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    Research Update 573

    FEATURED ARTICLE

    Sequential structural and functional change in geographic atrophy on multimodal imaging in non-exudative age-related macular degeneration.

    Graefe’s archive for clinical &experimental ophthalmology. 2023 Mar 6.

    Lee JH, Ahn J, Shin JY.

    Purpose: To investigate the temporal order of photoreceptor atrophy, retinal pigment epithelium (RPE) atrophy and visual acuity loss in patients with center-involving geographic atrophy (GA) in non-exudative age-related macular degeneration (neAMD).

    Methods: Forty eyes of 25 consecutive patients who eventually developed center-involving GA were investigated. Fundus autofluorescence (FAF) and infrared image coupled optical coherence tomography (OCT) were acquired at each visit. Development of RPE atrophy and photoreceptor atrophy was defined as abnormal hyper/hypo-fluorescence on FAF and photoreceptor loss on OCT over 50% of the vertical or horizontal diameters of the center 1 mm circle, respectively. Visual acuity loss was defined as worsening of more than 0.2 logMAR compared to baseline. Kaplan-Meier analyses was performed to compare the sequential order of these three events.

    Results: Mean age was 72.72 ± 8.63 years, and follow-up duration was 27.36 ± 17.22 months, with an average number of visits of 3.04 ± 1.54 during follow-up. GA progressed from photoreceptor atrophy on OCT, RPE atrophy on FAF, and then to vision loss (p < 0.001). The median survival time of photoreceptors preceded that of visual acuity by 16.3 months, and the median survival time of RPE preceded that of visual acuity by 7.0 months. At baseline, majority of eyes showed drusen only (57.5%), while the most common feature was incomplete RPE and outer retinal atrophy at 3-year follow-up (40.4%).

    Conclusion: In the progression of center-involving GA, photoreceptor atrophy on OCT and RPE atrophy on FAF precedes visual decline, and can act as biomarkers predicting future visual decline within the following years.

    DOI: 10.1007/s00417-023-06022-3

    DRUG TREATMENT

    Archway Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration 2-Year Results.

    Ophthalmology. 2023 Mar 2:

    Regillo C, Berger B, Brooks L, Clark WL, Mittra R, Wykoff CC, Callaway NF, DeGraaf S, Ding HT, Fung AE, Gune S, Le Pogam S, Smith R, Willis JR, Barteselli G.

    Purpose: To report 2-year results from the Archway clinical trial of the Port Delivery System with ranibizumab (PDS) for treatment of neovascular age-related macular degeneration (nAMD).

    Design: Phase 3, randomized, multicenter, open-label, active-comparator trial.

    Participants: Patients with previously treated nAMD diagnosed within 9 months of screening and responsive to anti-vascular endothelial growth factor therapy.

    Methods: Patients were randomized 3:2 to PDS with ranibizumab 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W) or intravitreal ranibizumab 0.5 mg injections every 4 weeks (monthly ranibizumab). Patients were followed through 4 complete refill-exchange intervals (∼2 years).

    Main Outcome Measures: Change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score from baseline averaged over weeks 60 and 64, and weeks 88 and 92 (noninferiority margin, -3.9 ETDRS letters).

    Results: PDS Q24W was noninferior to monthly ranibizumab, with differences in adjusted mean change in BCVA score from baseline averaged over weeks 60/64 and 88/92 of +0.4 (95% confidence interval [CI], -1.4 to +2.1) and -0.6 ETDRS letters (95% CI, -2.5 to +1.3). Anatomic outcomes were generally comparable between arms through week 96. Through each of 4 PDS refill-exchange intervals, 98.4%, 94.6%, 94.8%, and 94.7% of PDS Q24W patients assessed did not receive supplemental ranibizumab treatment. PDS ocular safety profile was generally unchanged from primary analysis. Prespecified ocular adverse events (AEs) of special interest were reported in 59 (23.8%) PDS and 17 (10.2%) monthly ranibizumab patients. Most common AE of special interest reported in both arms was cataract (PDS Q24W, 22 [8.9%]; monthly ranibizumab, 10 [6.0%]). Events in the PDS Q24W arm included (patient incidence) 10 (4.0%) conjunctival erosions, 6 (2.4%) conjunctival retractions, 4 (1.6%) endophthalmitis cases, and 4 (1.6%) implant dislocations. Serum ranibizumab sampling showed that the PDS continuously released ranibizumab over the 24-week refill-exchange interval and ranibizumab serum concentrations were within the range experienced with monthly ranibizumab.

