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    Research Update 578


    Capturing the Transition from Intermediate to Neovascular AMD: Longitudinal Inner Retinal Thinning and Factors Associated with Neuronal Loss.

    Investigative ophthalmology & visual science 2023 Apr 3;

    Borrelli E, Barresi C, Lari G, Berni A, Battista M, Reibaldi M, Cascavilla ML, Bandello F.

    Purpose: To estimate the impact of transition from intermediate to exudative neovascular age-related macular degeneration (AMD) on the inner retina and to assess the relationship of clinical characteristics and optical coherence tomography (OCT) findings with inner retinal changes.

    Methods: A total of 80 participants (80 eyes) with intermediate AMD at baseline who developed neovascular AMD within 3 months were included in the analysis. OCT scans at follow-up visits (after transition to neovascular AMD) were compared with values at the latest visit with evidence of intermediate AMD to quantify longitudinal inner retinal changes. OCT images were also reviewed for qualitative features reflecting distress of the outer retina or retinal pigment epithelium and for the presence and characteristics of exudation.

    Results: The parafoveal and perifoveal inner retinal thicknesses were 97.6 ± 12.9 µm and 103.5 ± 16.2 µm, respectively, at baseline, and a significant increase in values was detected at the visit with first evidence of neovascular AMD (parafoveal: 99.0 ± 12.8 µm, P = 0.040; perifoveal: 107.9 ± 19.0 µm, P = 0.0007). Conversely, the inner retina was significantly thinner at the 12-month follow-up visit after initiation of the anti-vascular endothelial growth factor therapy (parafoveal: 90.3 ± 14.8 µm, P < 0.0001; perifoveal: 92.0 ± 21.3 µm, P < 0.0001). At the 12-month follow-up visit, OCT evidence of alterations of the external limiting membrane and history of previous intraretinal fluid were associated with a greater inner retinal thinning.

    Conclusions: The development of exudative neovascularization is associated with significant neuronal loss that may be detected once the exudation is resolved. OCT analysis demonstrated a significant relationship between morphological alterations detected using structural OCT and the amount of inner neuronal loss.

    DOI: 10.1167/iovs.64.4.21


    Macular Perfusion Deficits on OCTA Correlate with Non-perfusion on Ultrawide-field FA in Diabetic Retinopathy.

    Ophthalmology, Retina. 2023 Apr 13

    Decker NL, Duffy BV, Boughanem GO, Fukuyama H, Castellanos Canales D, Nesper PL, Gill MK, Fawzi AA.

    Objective: To evaluate the correlation between non-perfusion parameters on optical coherence tomography angiography (OCTA) and ultrawide-field fluorescein angiography (UWF-FA) in subjects with diabetes mellitus (DM).

    Design: Prospective, cross-sectional study.

    Subjects: Subjects with DM and a wide range of diabetic retinopathy (DR) severity seen at a tertiary referral center. METHODS: We used averaged 3 x 3 mm OCTA scans to measure geometric perfusion deficits (GPD), vessel density (VD), and vessel length density (VLD) in the full retina, superficial (SCP), and deep capillary plexuses (DCP). Non-perfusion was manually delineated on UWF-FA to quantify central, peripheral, and total retinal non-perfusion (mm2 and % area).

    Main Outcome Measures: Correlation between OCTA parameters and UWF-FA non-perfusion, and accuracy of these OCTA and UWF-FA parameters in detecting clinically referable eyes, using receiver operating characteristic (ROC) curve analysis, sensitivity (SN), specificity (SP), and area under the ROC curve (AUC).

    Results: The study included 67 eyes (12 eyes with no signs of DR, 8 mild, 22 moderate, 14 severe non-proliferative DR, and 11 treatment naïve proliferative DR). There was a fair to moderate correlation between either central or total retinal non-perfusion on UWF-FA (mm2) and GPD in the SCP (r=0.482 and r=0.464, respectively) and DCP (r=0.470 and 0.456, respectively). ROC analysis showed the DCP GPD significantly superior to other OCTA parameters at the DCP with the largest overall AUC on OCTA for distinguishing referable DR (0.905). Further, the GPD parameter had the largest AUC in each respective capillary layer compared to other parameters. Overall, total UWF-FA non-perfusion area showed a comparable AUC (0.907) and performed significantly better than peripheral non-perfusion (p=0.041). Comparing the AUC values between GPD and UWF-FA non-perfusion parameters showed no significant difference in discerning referable DR.

    Conclusions: Non-perfusion as quantified on OCTA (3x3mm) correlated with UWF-FA parameters and both were comparable in detecting referable DR. These macular OCTA metrics, particularly DCP GPD, have the potential for gauging the overall ischemic status of the retina, with an important clinical role in identifying clinically referable eyes with DR.

