess the safety, tolerability, and preliminary efficacy of a single intravitreal injection of LX102-C01 in eyes with neovascular age-related macular degeneration (nAMD) followed up to 52 weeks. Design Open-label, single-center, dose-escalation investigator-initiated trial (IIT; NCT05831007) with two cohorts (3E10 vg and 1E11 vg per eye). Subjects Eyes with choroidal neovascularization secondary to nAMD, subretinal or intraretinal fluid, and a history of more than two anti-VEGF treatments in the past six months with a good response. Methods and Measures All patients received one injection of aflibercept two weeks before LX102-C01. Dose escalation started with 3E10 vector genomes (vg) and increased to 1E11 vg per eye. Visual acuity, anatomy, and adverse events were assessed. Macular choroidal thickness and vascularity were measured using a 6 × 6 mm scan on swept-source optical coherence tomography angiography (SS-OCTA) imaging. The primary endpoint was adverse events (AEs) at one year. Secondary endpoints were best-corrected visual acuity (BCVA), central subfield thickness (CST) and incidence of rescue treatment. Exploratory endpoints included the macular hypoautofluorescent area, choroidal thickness, and choroidal vascularity index. Results Six eyes of 6 patients were included. There was no LX102-C01-related non-ocular adverse events. All LX102-C01-related ocular AEs were mild, predominantly anterior inflammation. No evidence of vasculitis, retinitis, choroiditis, vascular occlusions or endophthalmitis. Two eyes from 2 patients developed recurrent subretinal fluid or hemorrhages that did not meet rescue criteria, and resolved spontaneously after 1 to 2 months. All patients were free of rescue anti-VEGF treatments till the latest visit. Compared to baseline, BCVA maintained and CST decreased up to 12 months in both cohorts. The area of hypo-autofluorescence remained stable in both groups. Mean choroidal thickness (MCT) decreased from 162.1 μm to 147.1 μm (P=0.03), but the choroidal vascularity index (CVI) measurement showed no significant change (P=0.6) up to 12 months. Changes in MCT and CVI showed no statistically significant differences compared to the control group receiving standard aflibercept treatment. Conclusions LX102-C01 showed a favorable safety profile and potential efficacy in this preliminary 52-week study, with no observed macular atrophy, suggesting short-term tolerability of gene therapy associated anti-VEGF expression.

A 31-year-old man presented with left eye redness for 5 days, irritation, and sudden vision loss to finger counting. A, Examination revealed creamy white aqueous humor without hypopyon. B, Anterior-segment OCT showed homogenous hyperreflectivity. Despite negative pathogen tests, he was diagnosed with diabetic ketoacidosis and severe hyperlipidemia (triglycerides 45.66 mmol/l, total cholesterol 22.33 mmol/l, positive urinary ketones). Urgent insulin and lipid-lowering treatment cleared the lipid-laden aqueous humor in 3 days, unveiling aqueous flare and peripheral lipemia retinalis. Disruption of the blood-aqueous barrier from iridocyclitis was hypothesized. The patient was administered dexamethasone eye drops. Visual acuity was restored to 20/20 within 1 week, which supported our hypothesis. (Magnified version of Figure A-B is available online at www.aaojournal.org).

Purpose:To describe and evaluate the multimodal imaging findings in retinal microvascular ischemia associated with COVID-19 infection. Methods:Patients with COVID-19 associated retinal microvascular ischemia and visiting the outpatient Department of Ophthalmology, Shanghai General Hospital from December 2022, to February 2023, were documented and their multimodal images were retrospectively reviewed. Retinal microvascular ischemia was defined as the presence of isolated or multiple focal retinal whitening(s) on color fundus images. Patients with retinal vessel occlusion or retinopathies secondary to systematic disorders diagnosed before infection were excluded. Results:A total of 32 eyes from 21 patients were included, 24 (75.00 %) eyes with multiple retinal whitenings, while 8 (25.00 %) eyes with isolated lesions. When divided by the types of ischemia, 9 (28.13 %) eyes had only inner retinal involvement (known as cotton wool spot, CWS), 4 (12.50 %) eyes had only middle retinal involvement (known as paracentral acute middle maculopathy, PAMM), and 19 (59.38 %) eyes had both. In addition, 4 (12.50 %) eyes had coincident angular sign of Henle fiber layer hyperreflectivity (ASHH). Patients with hypertension tended to have multiple lesions rather than isolated lesion of retinal microvascular ischemia (P = 0.008). Transient uncontrolled high blood pressure or acute kidney injury was simultaneously detected in some cases. Conclusions:Ocular manifestation of COVID-19 associated microvascular ischemia can be variable, including CWS, PAMM and ASHH. Multimodal fundus imaging technologies are useful tools to reveal involved retinal layers, extent, and severity. Moreover, ocular manifestations may serve as a window of COVID-19 related microcirculation in other systems throughout the body.