    Conclusions: PDS Q24W showed noninferior efficacy to monthly ranibizumab through approximately 2 years, with approximately 95% of PDS Q24W patients not receiving supplemental ranibizumab treatment in each refill-exchange interval. AEs were generally manageable, with learnings continually implemented to minimize PDS-related AEs.

    DOI: 10.1016/j.ophtha.2023.02.024

    PATHOPHYSIOLOGY

    Aberrant lncRNA expression in patients with proliferative diabetic retinopathy: preliminary results from a single-center observational study.

    BMC Ophthalmology. 2023 Mar 10;

    Zeng L, Zhou M, Wang X, Long X, Ye M, Yuan Y, Tan W.

    Background: Diabetic retinopathy (DR) is a leading cause of blindness. Vision threat is particularly severe in patients with retinal neovascularization. However, little is known about the role of long noncoding RNAs (lncRNAs) in proliferative diabetic retinopathy (PDR). The goal of this study was to identify lncRNAs involved in PDR.

    Methods: We compared lncRNA expression profiles in the vitreous between patients with PDR and those with idiopathic macular hole (IMH) and between patients with PDR who had received anti-vascular endothelial growth factor (VEGF) therapy and those who had not. Vitreous samples from patients with PDR and IMH were screened for lncRNAs using microarray-based analysis, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to confirm the microarray results. Bioinformatic analysis was also performed. Moreover, the effect of anti-VEGF therapy was investigated in vitreous samples of patients with PDR treated with anti-VEGF therapy and those who were not.

    Results: A total of 1067 differentially expressed noncoding RNA transcripts were found during screening in the vitreous humor of patients with PDR than in those with IMH. Five lncRNAs were subjected to qRT-PCR. RP11-573 J24.1, RP11-787B4.2, RP11-654G14.1, RP11-2A4.3, and RP11-502I4.3 were significantly downregulated; this was validated by the comparison using the microarray data. In addition, 835 differentially expressed noncoding RNA transcripts were found during screening in the vitreous humor of patients with PDR treated with anti-VEGF therapy compared with untreated PDR patients. RP4-631H13.2 was significantly upregulated, which is consistent with the trend of the microarray analysis.

    Conclusions: There were systemic expression differences in the vitreous at the microarray level between patients with PDR and those with IMH and between patients with PDR after anti-VEGF treatment and those that did not receive anti-VEGF treatment. LncRNAs identified in the vitreous humor may be a novel research field for PDR.

    DOI: 10.1186/s12886-023-02817-4

    DIAGNOSIS AND IMAGING

    Choriocapillaris Structure In The Fellow Eyes Of Patients With Neovascular Age-Related Macular Degeneration: An Oct Angiography Image Averaging Study.

    Retina (Philadelphia, Pa). 2023 Feb 1

    Kamei T, Ooto S, Uji A, Ichioka A, Tsujikawa A.

    Purpose: Histological choriocapillaris abnormalities have been reported in age-related macular degeneration (AMD). Averaging multiple en face optical coherence tomography angiography improves the quality of imaging of the choriocapillaris. This study used multiple en face swept source optical coherence tomography angiography image averaging to examine the structural changes in the choriocapillaris in the fellow eyes of patients with neovascular AMD.

    Methods: All patients underwent macular optical coherence tomography angiography imaging. One eye per subject was repeatedly imaged, and nine raster scan sets were obtained. Registered en face images were averaged, and area of flow voids and number of flow voids were measured using ImageJ software.

