This study aimed to obtain the first evidence-based microbiological confirmation of the efficacy and an assessment of the local tolerability of a combination of an ocular antibiotic and a non-steroidal anti-inflammatory drug in treating moderate-to-severe acute bacterial conjunctivitis (ABC). This was a phase II, randomized, parallel-group, masked-assessor, multicentre study to assess the non-inferiority of levofloxacin plus ketorolac eye drops versus levofloxacin eye drops alone in microbiological eradication (protocol number: LEVOKETO_02-2020). Treatment lasted 5 days. Non-inferiority was demonstrated if the lower bound of the two-sided 95

PURPOSE:To characterize the clinical and genetic features, investigate disease triggers, and explore factors associated with visual recovery in late-onset Leber Hereditary Optic Neuropathy (LHON). DESIGN:Retrospective cohort study. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS:Seventy-seven patients with late-onset LHON (onset ≥ 40 years of age) were identified from a larger cohort of 398 Italian LHON patients. Full clinical and genetic analyses were performed on 67 of these patients, while an internal control group of 562 healthy individuals was utilized for mitochondrial haplogroup comparisons. METHODS, INTERVENTION, OR TESTING:Patient medical records were retrospectively reviewed to assess demographics, environmental exposures (smoking history), hormonal status (menopause, hormonal therapy), systemic comorbidities, and idebenone treatment data. Genetic testing evaluated primary mitochondrial DNA (mtDNA) mutations, mitochondrial haplogroups, and NQO1 polymorphisms. Statistical relationships were investigated using an exploratory chi-square automatic interaction detection (CHAID) analysis to generate hypothesis-generating decision tree models. MAIN OUTCOME MEASURES:The primary outcome measures were the identification of precipitating factors (disease triggers) for LHON conversion and the rate of visual recovery, which was defined as an improvement of at least 0.3 LogMAR or a change from off-chart to on-chart visual acuity. RESULTS:The m.11778G>A variant was the predominant mtDNA mutation (62.7%), and the male-to-female ratio was lower than in canonical LHON (1.48:1). Smoking history was present in 58.2% of patients, and 85.2% of women were postmenopausal. Other relevant factors included primary open-angle glaucoma (6%) and the LHON 'plus' phenotype (7.5%). The overall visual recovery rate was 38.8%. Exploratory CHAID analysis suggested that idebenone treatment at a dosage of ≥900 mg/day and the presence of a J or T mitochondrial haplogroup were associated with a higher probability of visual recovery. CONCLUSIONS:Late-onset LHON represents a clinically relevant subset in which environmental and hormonal factors may contribute to disease conversion. In this retrospective cohort, high-dose idebenone treatment was associated with a higher probability of visual recovery, particularly among patients with a J or T haplogroup background. These exploratory findings should be considered hypothesis-generating and warrant confirmation in prospective studies.