Purpose: To further explore the influence of genotype, including mutation type and structural domain, on the severity of macular atrophy, we measured the central retinal thickness (CRT) in patients with ABCA4-related retinopathy. Methods: A total of 66 patients were included in the cohort. This was a retrospective investigation. The patients were tested using whole exon sequencing and ophthalmic exams, including slip lamp exams, best-corrected visual acuity, optical coherence tomography, fundus photo, and fundus autofluorescence. Results: In this study, we discovered that mutations on nucleotide binding domains (NBD) lead to less CRT (45.00 +/- 25.25 mu m, 95% CI: 31.54-58.46) had significantly less CRT than the others (89.75 +/- 71.17 mu m, 95% CI: 30.25-149.25, p = 0.032), and could accelerate the rate of CRT decrease. Conclusions: Our study provides new perspectives in the understanding of ABCA4-related retinopathy.

Abstract Background To investigate the clinical effects of double-dose (4 mg) aflibercept treatment in neovascular age-related macular degeneration (nAMD), compared with the standard-dose (2 mg) treatment. Methods A total of 108 eyes from 97 patients with nAMD and received intravitreal aflibercept 2 mg and/or 4 mg treatment were retrospectively reviewed. The changes of central macular thickness (CMT)/ pigmental epithelium detachment height and the recurrence rate of exudation during the 12-month follow-up were compared between the 2 mg group and the 4 mg group. Self-control comparisons (2 mg switch to 4 mg) were also made between two regimens. Results Compared with the 2 mg group, tendencies of lower intraretinal fluid incidence and more CMT reduction were observed in the 4 mg group. The later one was also observed when eyes switching from 2 mg to 4 mg regimen. The median remission interval was 5 months in the 4 mg group, 2 months longer than the 3 months in the 2 mg group (P = 0.452). Injections needed in the 4 mg group were 3.644 ± 1.670, less than the 4.286 ± 2.334 injections in the 2 mg group within 12 months as well (P = 0.151). However, no associated vision benefits were gained from the double-douse regimen. No markedly increased-intraocular pressure events, or other adverse events were found in two groups. Conclusions Compared to the aflibercept 2 mg treatment in nAMD, tendencies of anatomic gains and relieving treatment burden were brought by the aflibercept 4 mg treatment. This study may have additional importance, given the further application of high-dose aflibercept in real-world settings.

Chen, Chong MD; Liu, Kun MD, PhD; Gong, Yuanyuan MD; Yu, Suqin MD; Xu, Xun MD; Su, Li MD, PhDEditor(s): Grewal, Dilraj; Valikodath, Nita; Justin, Grant A. Author Information

Background To investigate the prevalence of outer retinal tubulation (ORT) and its correlations with optical coherence tomography (OCT) parameters in Chinese population with inherited retinal diseases (IRDs). Methods This retrospective study enrolled consecutive patients identified with IRDs and referred for genetic testing between February 2016 and April 2021. Clinical characteristics from medical records and features of cross-sectional B-scans were reviewed and analysed. The associations of patient-specific and ocular features with the presence of ORT were evaluated using univariate and multivariate analyses. Results Two hundred and three patients (401 eyes) with a mean age of 49.7 ± 16.7 years were enrolled. ORT was observed in 41 eyes (10.2%), including 26 of 28 eyes (92.9%) with Bietti crystalline corneoretinal dystrophy (BCD), 14 of 338 eyes (4.1%) with retinitis pigmentosa (RP), and 1 of 26 eyes (3.8%) in eyes with cone–rod dystrophy. Eyes with ORT showed significantly worse visual acuity than those without ORT ( P = 0.002). Multivariate analysis indicated that the presence of ORT was positively correlated with choroidal atrophy and inner nuclear layer (INL) cysts ( P < 0.01). ORTs were detected more frequently in eyes with BCD than RP ( P = 0.024), most of which located exclusively within the extrafoveal area. Large choroidal vessels were detected underneath the corresponding ORTs in both patients with BCD and RP. Conclusions The prevalence of ORT varies among different IRDs phenotypes, with the highest prevalence in BCD. The presence of choroidal atrophy and INL cysts may be associated with an increased risk of ORT formation in patients with IRD.

Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disorder with macular dystrophy and severe visual loss. Mutations in TIMP3 gene has been related to SFD with mechanisms unclear. We have successfully reprogrammed the peripheral blood mononuclear cells (PBMCs) from an SFD patient carrying c.484G>A mutation in TIMP3 gene to induced pluripotent stem cells (iPSCs) and characterized their pluripotency and genetic stability. This line may serve as a useful tool to explore the role of TIMP3 in SFD pathogenesis.

Purpose: To investigate the possible correlation factors of choroidal thickness in ABCA4-related retinopathy.Methods: A total of 66 patients were included in the cohort. It is a retrospective, cross-sectional laboratory investigation. The patients were tested using whole-exon sequencing and ophthalmic examinations, including slit-lamp examinations, best-corrected visual acuity, spectral-domain optical coherence tomography, fundus photograph, and fundus autofluorescence.Results: Besides demographic characteristics (age, onset age, duration), we selected genetic factors and ocular characteristics on spectral-domain optical coherence tomography as the candidates related to choroidal thickness. Mutation type (inframe mutation or premature termination codon), epiretinal membrane, retinal pigment epithelium- Bruch membrane integrity, and macular curvature changes were identified as related factors to choroidal thickness in ABCA4-related retinopathy after the adjustment of Logistic LASSO regression.Conclusion: Mutation type, epiretinal membrane, retinal pigment epithelium-Bruch membrane integrity, and macular curvature changes are related factors to choroidal thinning. These findings could provide us a further understanding for the pathological process and clinical features of ABCA4 mutation.

PURPOSE:To report a case of programmed cell death receptor-1 (PD-1) inhibitor induced panuveitis.METHOD:Observational case report of a 13-year-old Chinese girl presented as panuveitis. The clinical course, imaging performance, laboratory examination, differential diagnosis, treatment and prognosis were described.RESULT:Patient presented with bilateral anterior granulomatous uveitis, vitritis, papillitis, and various creamy yellow nodular lesions in the mid-peripheral fundus. She had a history of biopsy proven alveolar soft tissue sarcoma on the chest wall and pulmonary metastasis, and a PD-1 inhibitor (sintilimab) was intravenously administered. Blood tests, magnetic resonance imaging of the cranium and the orbit, aqueous humor assay of inflammatory cytokines and microbial DNA were performed to distinguish infectious and non-infectious uveitis, choroidal metastases, and intravenous injection-related endophthalmitis. The oncologist evaluated that the sarcoma was stable and terminated sintilimab dosage. After sintilimab withdrawal, the blurred vision improved. Then, the patient received oral corticosteroids, resulted in resolution of the panuveitis. A diagnosis of PD-1 inhibitor induced panuveitis was made.CONCLUSION:For patients taking PD-1 inhibitors, the major diagnostic challenge is to identify whether the cause of the uveitis is due to the antitumor treatment or not. It is suggested to be screened by eye care specialist and timely referral to uveitis specialist with any suspicion of intraocular inflammation for these patients.

BACKGROUND:Retinal arterial macroaneurysm (RAM) is a common clinical disease leading to vision loss in elderly individuals. The appropriate interpretation of swept-source optical coherence tomographic angiography (SS-OCTA), a noninvasive examination, is easy and convenient for detecting the status of RAMs and guiding treatment.METHODS:The objectives of this study were to describe the morphologic characteristics of RAMs using SS-OCTA and to observe whether there are differences in the morphologies of RAMs between SS-OCTA and fundus fluorescein angiography (FFA), before and after treatment. We retrospectively evaluated twenty-two eyes of 22 patients who were diagnosed with RAMs. All patients underwent a complete ophthalmologic examination, including a review of medical records, best-corrected visual acuity (BCVA), fundus photography, FFA and SS-OCTA. RAMs were recorded by SS-OCTA before any treatment or observation decisions were made. The morphologic findings of the RAMs on SS-OCTA were investigated.RESULTS:On SS-OCTA, RAMs can show local dilatation or an irregular linear blood flow signal, and the dilated cystic lumen may show thrombosis with a low reflection signal. After treatment, the shape of the RAMs will show reactive changes. The findings on SS-OCTA are not very consistent with those on FFA.CONCLUSIONS:The same RAM may have different manifestations on OCTA and FFA, and OCTA can more conveniently reflect the changes in blood flow signals and treatment response of RAMs.