    DOI: 10.1016/j.oret.2023.04.003

    Optical Coherence Tomography Angiography Biomarkers in Thai Patients With Diabetic Nephropathy: A Diabetic Eye and Kidney Diseases (DEK-D) Study.

    Translational vision science & technology 2023 Apr 3;

    Surawatsatien N, Pongsachareonnont PF, Kulvichit K, Varadisai A, Somkijrungroj T, Mavichak A, Kongwattananon W, Suwajanakorn D, Phasukkijwatana N, Srisawat N.

    Purpose: To identify optical coherence tomography angiography (OCTA) biomarkers to predict the diabetic nephropathy (DN) and their associations with 24-hour urine albumin levels in diabetic patients.

    Methods: This cross-sectional, observational study examined 186 eyes from 93 individuals subdivided into three groups according to 24-hour urine albumin levels: no DN, early DN, and late DN. Vessel density (VD), fractal dimension, foveal avascular zone area, intercapillary area, central retinal thickness, and subfoveal choroidal thickness were measured from OCTA images to determine their association with the DN stages.

    Results: VD values of the superficial capillary plexus, deep capillary plexus, and whole retina were significantly lower in the early DN group compared to the no DN group (adjusted P = 0.042, 0.016, and 0.008, respectively). VD values for the deep capillary plexus and whole retina were significantly decreased in the late DN group compared to the no DN group (adjusted P = 0.025 and 0.021, respectively). Mean fractal dimension, intercapillary area, foveal avascular zone area, central retinal thickness, and subfoveal choroidal thickness were not statistically different among the three groups.

    Conclusions: VD may be a useful parameter for the early non-invasive screening of DN. Further studies in larger populations are needed to establish a cutoff value for detection. TRANSLATIONAL

    Relevance: This study investigated the association of each retinal vasculature measurement by OCTA and diabetic nephropathy status which could serve as an alternative way to screen for albuminuria.

    DOI: 10.1167/tvst.12.4.19


    Pentosan polysulfate sodium (Elmiron) maculopathy: a genetic perspective.

    Retina. 2023 Mar 28.

    Kalaw FGP, Ignacio JCI, Wu CY, Ferreyra H, Nudleman E, Baxter SL, Freeman WR, Borooah S.

    Purpose: To assess genetic associations for pentosan polysufate sodium maculopathy.

    Methods: Genetic testing for inherited retinal dystrophy (IRD) genes using exome testing and for 14 age-related macular degeneration (AMD) associated single nucleotide polymorphisms (SNP) using panel testing were performed. Additionally, full-field electroretinograms (ffERG) were obtained to identify any cone-rod dystrophy.

    Results: Eleven out of fifteen patients were female, with a mean age of 69 (range 46-85). IRD exome testing in five patients revealed six pathogenic variants but failed to confirm IRD in any patient genetically. FfERG performed in 12 patients demonstrated only non-specific a- and b-wave abnormalities in 11 cases and was normal in one case. For AMD SNPs, CFH rs3766405 (p=0.003) and CETP (p=0.027) were found to be statistically significantly associated with pentosan polysulfate maculopathy phenotype compared to the control population.

    Conclusion: Pentosan polysulfate maculopathy is not associated with Mendelian IRD genes. However, several AMD risk alleles were identified to be associated with maculopathy compared to their frequency in the normal population. This suggests a role for genes in disease pathology, particularly the alternative complement pathway. These findings would benefit from further investigation to understand the risk of developing maculopathy in taking pentosan polysulfate.

    DOI: 10.1097/IAE.0000000000003794

    The prevalence and presentation patterns of microcystic macular oedema: a systematic review and meta-analysis of 2128 glaucomatous eyes.

    Eye (London, England) 2023 Apr 18

    Abdelaal A, Eltaras MM, Katamesh BE, Serhan HA, Farahat RA, Badr H, Abdelazeem B.

