Impaired Visual Function in Posterior Vitreous Detachment Assessed With the Active-Learning Quantitative Contrast Sensitivity Function Test.

Introduction: To investigate whether there is visual function impairment in patients with posterior vitreous detachment (PVD) using the active-learning quantitative contrast sensitivity function test. Methods: In this cross-sectional study, contrast sensitivity was measured in eyes with PVD and eyes without PVD using the quantitative contrast sensitivity function algorithm on the Adaptive Sensory Technology platform. Outcomes included the area under the log contrast sensitivity function curve, contrast acuity, and contrast sensitivity thresholds at 1 to 18 cycles per degree (cpd). Snellen visual acuity (VA) was also measured. Mixed-effects multiple linear regression analyses were performed to evaluate the association between the presence of PVD and visual function, controlling for age and lens status. Results: The cohort comprised 232 healthy eyes of 205 participants; of these, 80 eyes of 69 patients had PVD. There was no significant association between VA and PVD presence. However, PVD was significantly associated with decreased contrast sensitivity thresholds at 1.5 cpd (ß, -0.058; P = .003) and 3 cpd (ß, -0.067; P = .004). Contrast sensitivity thresholds at lower (1 cpd) or higher (6, 12, 18 cpd) spatial frequencies did not significantly correlate with PVD presence. Even in the subgroup of symptomatic PVD eyes, VA was not significantly decreased, while quantitative contrast sensitivity function outcomes showed visual function deficits at low spatial frequencies (1.5 cpd and 3 cpd). Conclusions: Contrast sensitivity measured with the quantitative contrast sensitivity function test showed visual function deficits in eyes with PVD that would have been missed with VA testing alone. Incorporating this test in the retina clinic might offer a more comprehensive functional assessment of eyes with PVD, serving as an adjunct outcome metric in clinical decision-making.

Multimodal Imaging Characteristics and Correlation to Outcomes in Patients with CRAO Presenting to a Large Academic Center.

PURPOSE: To characterize a large modern cohort of patients with central retinal artery occlusion (CRAO) by describing presenting features and outcomes relating to manually segmented optical coherence tomography (OCT) features, angiographic reperfusion, and visual recovery. DESIGN: Retrospective clinical cohort study. METHODS: Patients with CRAO (ICD-10: H34.1) initially presenting to a tertiary referral center between January 2017 and December 2021 were included. Demographics, eye exam findings, fundus photographs, OCT, and fluorescein angiography (FA) were analyzed. Main outcome measures included total and inner retinal thickness on macular OCT, reperfusion, visual outcomes, and development of neovascularization. RESULTS: 145 eyes of 144 patients with mean age at of 69.4±13.6 years were included. The mean time to presentation was 1.6±4.2 days, with 19% examined within 4.5 hours and 26% within 6 hours of vision loss. 19% had cilioretinal artery (CLRA) sparing. Mean initial visual acuity (VA) was 1.68±1.10 LogMAR (CLRA sparing) compared to 2.53±0.58 LogMAR (non-CLRA sparing), P<0.001. 32% had elevated inflammatory makers. Out of 47 eyes with final fluorescein angiography, one-third showed some reperfusion. Final vision was 1.40±1.16 LogMAR (CLRA sparing) compared to 2.46±0.81 (non-CLRA sparing), P<0.001. A third of patients improved in VA in both groups, 27% of patients gained more than 2 lines of vision in the CLRA sparing group and 36% in the non-CLRA sparing group. 17% improved to better than 20/200 in CLRA-sparing and 4% in non-CLRA sparing. 11% developed neovascularization all in non-CLRA sparing. In a multiple linear regression, VA at presentation was associated with regaining vision of 2 lines or more (OR=2.603, P=0.007). OCT showed progressive thinning over time, reaching lowest measurements at 6 months, and stabilizing thereafter. CONCLUSIONS: In this modern cohort of acute CRAO patients, presentation to a tertiary facility within 12 hours of symptoms was seen in almost half of the patients. Final visual acuity improved in almost a third of the patients, however, vision better than the legal blindness limit was rare (∼5%). Interestingly, a third of patients had some mild elevation of systemic inflammatory markers. Better visual acuity at presentation was associated with visual gain, while baseline OCT values had poor correlation with final outcome.