Purpose:To characterize etiologies and clinical-imaging features of peripapillary choroidal neovascularization (CNV) and identify predictors of underlying disease (i.e., including age-related macular degeneration [AMD] vs. non-AMD etiologies) and visual outcomes. Methods:This multicenter retrospective case series included 156 eyes of 138 treatment-naïve patients with peripapillary CNV from 12 tertiary centers. Peripapillary CNV was defined as sub-RPE or subretinal neovascularization within one disc diameter of the optic disc. Multimodal imaging (optical coherence tomography [OCT], fluorescein and indocyanine green angiography, and/or OCT angiography) was used to confirm CNV and etiology. Baseline OCT features included CNV type, exudation pattern, foveal involvement, peripapillary location, and distance to the disc. Longitudinal OCT and best-corrected visual acuity (BCVA, logMAR) were analyzed when available. Management followed routine clinical practice with variable administration of anti-VEGF therapy. Regression models and a conditional inference tree assessed predictors of diagnosis and visual outcome. Results:The most common etiologies were AMD (51.9%), pachychoroid disease (27.6%), and angioid streaks (6.4%). CNV most frequently involved the temporal peripapillary quadrant (84.6%). Aneurysmal type 1 CNV predominated in pachychoroid disease, whereas type 2 CNV was more common in other etiologies. Baseline BCVA was worse in AMD and angioid streaks and was independently associated with underlying disease and foveal involvement. The Conditional Inference Tree associated age >71 years and nonaneurysmal type 1 or type 2 CNV with AMD. Conclusions:Peripapillary CNV most commonly arises from AMD and pachychoroid disease. Simple clinical and imaging features can assist etiological classification and visual prognostication in clinical practice.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in developed countries, with prevalence expected to reach nearly 288 million by 2040. Accurate classification of AMD is critical for patient care and clinical research, guiding prognosis, therapeutic strategies, and the design of clinical trials. A widely adopted framework, the Beckman classification, stratifies AMD based primarily on color fundus photography (CFP) findings, defining stages from early to late disease. While simple and clinically applicable, such systems do not account for several key phenotypes revealed by advances in multimodal imaging. Such novel phenotypes include reticular pseudodrusen (RPD), acquired vitelliform lesions (AVL), non-exudative macular neovascularization (MNV), incomplete retinal pigment epithelium and outer retina atrophy (iRORA), and non-neovascular exudative fluid. Recent imaging modalities—including optical coherence tomography (OCT), fundus autofluorescence (FAF), and OCT angiography (OCTA)—have uncovered features with important prognostic implications that are currently misclassified with respect to AMD. For example, eyes with RPD or AVL in the absence of drusen are currently misclassified as “early AMD” or excluded altogether, despite their high risk of progression. Similarly, the ambiguous status of non-exudative MNV, which carries both protective and harmful potential, highlights the need for greater granularity. The Classification of Atrophy Meetings (CAM) group has also introduced refined OCT-based definitions such as iRORA and cRORA, underscoring early degenerative changes that precede geographic atrophy. Moreover, novel entities like non-neovascular intraretinal or subretinal fluid challenge the assumption that exudation is synonymous with neovascular AMD. This review synthesizes recent evidence highlighting the limitations of current classification systems in light of these advances. Furthermore, we emphasize that intermediate AMD, currently treated as a uniform category, actually encompasses highly heterogeneous phenotypes with distinct risks and trajectories. A more nuanced, imaging-integrated classification system is urgently needed to improve disease staging, identify high-risk eyes, and ensure appropriate patient selection for emerging therapies. Such a framework would not only better reflect the complex natural history of AMD but also facilitate the regulatory shift toward continuous, quantitative endpoints in clinical trials.

The aim of this study is to characterize the clinical indications, treatment patterns, and outcomes associated with intravitreal dexamethasone implant (DEX implant) in eyes with punctate inner choroidopathy (PIC). This retrospective observational case series included eyes with PIC treated with at least one DEX implant. Eyes were categorized according to the indication for treatment as (1) bridging therapy while initiating systemic immunomodulatory therapy (IMT), (2) adjunctive treatment for recurrent inflammatory activity despite ongoing IMT, or (3) local therapy in patients not receiving systemic IMT. Main outcome measures included best-corrected visual acuity (BCVA), inflammatory control, inflammatory recurrence, retreatment requirements, and safety. Twenty-five eyes from 22 patients were included. Mean age at index injection was 56.5 ± 11.1 years, and 18/22 patients (82

To provide consensus recommendations on the clinical use of aflibercept 8 mg in managing neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) in the real-world setting. A modified Delphi study was undertaken, involving ophthalmologists from specialized centers in Italy, to gauge consensus on statements related to the use of aflibercept 8 mg in nAMD and DME. Two initial rounds of online surveys were conducted, followed by 2 workshops to assess the clinical feasibility of selected statements and identify the behavioral drivers and barriers to their adoption in practice. Consensus was defined as ≥ 75 What is new