    We conducted this research to determine the prevalence rate and presentation patterns with microcystic macular oedema (MMO) in glaucoma patients. The protocol was pre-registered on PROSPERO ( CRD42022316367 ). PubMed, Scopus, Web of Science, EMBASE, ProQuest, EBSCOHost, CENTRAL,, and Google Scholar were searched for articles reporting MMO in glaucoma patients. The primary outcome was the prevalence of MMO, while secondary outcomes included the comparison between MMO and non-MMO in terms of patients’ characteristics (age, gender), glaucoma stage, and ocular parameters (axial length (AL), intraocular pressure, mean deviation, spherical equivalent). Data are reported as mean difference (MD) or log odds ratio (logOR) along with their corresponding 95% confidence intervals (CI) for continuous and dichotomous outcomes, respectively. The quality of included studies was assessed using the NIH tool, and the certainty of evidence was assessed using GRADE framework. Ten studies (2128 eyes) were included, revealing an overall prevalence rate of MMO of 8% (95%CI: 5-12%). When compared to non-MMO group, MMO was associated with lower age (MD = -5.91; 95%CI: -6.02: -5.20), greater risk of advanced glaucoma stage (LogOR=1.41; 95%CI: 0.72: 2.09), and lower mean deviation of the visual field (MD = -5.00; 95%CI: -7.01: -2.99). No significant difference was noted between both groups in terms of gender, axial length, or spherical equivalent. Three studies had good quality while seven had poor quality. MMO is a prevalent observation in glaucoma patients and is associated with patients’ age and stage of the disease. However, the certainty of evidence remains very low.

    DOI: 10.1038/s41433-023-02524-w


    Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration.

    JAMA ophthalmology. 2023 Apr 20:

    Rämö JT, Abner E, van Dijk EHC, Wang X, Brinks J, Nikopensius T, Nõukas M, Marjonen H, Silander K, Jukarainen S, Kiiskinen T, Choi SH, Kajanne R, Mehtonen J, Palta P, Lubitz SA, Kaarniranta K, Sobrin L, Kurki M, Yzer S, Ellinor PT, Esko T, Daly MJ, den Hollander AI, Palotie A, Turunen JA, Boon CJF, Rossin EJ

    Importance: Central serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases.

    Objective: To identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD.

    Design, Setting, And Participants: Using International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revision code-based inclusion and exclusion criteria, patients with CSC and controls were identified in both the FinnGen study and the Estonian Biobank (EstBB). Also included in a meta-analysis were previously reported patients with chronic CSC and controls. Data were analyzed from March 1 to September 31, 2022.

    Main Outcomes And Measures: Genome-wide association studies (GWASs) were performed in the biobank-based cohorts followed by a meta-analysis of all cohorts. The expression of genes prioritized by the polygenic priority score and nearest-gene methods were assessed in cultured choroidal endothelial cells and public ocular single-cell RNA sequencing data sets. The predictive utility of polygenic scores (PGSs) for CSC and AMD were evaluated in the FinnGen study.

    Results: A total of 1176 patients with CSC and 526 787 controls (312 162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343 461 controls were identified in the FinnGen study, 103 patients with CSC and 178 573 controls were identified in the EstBB, and 521 patients with chronic CSC and 3577 controls were included in a meta-analysis. Two previously reported CSC risk loci were replicated (near CFH and GATA5) and 3 novel loci were identified (near CD34/46, NOTCH4, and PREX1). The CFH and NOTCH4 loci were associated with AMD but in the opposite direction. Prioritized genes showed increased expression in cultured choroidal endothelial cells compared with other genes in the loci (median [IQR] of log 2 [counts per million], 7.3 [0.6] vs 4.7 [3.7]; P = .004) and were differentially expressed in choroidal vascular endothelial cells in single-cell RNA sequencing data (mean [SD] fold change, 2.05 [0.38] compared with other cell types; P < 7.1 × 10-20). A PGS for AMD was predictive of reduced CSC risk (odds ratio, 0.76; 95% CI, 0.70-0.83 per +1 SD in AMD-PGS; P = 7.4 × 10-10). This association may have been mediated by loci containing complement genes.

    Conclusions And Relevance: In this 3-cohort genetic association study, 5 genetic risk loci for CSC were identified, highlighting a likely role for genes involved in choroidal vascular function and complement regulation. Results suggest that polygenic AMD risk was associated with reduced risk of CSC and that this genetic overlap was largely due to loci containing complement genes.

    DOI: 10.1001/jamaophthalmol.2023.0706

    Rare CIDEC coding variants enriched in age-related macular degeneration patients with small low-luminance deficit cause lipid droplet and fat storage defects.

    PloS one. 2023 Apr 20;

    Kim S, Stockwell A, Qin H, Gao SS, Sagolla M, Stoilov I, Wuster A, Lai P, Yaspan BL, Jeanne M.

    Background: The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients.

    Methods: AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro.

    Results: We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better anti-VEGF treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes.

    Conclusions: As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity.

    DOI: 10.1371/journal.pone.0280484

    Visual and cognitive functioning among older adults with low vision before vision rehabilitation: A pilot study.

    Frontiers in psychology. 2023 Mar 22;

    Aubin G, Phillips N, Jaiswal A, Johnson AP, Joubert S, Bachir V, Kehayia E, Wittich W.