Epigenetic adaptation drives monocyte differentiation into microglia-like cells upon engraftment into the retina.

The identification of specific markers for microglia has been a long-standing challenge. Recently, markers such as P2ry12, TMEM119, and Fcrls have been proposed as microglia-specific and widely used to explore microglial functions within various central nervous system (CNS) contexts. The specificity of these markers was based on the assumption that circulating monocytes retain their distinct signatures even after infiltrating the CNS. However, recent findings reveal that infiltrating monocytes can adopt microglia-like characteristics while maintaining a pro-inflammatory profile upon permanent engraftment in the CNS.In this study, we utilize bone marrow chimeras, single-cell RNA sequencing, ATAC-seq, flow cytometry, and immunohistochemistry to demonstrate that engrafted monocytes acquire expression of established microglia markers-P2ry12, TMEM119, Fcrls-and the pan-myeloid marker Iba1, which has been commonly mischaracterized as microglia-specific. These changes are accompanied by alterations in chromatin accessibility and shifts in chromatin binding motifs that are indicative of microglial identity. Moreover, we show that engrafted monocytes dynamically regulate the expression of CX3CR1, CCR2, Ly6C, and transcription factors PU.1, CTCF, RUNX, AP-1, CEBP, and IRF2, all of which are crucial for shaping microglial identity. This study is the first to illustrate that engrafted monocytes in the retina undergo both epigenetic and transcriptional changes, enabling them to express microglia-like signatures. These findings highlight the need for future research to account for these changes when assessing the roles of monocytes and microglia in CNS pathology.

Targeting the Tie-2 Receptor With Faricimab in Central Serous Chorioretinopathy: A Case Series Motivated by a Genetic Finding.

PURPOSE: To investigate the effects of faricimab, a bispecific antibody targeting VEGF and Ang-2 (thus increasing Tie-2 activity), in patients with CSC based on a recent genetic study that implicated Tie-2 signaling in CSC pathophysiology. DESIGN: A retrospective interventional multicenter case series. METHODS: We included patients with chronic CSC (persistent or recurrent SRF for ≥6 months) who received at least one faricimab 6 mg injection between January 1 2022, and April 1 2024,. Study sites included Massachusetts Eye and Ear and University of California San Francisco. Patients with evidence of a choroidal neovascular membrane on color photos, optical coherence tomography (OCT) and/or fluorescein angiography were excluded. 16 eyes (15 patients) met the inclusion criteria. The median central macular thickness at each visit from 52 weeks before to 52 weeks after the first faricimab injection was calculated using automated Heidelberg Spectralis ETDRS subfield measurements. RESULTS: Prior to treatment with faricimab, CSC had been diagnosed a median of 4.1 years (range 0.9-8) earlier and SRF (and intraretinal fluid [IRF] in a subset) had been continuously present for a median of 30 weeks (range 9-257). Decreases in macular thickness were observed in 14/16 eyes after the first faricimab injection and in 14/16 eyes in the full follow-up period compared with prior, 10 of which experienced complete resolution of SRF following the start of the first series of injections at a median of 4 weeks (range 2-25). One eye worsened after the second injection. The median improvement in macular thickness was 40 µm [range -3 to 89.5] (P = .0007). Upon review of OCT images, reductions in macular thickness were consistent with reductions in SRF and/or IRF. Visual acuity improved by 2 lines or more in 6/16 eyes. CONCLUSIONS: In a retrospective case series of patients with chronic CSC and longstanding SRF, we observed improvement in macular thickness after intravitreal faricimab. While the small number of patients and variable natural history of CSC preclude definitive conclusions, a randomized controlled trial seems warranted.

A novel homozygous nonsense variant in CABP4 causing stationary cone/rod synaptic dysfunction.