PURPOSE:Consensus efforts by the Multimodal Imaging in Uveitis (MUV) Task Force have established standardized diagnostic criteria for the major non-infectious posterior and panuveitides (NIPUs), historically referred to as "white dot syndromes". Nevertheless, a substantial proportion of cases deviate from classical presentations and fall into diagnostic "grey zones", blurring boundaries between diseases entities and complicating both differential diagnosis and management. This paper aims to describe the broad spectrum of atypical, variant, and secondary forms of NIPUs as well as masquerade syndromes. METHODS:Perspective article with narrative review and illustrative cases. RESULTS:Atypical multiple evanescent white dot syndrome (MEWDS) includes bilateral presentations or complicated courses, while multifocal choroiditis and panuveitis/punctate inner choroiditis (MFCPU/PIC) with outer retinal atrophy emerges as a notable entity with unclear therapeutic implications. Inflammatory reactions resembling both MEWDS and MFCPU/PIC may also occur as secondary phenomena, triggered by other chorioretinal disorders, most notably inherited retinal diseases (IRDs). Placoid chorioretinopathies, including acute posterior multifocal placoid pigment epitheliopathy, persistent placoid maculopathy, serpiginous choroiditis, and relentless placoid chorioretinitis, are often distinguished only a posteriori based on disease course, but likely represent a continuum of disorders unified by choroidal ischemia. Atypical presentations of birdshot chorioretinopathy may feature extensive outer retinal damage, mimicking IRDs. Equally important is the consideration of masquerade syndromes in all suspected cases of NIPUs, as they can present with similar features yet require entirely different treatments. Infectious masquerades include tuberculosis-associated serpiginous-like choroiditis, acute syphilitic posterior placoid chorioretinopathy, and West Nile virus chorioretinitis, whereas vitreoretinal lymphoma is the most frequent neoplastic masquerade. CONCLUSIONS:Integrating clinical context with high-quality multimodal imaging remains essential to navigate the jungle of differential diagnosis in NIPUs. Future studies should aim to integrate imaging phenotypes with immunologic and molecular biomarkers to refine disease classification and support more targeted therapeutic strategies.

Purpose:To evaluate the 1-year progression of retinal capillary nonperfusion in eyes with mild to severe nonproliferative diabetic retinopathy (NPDR) using noninvasive retinal imaging. Methods:The CHART study (Clinicaltrials.gov: NCT04636307) is a multicenter, observational, longitudinal study involving five European research centers and included 202 eyes from 155 participants with type 2 diabetes and mild to severe NPDR. Participants underwent comprehensive ophthalmologic examinations at baseline and 3, 6, and 12 months, including best-corrected visual acuity, color fundus photography (Early Treatment Diabetic Retinopathy Study [ETDRS] severity scale), optical coherence tomography (OCT), and OCT angiography (OCTA). Disease progression was evaluated using mixed-effects models. Results:Of the 202 eyes, 81 eyes were graded as ETDRS level 35, 63 eyes as level 43, 46 eyes as level 47, and 12 eyes as level 53. At baseline, significant differences were observed in OCTA metrics between diabetic retinopathy severity groups. A total of 169 eyes (84%) completed the 1-year follow-up. Over 1 year, eyes with ETDRS levels 35 and 43 showed significant increases in capillary nonperfusion, identified by decreases in skeletonized vessel density in the superficial capillary plexus (rates of progression: β = -0.217 mm-1/y, P = 0.006 and β = -0.310 mm-1/y, P = 0.002, respectively). Eyes with level 47 showed only a borderline statistically significant decrease (P = 0.074), while eyes with level 53 remained stable. Microaneurysm turnover (MAT), formation, and disappearance rates increased in more severe NPDR stages (levels 47 and 53). Conclusions:Retinal capillary nonperfusion progresses significantly over 1 year in mild to moderate NPDR, identified by changes in rates of progression of vessel and perfusion densities. In more severe stages (levels 47 and 53), capillary nonperfusion stabilizes, and a hyperperfusion response is identified by increases in MAT associated with the development of intraretinal microvascular abnormalities. Translational Relevance:This study provides quantitative data on 1-year progression of retinal capillary nonperfusion in NPDR using noninvasive imaging, offering the basis for future interventional trials.