    Introduction: The occurrence of age-related vision changes is inevitable. However, some of these changes can become pathological. Research indicates that vision and hearing loss is correlated with age-related cognitive decline, and with a higher risk of developing dementia due to Alzheimer’s disease. Low vision rehabilitation could possibly be a protective factor against cognitive decline, as it provides the clients with compensatory strategies to overcome their visual deficits.

    Objectives And Hypothesis: The aim of this pilot study was to assess correlations between visual and cognitive functions in older adults referred for low vision rehabilitation. We hypothesized that more severe impairment of visual acuity and contrast sensitivity would be correlated with more advanced levels of cognitive impairment. The second objective was to examine which of these correlations would remain significant once established variables that influence cognition are statistically removed (e.g., age, education).

    Methods: Thirty-eight older adults (age range: 66-97 years old) with a visual impairment (acuity <20/70) were recruited before the onset of their low vision rehabilitation. They underwent vision (reading acuity, reading speed, contrast sensitivity), hearing (audiogram, speech-in-noise perception) and cognitive (global cognition, memory, executive functions) testing, and demographic information was obtained.

    Results And Discussion: Correlations among global cognition and visual aid use, memory and reading speed, memory and contrast sensitivity, memory, and visual aid use, and between executive functions and contrast sensitivity were significant. Correlations between contrast sensitivity and memory, as well as between global cognition and visual aid use remained significant after controlling for age and education. The present study is relevant to clinicians who are assessing the cognitive status of older adults, such as neuropsychologists, because it highlights the importance of considering low vision when administering neuropsychological tests, especially to persons who have not yet received rehabilitation for their visual impairment.

    DOI: 10.3389/fpsyg.2023.1058951


    Management of macular oedema due to retinal vein occlusion: An evidence-based systematic review and meta-analysis.

    Clinical & experimental ophthalmology. 2023 Apr 14

    Cornish EE, Zagora SL, Spooner K, Fraser-Bell S.

    Background: Central retinal vein occlusion and branch retinal vein occlusion are common causes of visual loss due to associated macular oedema. The aim of this review was to assess the effectiveness of interventions improving vision and treating macular oedema in central retinal vein occlusion and branch retinal vein occlusion.

    Methods: Medical search engines and clinical trial registries were systematically searched. Randomised clinical trials with ≥90 eyes and real-world outcome studies with ≥100 eyes each with ≥6 months follow-up were included.

    Results: There were 11 randomised controlled trials evaluating treatments for central retinal vein occlusion which met the inclusion criteria and 10 for branch retinal vein occlusion. There were 10 real world outcome studies of central retinal vein occlusion and 5 real world outcome studies of branch retinal vein occlusion. Meta-analysis was performed on studies that met the defined inclusion criteria. Main outcomes were change in visual acuity at 6-, 12-, 24- and 36 months by treatment.

    Conclusions: Intravitreal anti-vascular endothelial derived growth factor is recommended as first line treatment over intravitreal corticosteroid due to its effectiveness and lower rate of ocular adverse events. Best outcomes are achieved when intravitreal treatment is started early. Macular laser may have an adjunctive role in branch retina vein occlusion but not central retinal vein occlusion.

    DOI: 10.1111/ceo.14225


    Long-term preservation of visual acuity after resorption of acquired vitelliform lesions in age-related macular degeneration.

    Retinal cases & brief reports. 2023 Apr 17.

    Ramtohul P, Freund KB.

    Purpose: To report the long-term (23 years) clinical and multimodal imaging features of acquired vitelliform lesions (AVLs) associated with non-neovascular age-related macular degeneration (AMD).

    Methods: Retrospective case report. Color and red free fundus photographs, high-resolution optical coherence tomography (High-Res OCT), fluorescein (FA) and indocyanine green angiography (ICGA), and OCT-angiography (OCTA) were performed.

    Results: A 58-year-old man presented with bilateral AVLs in the setting of non-neovascular AMD. At baseline, his best-corrected visual acuity (BCVA) was 20/30 in his right eye and 20/20 in his left eye. Red free fundus photographs showed AVLs with cuticular drusen in both eyes corresponding to a “stars-in-the-sky” pattern on FA. ICGA showed no evidence of macular neovascularization (MNV). Throughout the 23-year follow-up, the patient reported consuming 20mg/day of lutein supplement. At the end of follow-up, his BCVA was 20/20 in both eyes. Color fundus photographs showed resorption of the AVLs in both eyes and High-Res OCT showed relative preservation of the outer retinal bands in the fovea. OCTA confirmed the absence of MNV.

    Conclusion: In non-neovascular AMD, spontaneous resorption of AVLs may be associated with long-term maintenance of visual acuity and relative preservation of the outer retinal morphology.

    DOI: 10.1097/ICB.0000000000001429