    Results: Forty-eight patients with neovascular AMD were recruited for analysis. Twenty-seven patients had polypoidal choroidal vasculopathy, and 22 eyes had soft drusen. Twenty-six eyes of 26 healthy individuals were included as age-matched normal controls. The choriocapillaris had a meshwork appearance in all eyes. The mean flow void area of the choriocapillaris was larger in patients with AMD than normal controls (1.14 ± 0.16 mm2 vs. 1.01 ± 0.12 mm2, P = 0.002). The mean size of each flow void was greater in patients with AMD than normal controls (729 ± 210 µm2 vs. 583 ± 120 µm2, P = 0.003). The mean flow void area of the choriocapillaris was larger in eyes with soft drusen than without soft drusen (1.2 ± 0.2 mm2 vs. 1.1 ± 0.1 mm2, P = 0.024).

    Conclusion: Multiple en face image averaging revealed precise choriocapillaris structures in the fellow eyes of patients with neovascular AMD.

    DOI: 10.1097/IAE.0000000000003660

    PATHOGENESIS

    Aqueous microRNA Profiling In Age-Related Macular Degeneration And Polypoidal Choroidal Vasculopathy By Next-Generation Sequencing.

    Scientific reports. 2023 Jan 23

    Choi YA, Jeong A, Woo CH, Cha SC, Park DY, Sagong M.

    Although many studies demonstrated the differences of clinical features, natural course, and response to treatment between typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV), differential microRNAs (miRNAs) expression in the aqueous humor (AH) between them has not been reported yet. We investigated the roles of miRNAs in the AH of patients with typical AMD and PCV using next-generation sequencing (NGS) and quantitative PCR (qPCR). Target genes and predicted pathways of miRNAs were investigated via pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes database. A total of 161 miRNAs from eyes with typical AMD and 185 miRNAs from eyes with PCV were differentially expressed. 33 miRNAs were commonly upregulated, and 77 miRNAs were commonly downregulated in both typical AMD and PCV groups. Among them, hsa-miR-140-5p, hsa-miR-374c-3p, and hsa-miR-200a-5p were differentially expressed and were predicted to regulate proteoglycans in cancer, p53 signaling pathway, Hippo signaling pathway, and adherens junction. The differential expression profiles and target gene regulation networks of AH miRNAs may contribute to the development of different pathological phenotypes in typical AMD and PCV. The results of this study provide novel insights into the pathogenesis, associated prognostic biomarkers, and therapeutic targets in AMD and PCV.

    DOI: 10.1038/s41598-023-28385-7

    DIAGNOSIS AND IMAGING

    Hyper-Reflective Foci in Intermediate Age-Related Macular Degeneration: Spatial Abundance and Impact on Retinal Morphology.

    Investigative ophthalmology& visual science. 2023 Jan 3;

    Saßmannshausen M, Vaisband M, von der Emde L, Sloan KR, Hasenauer J, Holz FG, Ach T.

    Purpose: The purpose of this study was to analyze spatially resolved structural changes at retinal locations in presence (+) or absence (-) of hyper-reflective foci (HRF) in eyes with subretinal pigment epithelium (RPE) drusen in intermediate age-related macular degeneration (iAMD).

    Methods: Patients with IAMD (n = 40; mean age = 69.7 ± 9.2 [SD] years) and healthy controls (n = 27; 64.2 ± 9.0) underwent spectral-domain optical-coherence-tomography imaging and fundus-controlled perimetry testing. After reviewing retinal layer segmentation, presence of HRF was annotated and retinal layer thicknesses (RLTs) extracted using ImageJ. Localized RLTs were compared between +HRF and -HRF positions. Univariate mixed linear models were used to investigate associations among RLT, HRF presence, and HRF size.

    Results: In iAMD eyes, a mean of 11.1 ± 12.5 HRF were detected with a peak abundance at 0.5 to 1.5 mm eccentricity to the fovea. At +HRF positions, outer nuclear layer (ONL; P = 0.0013, average difference = -12.4 µm) and retinal pigment epithelium drusen complex (RPEDC; P < 0.0001, +45.6 µm) thicknesses differed significantly compared to -HRF positions, even after correcting for accompanying drusen-related RPEDC layer thickening (P = 0.01). Mixed linear models revealed a significant association between increasing HRF area and decreasing ONL (association score = -0.17, P < 0.0001; 95% confidence interval [CI] = -0.22 to -0.11), and inner photoreceptor segments (IS) layer thicknesses (-0.08, P = 0.005; 95% CI = -0.14 to -0.03). Spearman rank correlation analysis yielded a significant correlation between total HRF area and mesopic (P = 0.015), but not scotopic (P = 0.305) retinal sensitivity losses.