Purpose:To quantify the role of aging and sex in corneal nerve morphology and function and to identify cellular and molecular mechanisms involved in corneal nerve aging in male and female mice. Methods:This study included young (8-week-old) and old (52-week-old) C57BL/6N male and female mice. Corneal nerve function was measured using eye wiping and Cochet-Bonnet tests. Corneal nerve density was analyzed after β3-tubulin staining in the sub-basal nerve plexus, the vertical nerve projections, and the superficial nerve terminals. Neuronal and neuroinflammatory markers were quantified in the trigeminal ganglia using immunofluorescence and real-time PCR. Results:Aging significantly reduces nerve density and the corneal nociceptive response (P < 0.0001). Mechanical sensitivity was decreased in male mice (P < 0.0001), but not in females. Female mice showed milder nerve fiber degeneration compared to males (P = 0.0453). Moreover, we identified an age-dependent decrease of substance P-positive neurons in the ophthalmic branch of the trigeminal ganglion (P = 0.0003), which was milder in females (P = 0.0005). Gene expression analysis in the trigeminal ganglion revealed a higher expression of neuroprotective and pro-regenerative markers in female mice. Immunofluorescence analysis revealed an age-dependent increase in the uptake of leukocytes in the trigeminal ganglion (P = 0.0068). M2 anti-inflammatory macrophage numbers were preserved in aging females versus males (P = 0.0008). Conclusions:Aging was associated with sensory corneal neuropathy, altered sensory abnormalities, and neuroinflammation. Interestingly, female mice appeared to be protected from nerve degeneration compared to males.

PURPOSE:Benign yellow dot maculopathy (BYDM) is a rare macular phenotype first described in 2017, characterized by yellow macular dots with preserved visual function. Although it is considered a nonprogressive condition, long-term follow-up data are limited. This case report presents a 12-year follow-up of a patient with BYDM, offering insights into its long-term stability over time. METHODS:The patient underwent comprehensive multimodal imaging, including optical coherence tomography, fundus autofluorescence, electro-oculography, and microperimetry. Genetic analysis through next-generation sequencing was also performed to explore potential genetic associations. RESULTS:At baseline, fundus autofluorescence revealed characteristic hyperautofluorescent yellow dots in the macular and midperipheral retina, while optical coherence tomography showed no structural abnormalities. Electro-oculography demonstrated subnormal responses, suggesting retinal pigment epithelium dysfunction, and microperimetry indicated a global reduction in retinal sensitivity. Genetic testing identified two heterozygous variants of uncertain significance ( ALMS1 and GPR179 ), but no pathogenic mutations associated with macular dystrophies. During the 12-year follow-up, no progression of structural or functional abnormalities was observed, supporting the nonprogressive nature of BYDM. CONCLUSION:This case represents one of the longest follow-ups reported for BYDM, confirming its long-term stability. Despite subtle functional alterations, the absence of disease progression supports its benign nature. Further research is needed to refine the clinical spectrum of BYDM and distinguish it from other macular disorders.

Objective To characterize peripheral retinal vascular alterations in USH2A-related retinitis pigmentosa (RP) using widefield optical coherence tomography angiography (WF-OCTA), and to investigate their relationship with macular changes assessed by multimodal retinal imaging. Design Cross-sectional observational study. Participants Thirty eyes of 30 patients with genetically confirmed USH2A-related RP and 30 age- and gender-matched healthy controls. Methods We performed complete ophthalmologic examination and multimodal retinal imaging, including fundus autofluorescence (FAF), optical coherence tomography (OCT), OCT angiography (OCTA), autofluorescence-based macular pigment optical density (AF-MPOD), and 130° WF-OCTA. A quantitative WF-OCTA analysis pipeline was developed to assess peripheral perfusion through concentric fovea-centered retinal rings. The Concentric Peripheral Perfusion Index (CPPI), Peripheral Perfusion Loss Gradient (PPLG), and Perfusion Profile Slope (PPS) were calculated. Associations between peripheral vascular status and central retinal imaging biomarkers were analyzed. Results Compared with controls, RP eyes showed significantly lower WF-OCTA perfusion indices across all eccentricity rings (all p<0.05), with more pronounced perfusion loss in the outer retina and a steeper perfusion decline toward the periphery. Peripheral vascular impairment significantly correlated with visual field indices, preserved FAF area, retinal layer thicknesses, and macular vascular density, particularly at the intermediate capillary plexus. Eyes with bone spicule pigmentation or retinal vascular attenuation showed more severe peripheral vascular loss, whereas eyes with hyperautofluorescent ring demonstrated more preserved perfusion profiles. AF-MPOD values were reduced in RP and significantly associated with central vascular and structural parameters. Hyperreflective ganglion cell band (HGB) was associated with more severe peripheral vascular impairment and worse macular vascular status. Conclusions USH2A-related RP is characterized by marked peripheral retinal vascular rarefaction, more evident at increasing eccentricities, and closely associated with central retinal structural, vascular, and pigmentary alterations. These findings support the concept of RP as a diffuse neurovascular retinal disorder extending beyond the outer retina. Quantitative WF-OCTA may provide clinically meaningful biomarkers for disease characterization and monitoring.

