Diagnostic Challenges in Inflammatory Choroidal Neovascularization.

Inflammation plays a key role in the induction of choroidal neovascularization (CNV). Inflammatory choroidal neovascularization (iCNV) is a severe but uncommon complication of both infectious and non-infectious uveitides. It is hypothesized that its pathogenesis is similar to that of wet age-related macular degeneration (AMD), and involves hypoxia as well as the release of vascular endothelial growth factor, stromal cell-derived factor 1-alpha, and other mediators. Inflammatory CNV develops when inflammation or infection directly involves the retinal pigment epithelium (RPE)-Bruch's membrane complex. Inflammation itself can compromise perfusion, generating a gradient of retinal-choroidal hypoxia that additionally promotes the formation of choroidal neovascularization in the course of uveitis. The development of choroidal neovascularization may be a complication, especially in conditions such as punctate inner choroidopathy, multifocal choroiditis, serpiginous choroiditis, and presumed ocular histoplasmosis syndrome. Although the majority of iCNV cases are well defined and appear as the "classic" type (type 2 lesion) on fluorescein angiography, the diagnosis of iCNV is challenging due to difficulties in differentiating between inflammatory choroiditis lesions and choroidal neovascularization. Modern multimodal imaging, particularly the recently introduced technology of optical coherence tomography (OCT) and OCT angiography (noninvasive and rapid imaging modalities), can reveal additional features that aid the diagnosis of iCNV. However, more studies are needed to establish their role in the diagnosis and evaluation of iCNV activity.

Association of HERPUD1 genetic variant rs2217332 with age-related macular degeneration and polypoidal choroidal vasculopathy in an Indian cohort.

PURPOSE: Age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are sister diseases and have several similar clinical features and still have few genetic differences. The association of HERPUD1 (homocysteine inducible ER protein with ubiquitin like domain 1) gene variant rs2217332 with PCV is known; however, such association with AMD has not been reported in the Indian population. We analyzed the association of rs2217332 with PCV and AMD to identify the preferential association of this variant with these diseases. METHODS: This is a population-based case-control study consisting of 422 patients (129 AMD cases; 101 PCV cases, 192 healthy controls) recruited from the vitreoretinal clinic Sankara Nethralaya. The sample size for the study was calculated using appropriate power calculation methods. Genotype was determined using PCR-based Sanger sequencing. The SPSS V23.0 statistical package tool was used to calculate chi-square and ROC to determine the association of rs2217332 with control, AMD, and PCV. RESULTS: Here, we report for the first time the association of this genetic variant (rs2217332) with AMD and PCV in the Indian population. The case-control study shows a significant association of this SNP with PCV (P value = 0.002); however, this variant is not significantly associated with AMD (P value = 0.602). Comparison between AMD (as control) and PCV (as case) also showed significant association of the SNP with PCV (P value = 0.02). Minor allele A conferred to increase the risk of PCV. CONCLUSIONS: The study concludes that the genetic variant rs2217332 in HERPUD1 gene is highly significantly associated with PCV and not with AMD in Indian populations.

INFLAMMATORY CELL ACTIVITY IN TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Histologic Case Study.

BACKGROUND: Imaging indicators of macular neovascularization risk can help determine patient eligibility for new treatments for geographic atrophy secondary to age-related macular degeneration. Because type 1 macular neovascularization includes inflammation, we assessed by histology the distribution of cells with inflammatory potential in two fellow eyes with age-related macular degeneration. METHODS: Two eyes of a White woman in her 90's with type 3 macular neovascularization treated with antivascular endothelial growth factor were prepared for high-resolution histology. Eye-tracked spectral domain optical coherence tomography applied to the preserved donor eyes linked in vivo imaging to histology. Cells were enumerated in the intraretinal, subretinal, and subretinal retinal pigment epithelium (RPE)-basal lamina compartments on 199 glass slides. Cells with numerous organelles were considered to RPE-derived; cells with sparse RPE organelles were considered non-RPE phagocytes. RESULTS: Both eyes had soft drusen and abundant subretinal drusenoid deposit. In the retina and subretinal space, RPE-derived cells, including hyperreflective foci, were common (n = 125 and 73, respectively). Non-RPE phagocytes were infrequent (n = 5 in both). Over drusen, RPE morphology transitioned smoothly from the age-normal layer toward the top, suggesting transdifferentiation. The sub-RPE-basal lamina space had RPE-derived cells (n = 87) and non-RPE phagocytes (n = 49), including macrophages and giant cells. CONCLUSION: Numerous sub-RPE-basal lamina cells of several types are consistent with the documented presence of proinflammatory lipids in drusen and aged Bruch's membrane. The relatively compartmentalized abundance of infiltrating cells suggests that drusen contents are more inflammatory than subretinal drusenoid deposit, perhaps reflecting their environments. Ectopic RPE occurs frequently. Some manifest as hyperreflective foci. More cells may be visible as optical coherence tomography technologies evolve.