INTRODUCTION: Variants in the CABP4 gene cause a phenotype to be included in the spectrum of congenital stationary night blindness, though some reports suggest that the clinical abnormalities are more accurately categorized as a synaptic disease of the cones and rods. We report a novel homozygous nonsense variant in CABP4 in a patient complaining of non-progressive reduced visual acuity and photophobia but not nyctalopia. METHODS: Complete ocular examination, fundus photographs, autofluorescence, optical coherence tomography, electroretinography, and targeted sequencing of known inherited retinal disease-associated genes. RESULTS: A 25-year-old man monitored for 13 years complains of a lifelong history of stable reduced visual acuity (20/150), impaired color vision (1 of 14 plates), small-amplitude nystagmus, and photophobia without nyctalopia. He is also hyperopic (+7D), and his electroretinography shows significantly reduced rod and cone responses. Targeted genetic analysis revealed a novel homozygous variant in the CABP4 gene at c.181C>T, p. (Gln61*) underlying his clinical presentation. CONCLUSIONS: A novel variant in CABP4 is associated with stationary cone and rod dysfunction resulting in decreased acuity, color deficit, and photophobia, but not nyctalopia.

Progressive Choriocapillaris Changes on Optical Coherence Tomography Angiography Correlate With Stage Progression in AMD.

Purpose: We investigated the association between inner choroid flow deficit percentage (IC-FD%) using swept-source optical coherence tomography angiography (SS-OCTA) and progression of AMD. Methods: Retrospective, observational study including 64 eyes (42 participants) with early or intermediate AMD at baseline. Participants had two or more consecutive swept-source optical coherence tomography angiography covering a period of at least 18 months. Demographics, visual acuity, and AMD staging based on Beckman classification were reviewed. OCT was analyzed for hyperreflective foci, subretinal drusenoid deposits, hyporeflective drusen cores, and subfoveal choroidal thickness. IC-FD% was measured within the central 3- and 6-mm using a 16-µm slab, after compensation and binarization (Phansalkar method). Mixed-effects Cox regression models assessed the association between imaging biomarkers and AMD progression. Results: During follow-up (37 ± 9 months), 4 eyes with early AMD (31%) progressed to intermediate AMD and 30 (59%) eyes with intermediate AMD developed late AMD (19 geographic atrophy; 11 wet AMD). Baseline hyporeflective drusen core was associated with geographic atrophy development (P < 0.01), whereas greater IC-FD% (3-mm) was associated with wet AMD (P = 0.03). Time-varying analysis showed that faster subfoveal choroidal thickness reduction and IC-FD% (6-mm) increase were associated with geographic atrophy onset (P < 0.05), whereas IC-FD% (3-mm) increase was associated with wet AMD (P = 0.03). Notably, greater IC-FD% increases in the 3 mm (area under the curve = 0.72) and 6 mm (area under the curve = 0.89) were better predictive of wet AMD and geographic atrophy development, respectively. Conclusions: Our longitudinal IC-FD% assessment emphasizes the role of progressive choriocapillaris changes as a biomarker for AMD progression. Our findings support that widespread choriocapillaris alterations (6 mm) may precede progression to geographic atrophy, whereas more central choriocapillaris loss (3 mm) may provide an ischemic stimulus for wet AMD.

Longitudinal Assessment of Intraretinal Microvascular Abnormalities in Diabetic Retinopathy Using Swept-Source Optical Coherence Tomography Angiography.

Purpose: To longitudinally investigate the changes in intraretinal microvascular abnormalities (IRMAs) over time, employing swept-source optical coherence tomography angiography in eyes with diabetic retinopathy. Methods: In this retrospective, longitudinal study, we evaluated 12 × 12-mm swept-source optical coherence tomography angiography centered on the macula at baseline and last available follow-up visit for (1) IRMA changes during follow-up, defined as (a) stable, (b) regressed, (c) obliterated, and (d) progressed; and the (2) development of new neovascularization (NV) and their origins. Competing-risk survival analysis was used to assess the factors associated with these changes. Results: In total, 195 eyes from 131 participants with diabetic retinopathy were included. Stable, regressed, obliterated, and progressed IRMA were observed in 65.1%, 12.8%, 11.3%, and 19% of eyes with diabetic retinopathy, respectively. Anti-VEGF injections during the follow-up periods and a slower increase of foveal avascular zone were associated with IRMA regression (P < 0.001 and P = 0.039). Obliterated IRMA were correlated with previous panretinal photocoagulation (P < 0.001) and a lower deep capillary plexus vessel density at baseline (P = 0.007), as well as with follow-up anti-VEGF injections (P = 0.025). A higher baseline ischemia index (ISI) and panretinal photocoagulation during the follow-up periods were associated with IRMA progression (P = 0.049 and P < 0.001). A faster increase in ISI predicted the development of NV elsewhere (NVE) from veins (P < 0.001). No significant factors were found to be associated with NVE originating from IRMA. Conclusions: Changes in IRMA closely correlated with the severity of retinal ischemia and treatment. Notably, our study confirmed the potential, yet relatively rare, development of NVE from IRMA in a large cohort; however, the risk factors associated with this transformation require further exploration.