Age-related macular degeneration (AMD) is a leading cause of vision loss worldwide, driven by complex interactions within the photoreceptor-retinal pigment epithelium (RPE)-choroid unit. Understanding these processes requires integrating in vivo imaging with histopathological evidence, as each provides complementary insights into disease mechanisms. Historically, landmark discoveries-including the characterization of drusen, RPE alterations, and the introduction of optical coherence tomography (OCT)-have led to major paradigm shifts in the diagnosis and management of AMD. Recent advances in multimodal imaging, particularly OCT and OCT angiography (OCTA), have enabled high-resolution, non-invasive visualization of structural and vascular changes, facilitating the identification of clinically relevant biomarkers. When interpreted in the context of histology, these imaging findings have significantly advanced our understanding of AMD pathogenesis, revealing dynamic interactions between neuronal degeneration, outer retinal dysfunction, and vascular impairment. In this review, we synthesize key imaging features of AMD alongside their histopathological correlates, highlighting how this integrative approach has refined disease classification, improved prognostic assessment, and informed therapeutic strategies. We further discuss emerging imaging technologies and their potential to bridge the gap between tissue-level pathology and clinical practice. By linking historical insights with contemporary advances, this review provides a comprehensive framework for understanding AMD and its management.

Purpose:To longitudinally characterize and redefine the structural basis and clinical significance of the pitchfork sign in type 2 choroidal neovascularization (CNV) using multimodal imaging with 3-dimensional confirmation. Design:Retrospective observational study. Subjects:Thirty-nine eyes with treatment-naive type 2 CNV showing a pitchfork sign on spectral-domain OCT. Methods:Outer retinal changes were graded, focusing on splitting at the ellipsoid zone (EZ) and infolding of the external limiting membrane (ELM). Quantitative measures included projection number, maximal fold height, subretinal fluid (SRF) height, subretinal hyperreflective material (SHRM) height, and posttreatment pigment epithelial detachment (PED) height; correlations with best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution) were assessed. Three-dimensional reconstructions of the outer retina were generated to verify the spatial configuration of folds. Main Outcome Measures:Structural characterization of the retinal layer involved in the pitchfork sign; quantitative morphologic parameters (projection number and maximal fold height); their correlation with exudative and anatomical features (SRF, SHRM, PED height); and association with BCVA. Results:The pitchfork sign occurred in idiopathic (69%), inflammatory (23%), and myopic (8%) CNV, indicating it is not disease-specific. Imaging revealed a reproducible mechanical sequence: elevation of the outer retina by type 2 CNV; cleavage at the EZ with formation of a new fluid-filled split between the EZ and ELM; centrifugal buckling and infolding from the lesion margin toward the CNV core; and, in some eyes, transient partially enclosed "mushroom-shaped" closed folds that trapped fluid. These folds ultimately collapsed into sharply angulated vertical hyperreflective lines-the pitchfork configuration. Three-dimensional reconstructions confirmed that the apparent "tines" are radially arranged outer retinal folds anchored to the neovascular complex. Quantitatively, fold number correlated with SRF height (r = 0.40, P = 0.01), SHRM height (r = 0.41, P = 0.009), and maximal fold height (r = 0.49, P = 0.002). Greater maximal fold height was associated with worse presenting BCVA (r = 0.48, P = 0.003). After anti-VEGF, all folds resolved, and the CNV regressed beneath a continuous retinal pigment epithelium, forming a fibrovascular PED whose height at follow-up correlated with baseline fold count (r = 0.35, P = 0.04). Conclusions:The pitchfork sign in type 2 CNV reflects transient, mechanically induced folding and splitting of the outer retina overlying subretinal neovascular tissue, rather than an inflammatory biomarker. Greater retinal deformation at presentation was associated with worse presenting vision and with a higher fibrovascular PED after treatment. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Despite the availability of various anti-vascular endothelial growth factor (anti-VEGF) therapies for diabetic macular edema (DME), high treatment burden remains a significant issue in many European countries, including Italy. This burden impacts healthcare costs, clinic capacities, and patient adherence. Aflibercept 8 mg was developed to reduce treatment burden by requiring only three monthly injections before allowing extended dosing intervals up to 6 months, without compromising efficacy and safety. This analysis aimed to evaluate the efficacy, safety, and treatment burden of aflibercept 8 mg regimens compared to other anti-VEGF options (aflibercept 2 mg, ranibizumab 0.5 mg, faricimab 6 mg, brolucizumab 6 mg, and bevacizumab 1.25 mg) in Italy. A systematic literature review identified randomised controlled trials of anti-VEGF therapies for DME with a 2-year follow-up. This informed a Bayesian network meta-analysis (NMA) assessing efficacy, safety, and treatment burden. A cost-minimisation analysis (CMA) was conducted from the perspective of the Italian National Health System over a 2-year horizon. The NMA, involving nine studies, showed no significant differences in best-corrected visual acuity, anatomical outcomes, and safety between aflibercept 8 mg and the other anti-VEGF agents. Aflibercept 8 mg required fewer injections than the comparators, with a mean of 9.3 injections over 2 years for T E (Q12) and 8.4 for T E (Q16) regimens. Economically, aflibercept 8 mg was the least costly licensed and reimbursed anti-VEGF in Italy. Aflibercept 8 mg may be the most advantageous anti-VEGF option for reducing treatment burden in Italian patients with DME, benefiting healthcare providers, clinics, and the healthcare system. Aflibercept 8 mg offers comparable efficacy and safety to other anti-VEGF therapies, with fewer injections and potentially lower overall costs. Diabetic macular edema is a common complication of diabetes that causes fluid build-up and vision loss in the central part of the retina. The most often used treatments block vascular endothelial growth factor, a protein that causes leaking blood vessels in the eye. These drugs work well, but patients often need frequent eye injections. Frequent injections increase costs for the healthcare system and patients too, clinic visits, and make it harder for patients to stick with treatment. We reviewed 2-year results from clinical trials of several anti-vascular endothelial growth factor drugs. We combined the trial data using a statistical method that lets us compare many treatments even when trials did not directly compare every option. We also compared 2-year healthcare costs from the Italian public health system perspective. The newest drug, aflibercept at an 8 mg dose, delivered vision and retinal outcomes similar to other available drugs. It showed similar safety. Patients receiving aflibercept 8 mg needed fewer injections over 2 years, about 8 to 9 injections in 2 years. In the cost analysis, aflibercept 8 mg was the least costly option among licensed and reimbursed drugs in Italy. All this means that aflibercept 8 mg may reduce the number of injections and clinic visits without sacrificing effectiveness or safety. This can lower strain on clinics, reduce costs for the health system, and make it easier for patients to stay on treatment.