FIVE-YEAR INCIDENCE OF FELLOW EYE NEOVASCULAR INVOLVEMENT IN AGE-RELATED MACULAR DEGENERATION AND POLYPOIDAL CHOROIDAL VASCULOPATHY IN AN ASIAN POPULATION.

PURPOSE: To assess 5-year cumulative incidence and risk factors of fellow eye involvement in Asian neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy. METHODS: In a prospective cohort study of Asian nAMD and polypoidal choroidal vasculopathy, the fellow eyes were evaluated for exudation. The 5-year incidence of exudation was compared between nAMD and polypoidal choroidal vasculopathy. RESULTS: A total of 488 patients were studied. The 5-year incidence of exudation in fellow eyes was 16.2% (95% confidence interval: 12.0-20.2). Polypoidal choroidal vasculopathy compared with nAMD in the first eye was associated with lower fellow eye progression (9.8% [95% confidence interval: 5.1-14.3]) vs. 22.9% [95% confidence interval: 15.8-29.3], P < 0.01). Drusen (hazards ratio 2.11 [95% confidence interval: 1.10-4.06]), shallow irregular retinal pigment epithelium elevation (2.86 [1.58-5.18]), and pigment epithelial detachment (3.01 [1.27-7.17]) were associated with greater progression. A combination of soft drusens and subretinal drusenoid deposits, and specific pigment epithelial detachment subtypes (multilobular, and sharp peaked) were associated with progression. Pigment epithelial detachment, shallow irregular retinal pigment epithelium elevation, and new subretinal hyperreflective material occurred at 10.4 ± 4.2 months, 11.1 ± 6.0 months, and 6.9 ± 4.3 months, respectively, before exudation. CONCLUSION: The 5-year incidence of fellow eye involvement in Asian nAMD is lower than among Caucasians because of a higher polypoidal choroidal vasculopathy prevalence. Drusens, shallow irregular retinal pigment epithelium elevation, and pigment epithelial detachment are risk factors for fellow eye progression.

QUANTIFIED ANASTOMOTIC AREAS OF NEOVASCULARIZATION AS FACTORS ASSOCIATED WITH FREQUENT RECURRENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the quantitative characteristics of anastomoses of macular neovascularization (MNV) in neovascular age-related macular degeneration using optical coherence tomography angiography according to the frequency of intravitreal injections. METHODS: Eighty-six eyes of 86 patients treated for neovascular age-related macular degeneration were classified into two groups based on the number of intravitreal injections administered over 12 months: stable (<3) and unstable (≥3). Anastomotic areas were defined as areas surrounded by neighboring vessels in the MNV; their total number, mean area, maximal and minimal diameters (i.e., maximal and minimum Feret diameters), and ratio (Feret aspect ratio) were analyzed in the inner and outer areas of the MNV. RESULTS: Forty-four and 42 eyes were classified into the stable and unstable groups, respectively. The eyes in the unstable group had larger anastomotic areas with longer minimum Feret diameters and longer perimeters in the outer MNV. In the logistic regression analysis, instability was associated with a larger anastomotic area and a longer minimum Feret diameter in the outer MNV. Multivariate analysis revealed that a longer minimum Feret diameter in the outer MNV was the most significant factor ( P = 0.03). CONCLUSION: The quantitative characteristics of the anastomotic areas in the MNV might indicate the need for intravitreal injections in patients with neovascular age-related macular degeneration.

Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy.

PURPOSE: To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC). DESIGN: Genome-wide survival analysis using a longitudinal cohort study. PARTICIPANTS: We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain OCT, and fluorescein angiography/indocyanine green angiography or OCT angiography. METHODS: We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P values < 1.0 × 10-5 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis. MAIN OUTCOME MEASURES: The association between SNPs and MNV development in patients with CSC. RESULTS: Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]meta, 3.63; Pmeta = 5.76 × 10-9). Among previously reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR, 0.39, P = 2.55 × 10-4), COL4A3 rs4276018 (HR, 0.26, P = 1.56 × 10-3), and B3GALTL rs9564692 (HR, 0.56, P = 8.30 × 10-3) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of 8 pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport. CONCLUSIONS: ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. These 4 genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.

Histology and clinical imaging lifecycle of black pigment in fibrosis secondary to neovascular age-related macular degeneration.