    Conclusions: Descriptive analysis of this study demonstrated a predominant distribution of HRF at a foveal eccentricity of 0.5 to 1.5 mm, whereas further refined topographic analysis revealed a significant ONL layer thinning in presence of HRF even after correction for sub-RPE drusen presence compared to lesions in absence of HRF. Longitudinal studies are further needed to analyze the prognostic impact as well as the role of HRF presence in the context of iAMD.

    DOI: 10.1167/iovs.64.1.20

    REVIEWS

    Association between oral metformin use and the risk of age-related macular degeneration: A systematic review with meta-analysis.

    Acta ophthalmologica. 2023 Mar 6.

    Holtz JK, Thinggaard BS, Grauslund J, Subhi Y.

    Rodent studies demonstrate that oral metformin use may reduce chronic low-grade inflammation, downregulate apoptosis and extend life span. Emerging epidemiological evidence suggests that oral metformin use may protect against development of age-related macular degeneration (AMD) in humans. In this study, we systematically reviewed the literature on the association between oral metformin use and AMD in patients with type 2 diabetes and conducted a quantitative meta-analysis to provide a summary estimate of the association. We searched 12 literature databases on 10 August 2022 and identified nine eligible studies with data on a total of 1 427 074 individuals with diabetes. We found that patients with diabetes using metformin had a significantly lower odds ratio (OR) of having or developing AMD (OR 0.63; 95% CI: 0.46-0.86; p = 0.004). Our analyses also revealed that although the findings were robust in the sensitivity analysis, the Funnel plot indicated a certain publication bias towards finding a protective effect. Results of individual studies suggested inconsistent findings, as some studies found lower risk of AMD from higher total metformin exposure, whereas other studies found a higher risk of AMD from higher total metformin exposure. Taken together, there may be a link between metformin use and lower risk of AMD, but the relationship is only studied in observational studies, various sources of bias can be speculated to influence, and careful interpretation is warranted.

    DOI: 10.1111/aos.15655

    CASE REPORTS

    Combined Central Retinal Vascular Occlusion as the Presenting Feature in β-thalassemia with Iron Deficiency Anemia.

    Retinal Cases Brief reports 2022 Dec 8.

    Li H, Liu C, Huang AM, Zhang J, Yang R, Sha X, Liu Z.

    Purpose: To report a case of β-thalassemia trait (β-TT) with iron deficiency anemia (IDA) presenting as a combined central retinal vein and artery occlusion (CCRVAO).

    Methods: Case report. A 22-year-old female presented with sudden-onset blurry vision in the left eye of 3-days duration.

    Results: Best corrected visual acuity was 20/20 and 20/1000 in right and left eyes, respectively. Fundus examination of left eye revealed optic disc edema, macular whitening with a cherry-red spot, markedly dilated and tortuous retinal veins, and hemorrhages both around the disc and extending into the macula and the periphery. Fundus fluorescein angiography (FFA) showed delayed filling of retinal vasculature, dilated and tortuous retinal veins, blocked fluorescence around and beyond the optic disc. OCT scan at presentation showed hyperreflective inner retinal layers with neurosensory detachment. OCTA showed that the vessel densities of superficial and deep capillary plexus were remarkably reduced.A diagnosis of β-TT combined with IDA was made after hematologic work-up. The patient was treated with a course of oral iron supplements, vasodilator (Compound Xueshuantong), inhalation of a mixture of 5% carbon dioxide and 95% oxygen, and a nutritional agent (compound anisoine). By six months later, her visual acuity improved to 20/60 in the left eye with complete resolution of all clinical signs.

    Conclusion: CCRVAO is a rare emergency leading to acute vision loss and can manifest in patients with β-TT with IDA. Prompt diagnosis and early management is important to treat underlying systemic disorders and to prevent occurrence of a similar episode in fellow eye.

    DOI: 10.1097/ICB.0000000000001392