BACKGROUND/OBJECTIVES:Real-world data (RWD) is becoming increasingly important in ophthalmology, offering insights into clinical outcomes, therapeutic approaches, and healthcare practices. However, methodological variability limits comparability and generalisability across RWD studies. This Delphi consensus aimed to establish expert agreement on the need for standardised methodologies in ophthalmology RWD studies, identify the key clinical and patient-reported data elements that should be collected, and explore strategies for consistent implementation. METHODS:A modified Delphi methodology was followed. A steering committee (SC) of three ophthalmologists developed 38 consensus statements across five key topics. These statements were developed into an online four-point Likert scale survey and distributed to healthcare professionals experienced in managing retinal diseases via members of The Ophthalmology Network. Consensus was defined a priori as ≥75% agreement. Results were shared with the SC and key recommendations were discussed. RESULTS:A total of 244 responses were received, predominantly from retina specialists (n = 232, 95%), with broad representation across six regions, the largest being Europe (n = 116, 48%). Consensus was achieved for all 38 statements, with 36 (95%) reaching ≥90%. These statements covered key principles, including: variability of current standards, ideal clinical standards for RWD collection, RWD analysis methodology, ideal patient-reported standards, and implementing and reporting consistent standards/frameworks. As the stopping criteria were met, no further Delphi rounds were conducted. Eight key recommendations were developed. CONCLUSIONS:The outputs from this consensus aim to guide future ophthalmology RWD studies towards improved consistency, reliability, and generalisability, ultimately strengthening the evidence base for clinical decision-making to improve patient outcomes.

PURPOSE:To investigate peripheral retinal findings in BEST1 -related retinopathies by means of ultra-widefield (UWF) imaging. METHODS:Observational, case-control study. All subjects underwent comprehensive ophthalmologic evaluation, including ultrawide-field fundus photography (UWF-FP) and UWF fundus autofluorescence, and selected cases also received UWF optical coherence tomography. Peripheral retinal changes, including white or dark without pressure and vascular abnormalities, were assessed, and their prevalence was compared with a control group. RESULTS:Seventy-two eyes from 36 patients with BEST1 -related retinopathy (58 eyes from 29 patients with autosomal dominant Best vitelliform macular dystrophy [BVMD]), 14 eyes from seven patients with autosomal recessive bestrophinopathy (ARB), and 78 eyes from 39 control subjects were enrolled. Compared with controls, patients had significantly higher odds of exhibiting peripheral alterations. White without pressure (WWP) and dark without pressure (DWP) were the most frequent findings, especially in ARB, where WWP and DWP were present in 86% of eyes. OCT imaging confirmed EZ reflectivity attenuation in areas of DWP, without signs of vitreous traction. Vascular abnormalities were detected in nearly half of all eyes, with intraretinal microvascular abnormalities (IRMAs) and vessel tortuosity more common in BVMD, and focal narrowing more frequent in ARB. Overall, peripheral changes were evenly distributed across Gass stages in BVMD. CONCLUSION:BEST1 -related retinopathies are associated with a spectrum of peripheral retinal changes, particularly retinal reflectance alterations.

Purpose:The purpose of this study was to characterize the longitudinal evolution and prognostic associations of age-related scattered hypofluorescent spots on late-phase indocyanine green angiography (ICGA; ASHS-LIA), a putative marker of early retinal pigment epithelium/Bruch's membrane (RPE/BM) dysfunction, in a Caucasian cohort. Methods:Retrospective longitudinal study of patients with ASHS-LIA who underwent optical coherence tomography (OCT) and ICGA. ASHS-LIA extent was graded from 1 (posterior pole) to 3 (beyond vascular arcades). Structural OCT features were categorized into three structural categories based on drusen status: S0 (no drusen), S1 (small drusen <63 µm), and S2 (large drusen ≥63 µm). Subretinal drusenoid deposits (SDDs) and choroidal neovascularization (CNV) were evaluated at each visit. Transitions between structural categories were analyzed using mixed-effects ordinal regression models adjusted for time, and the incidence of SDDs and CNV was evaluated using Cox regression. Results:A total of 278 eyes of 144 patients (mean age = 69.5 ± 9.3 years, 53% male patients) were followed for a mean of 6.2 years. At baseline, 56% of eyes were S0, 31% were S1, and 14% were S2, with age and ASHS-LIA extension increasing stepwise across structural categories (P < 0.001). CNV was observed across all categories. During follow-up, 16 incident CNV lesions were identified, showing heterogeneous presentations, including aneurysmal type 1 CNV in drusen-free eyes and mixed types 1 and 2 CNV in eyes with larger drusen. A change in structural categories occurred in 11% of eyes and was associated with older age (odds ratio [OR] = 1.73 per 10 years, P < 0.001) and greater ASHS-LIA extension (OR = 2.57 for grade 3 vs. 1, P = 0.03). Older age, extensive ASHS-LIA, and large drusen were also associated with increased risk of incident SDDs and CNV, whereas greater choroidal thickness was inversely associated with SDDs. The presence of a double-layer sign (DLS) was associated with CNV onset. Conclusions:ASHS-LIA is associated with long-term structural changes and neovascular complications in eyes exhibiting this phenotype. These findings support its role as a risk stratification feature within ASHS-LIA-positive eyes, although its relationship with AMD progression cannot be established from the present study.