Visual restoration with KPro after face allotransplantation with a grade III phthisical eye.

The Boston Keratoprosthesis type I (KPro-I) has been shown to be successful in restoring vision after severe ocular burns; however, its long-term outcomes in phthisical eyes have rarely been reported. A monocular woman with a history of severe alkali chemical injury necessitating facial transplantation presented with a light perception left eye after a complicated course, including failed KPro-I, therapeutic penetrating keratoplasty, endophthalmitis, hypotony, total retinal detachment, and structural changes, including a shrunken 18 mm axial length and eye wall thickening. The patient underwent a combined vitrectomy with silicone oil and KPro-I implantation, resulting in her regaining ambulatory visual acuity (20/250) at 3 years' follow-up.

Contrast Sensitivity Better Reflects Wide-Field Swept-Source Optical Coherence Tomography Angiography Vascular Metrics Among Healthy Eyes Compared to Visual Acuity.

BACKGROUND AND OBJECTIVE: To evaluate the association between widefield swept-source optical coherence tomography angiography (WF SS-OCTA) and visual function in healthy eyes. PATIENTS AND METHODS: Fifty-seven eyes of 45 patients were evaluated with visual acuity (VA), contrast sensitivity (CS), and WF SS-OCTA (3 × 3, 6 × 6, and 12 × 12 mm images) on the same day. Mixed-effects multivariable regression analyses were performed. RESULTS: Contrast sensitivity metrics, including CS between 6 to 18 cycles per degree (cpd) and area under the logarithm CS function, were significantly associated with vessel density (VD) and vessel skeletonized density (VSD), whereas VA was not. The largest effect size was between CS at 18 cpd and VD (ß = 0.41, P = 0.007) and VSD (ß = 0.42, P = 0.006) on 12 × 12 mm images. CONCLUSIONS: Reduced VSD and VD on WF SSOCTA was significantly associated with decreased CS, whereas VA was not. These results suggest CS could serve as a screening tool for early stage retinal and neurologic disorders. [Ophthalmic Surg Lasers Imaging Retina 2024;55:494-502.].

Decreased Macular Choriocapillaris Perfusion Correlates with Contrast Sensitivity Function in Dry Age-Related Macular Degeneration.

PURPOSE: To investigate the relationships between contrast sensitivity (CS), choriocapillaris perfusion, and other structural OCT biomarkers in dry age-related macular degeneration (AMD). DESIGN: Cross-sectional, observational study. PARTICIPANTS: One hundred AMD eyes (22 early, 52 intermediate, and 26 late) from 74 patients and 45 control eyes from 37 age-similar subjects. METHODS: All participants had visual acuity (VA) assessment, quantitative CS function (qCSF) testing, macular OCT, and 6 × 6-mm swept-source OCT angiography scans on the same day. OCT volumes were analyzed for subretinal drusenoid deposits and hyporeflective drusen cores, and to measure thickness of the outer nuclear layer. OCT angiography scans were utilized to calculate drusen volume and inner choroid flow deficit percentage (IC-FD%), and to measure the area of choroidal hypertransmission defects (HTDs). Inner choroid flow deficit percentage was measured from a 16-µm thick choriocapillaris slab after compensation and binarization with Phansalkar's method. Generalized linear mixed-effects models were used to evaluate the associations between functional and structural variables. MAIN OUTCOME MEASURES: To explore the associations between qCSF-measured CS, IC-FD%, and various AMD imaging biomarkers. RESULTS: Age-related macular degeneration exhibited significantly reduced qCSF metrics eyes across all stages compared with controls. Univariate analysis revealed significant associations between various imaging biomarkers, reduced qCSF metrics, and VA in both groups. Multivariate analysis confirmed that higher IC-FD% in the central 5 mm was significantly associated with decreases in all qCSF metrics in AMD eyes (ß = -0.74 to -0.25, all P < 0.05), but not with VA (P > 0.05). Outer nuclear layer thickness in the central 3 mm correlated with both VA (ß = 2.85, P < 0.001) and several qCSF metrics (ß = 0.01-0.90, all P < 0.05), especially in AMD eyes. Further, larger HTD areas were associated with decreased VA (ß = -0.89, P < 0.001) and reduced CS at low-intermediate frequencies across AMD stages (ß = -0.30 to -0.29, P < 0.001). CONCLUSIONS: The significant association between IC-FD% in the central 5 mm and qCSF-measured CS reinforces the hypothesis that decreased macular choriocapillaris perfusion contributes to visual function changes in AMD, which are more pronounced in CS than in VA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease.

Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.

Metabolomic-derived endotypes of age-related macular degeneration (AMD): a step towards identification of disease subgroups.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using a discovery cohort of 163 AMD patients from Boston, US, and a validation cohort of 214 patients from Coimbra, Portugal, we identified four distinct metabolomics-derived endotypes with varying retinal structural and functional characteristics, confirmed across both cohorts. Patients clustered into Endotype 1 exhibited a milder form of AMD and were characterized by low levels of amino acids in specific metabolic pathways. Meanwhile, patients clustered into both Endotype 3 and 4 were associated with more severe AMD and exhibited low levels of fatty acid metabolites and elevated levels of sphingomyelins and fatty acid metabolites, respectively. These preliminary findings indicate that metabolomics-derived endotyping may offer a refined strategy for categorizing AMD patients based on their specific pathophysiological underpinnings, rather than relying solely on traditional observational clinical indicators.

Associations of quantitative contrast sensitivity with vascular metrics on widefield swept-source OCT angiography across stages of diabetic retinopathy.

PURPOSE: To investigate structure-function associations between contrast sensitivity (CS) and widefield swept-source optical coherence tomography angiography (WF SS-OCTA) vascular metrics across stages of non-proliferative (NPDR) and proliferative diabetic retinopathy (PDR), without diabetic macular oedema. METHODS: Prospective cross-sectional study in 140 eyes of 99 patients: 33 mild NPDR, 24 moderate/severe NPDR, 15 PDR, 33 diabetic without DR (DMnoDR) and 46 control eyes. Mixed-effects multivariable regression models to evaluate associations between quantitative contrast sensitivity function (Adaptive Sensory Technology) and vessel density (VD) and vessel skeletonised density (VSD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) on same-day imaging with WF SS-OCTA (Plex Elite 9000, Carl Zeiss Meditec). RESULTS: Standardised ß coefficients for area under the logarithm of contrast sensitivity function curve (AULCSF) versus visual acuity (VA) at 3×3 mm scans: SCP VSD (ß=0.32, p<0.001 vs -0.18, p=0.044), DCP VSD (ß=0.30, p<0.001 vs -0.21, p=0.02), SCP VD (ß=0.25, p=0.004 vs -0.13, p=0.129), DCP VD (ß=0.26, p=0.003 vs -0.19, p=0.034). AULCSF was significantly reduced in mild NPDR (ß=-0.28, p<0.001) and DMnoDR (ß=-0.19, p=0.005) versus controls, while VA was not significantly different. AULCSF performed better than VA in differentiating between controls and DMnoDR (0.69 vs 0.50), controls and mild NPDR (0.76 vs 0.61) and controls and moderate/severe NPDR (0.89 vs 0.73). CONCLUSIONS: DR-induced microvascular changes on OCTA are associated with larger changes on CS than in VA. CS is affected earlier than VA in the course of DR and performed better in discriminating between controls, DMnoDR and across DR stages.

Correction: AMPK-Activated Protein Kinase Suppresses Ccr2 Expression by Inhibiting the NF-κB Pathway in RAW264.7 Macrophages.

[This corrects the article DOI: 10.1371/journal.pone.0147279.].