Purpose:To use the machine learning algorithm archetypal analysis (AA) to characterize visual field (VF) loss patterns in patients with chronic Leber hereditary optic neuropathy (LHON) and to determine whether these VF patterns differentiate for patients who recovered visual acuity (VA). Methods:For patients with molecularly confirmed LHON, we retrospectively collected 30-2 or 24-2 VFs (Humphrey VF analyzer) performed at least 3 years after disease onset. A total of 220 VFs (220 eyes, 117 patients) were used as input for the AA algorithm. Archetypes (ATs) and relative weights were statistically compared between VA-recovered and not-recovered groups and among primary mitochondrial DNA mutations. K-means clustering and principal component analysis enabled two-dimensional visualization of the relationship among VFs, ATs, mean deviation, and VA. Results:The LHON-AA model consisted of seven ATs: AT1 resembled a total loss VF pattern (30%) and AT2 a normal VF (23%). Small (AT3, 15%) and large (AT4, 10%) central scotomas followed as representative patterns. AT1 was significantly more prevalent in the not-recovered group, whereas AT2 and AT3 predominated in the recovered VA group. Less severe patterns were more present for m.14484T>C/ND6 than the other primary mutations. Two-dimensional visualization highlighted the nonlinear relationship between VA and VF outcome. Conclusions:AA is a robust method for categorizing and quantifying VF damage in patients with chronic LHON, providing novel insights into the complexity of the disease. The findings suggest that the recovery of VA and VF damage are not transposable, although not entirely independent either, and that both parameters should be considered in the comprehensive assessment of functional recovery in LHON.

Purpose:To characterize the transition from subretinal fluid (SRF)-dominant to intraretinal fluid (IRF)-dominant exudation in type 1 macular neovascularization (MNV) secondary to neovascular age-related macular degeneration (nAMD), using longitudinal optical coherence tomography (OCT) phenotyping and exploratory clinicopathologic correlation. Methods:Serial OCT volumes from eyes with type 1 MNV and baseline SRF without IRF were retrospectively reviewed to define the temporal sequence of subretinal hyperreflective material (SHRM) formation, external limiting membrane (ELM) disruption and descent, IRF emergence, and outer retinal remodeling. Time-dependent Cox regression identified predictors of IRF development, and linear mixed-effects models related structural transitions to visual acuity (VA). Exploratory immunohistochemistry for glial fibrillary acidic protein and aquaporin-4 (AQP4) was performed in a donor eye with nAMD. Results:Among 143 eyes (130 patients; median follow-up, 49.2 months [interquartile range, 28.2-90.8]), SHRM developed in 85 eyes (59%), ELM disruption or descent in 67 eyes (47%), and IRF in 44 eyes (31%). ELM alterations preceded IRF occurrence in 74% of eyes (hazard ratio, 12.94; 95% CI, 6.41-26.11). IRF onset was associated with worse VA (β = +0.07 logMAR; P < 0.001) and accelerated visual decline (time × IRF interaction: β = +0.019 logMAR/year; P = 0.004). Histopathology demonstrated Müller cell extension beyond the ELM into fibrovascular tissue, reactive gliosis, and AQP4 redistribution, mirroring ELM descents and outer retinal adhesions observed on OCT. Conclusions:In type 1 MNV, the shift to IRF-dominant exudation may reflect a structural disease state transition in which ELM disruption, Müller cell remodeling, and altered AQP4-mediated fluid transport are contributing mechanisms. These findings provide a possible clinicopathologic framework for developing outer retina-preserving therapeutic strategies in nAMD.