PURPOSE: Melanotic cells with large spherical melanosomes, thought to originate from retinal pigment epithelium (RPE), are found in eyes with neovascular age-related macular degeneration (nvAMD). To generate hypotheses about RPE participation in fibrosis, we correlate histology to clinical imaging in an eye with prominent black pigment in fibrotic scar secondary to nvAMD. METHODS: Macular findings in a white woman with untreated inactive subretinal fibrosis due to nvAMD in her right eye were documented over 9 years with color fundus photography (CFP), fundus autofluorescence (FAF) imaging, and optical coherence tomography (OCT). After death (age 90 years), this index eye was prepared for light and electron microscopy to analyze 7 discrete zones of pigmentation in the fibrotic scar. In additional donor eyes with nvAMD, we determined the frequency of black pigment (n = 36 eyes) and immuno-labeled for retinoid, immunologic, and microglial markers (RPE65, CD68, Iba1, TMEM119; n = 3 eyes). RESULTS: During follow-up of the index eye, black pigment appeared and expanded within a hypoautofluorescent fibrotic scar. The blackest areas correlated to melanotic cells (containing large spherical melanosomes), some in multiple layers. Pale areas had sparse pigmented cells. Gray areas correlated to cells with RPE organelles entombed in the scar and multinucleate cells containing sparse large spherical melanosomes. In 94% of nvAMD donor eyes, hyperpigmentation was visible. Certain melanotic cells expressed some RPE65 and mostly CD68. Iba1 and TMEM119 immunoreactivity, found both in retina and scar, did not co-localize with melanotic cells. CONCLUSION: Hyperpigmentation in CFP results from both organelle content and optical superimposition effects. Black fundus pigment in nvAMD is common and corresponds to cells containing numerous large spherical melanosomes and superimposition of cells containing sparse large melanosomes, respectively. Melanotic cells are molecularly distinct from RPE, consistent with a process of transdifferentiation. The subcellular source of spherical melanosomes remains to be determined. Detailed histology of nvAMD eyes will inform future studies using technologies for spatially resolved molecular discovery to generate new therapies for fibrosis. The potential of black pigment as a biomarker for fibrosis can be investigated in clinical multimodal imaging datasets.

Soluble very low-density lipoprotein receptor (sVLDLR) inhibits fibrosis in neovascular age-related macular degeneration.

Subretinal fibrosis is a key pathological feature in neovascular age-related macular degeneration (nAMD). Previously, we identified soluble very low-density lipoprotein receptor (sVLDLR) as an endogenous Wnt signaling inhibitor. This study investigates whether sVLDLR plays an anti-fibrogenic role in nAMD models, including Vldlr-/- mice and laser-induced choroidal neovascularization (CNV). We found that fibrosis factors including P-Smad2/3, α-SMA, and CTGF were upregulated in the subretinal area of Vldlr-/- mice and the laser-induced CNV model. The antibody blocking Wnt co-receptor LRP6 significantly attenuated the overexpression of fibrotic factors in these two models. Moreover, there was a significant reduction of sVLDLR in the interphotoreceptor matrix (IPM) in the laser-induced CNV model. A transgenic strain (sVLDLR-Tg) with sVLDLR overexpression in the IPM was generated. Overexpression of sVLDLR ameliorated the profibrotic changes in the subretinal area of the laser-induced CNV model. In addition, Wnt and TGF-ß signaling synergistically promoted fibrogenesis in human primary retinal pigment epithelium (RPE) cells. CRISPR/Cas9-mediated LRP6 gene knockout (KO) attenuated this synergistic effect. The disruption of VLDLR expression promoted, while the overexpression of sVLDLR inhibited TGF-ß-induced fibrosis. These findings suggest that overactivated Wnt signaling enhances the TGF-ß pathway in subretinal fibrosis. sVLDLR confers an antifibrotic effect, at least partially, through the inhibition of Wnt signaling and thus, has therapeutic potential for fibrosis.

FOCAL CHOROIDAL THICKNESS HEMODYNAMICS AS a SIGN OF MACULAR NEOVASCULARIZATION ACTIVITY IN PATHOLOGIC MYOPIA.

PURPOSE: To analyze the relationship between a focal increase of choroidal thickness (ChT) and exudative activity of macular neovascularization (MNV) secondary to pathologic myopia. METHODS: Retrospective analysis including eyes with pathologic myopia presenting with a focally increased ChT underneath active MNV. All patients included were treated, and ChT was measured before and after each intravitreal injection by two experienced ophthalmologists. RESULTS: Fifty-two eyes of 52 patients with myopic MNV (19 men and 33 women) were included in this analysis. ChT at T-1 averaged 51.09 ± 33.56 µ m, whereas at the time of MNV activation (T0), ChT was significantly thicker: 85.11 ± 43.99 µ m ( P < 0.001). After a single intravitreal injection, the ChT significantly decreased to 53.23 ± 34.15 µ m ( P < 0.001). CONCLUSION: This study showed that focal ChT variations may be considered an interesting corollary sign of MNV in high myopic patients, indicating the activity of myopic neovascularization.

STATIN USE AND THE INCIDENCE OF AGE-RELATED MACULAR DEGENERATION: A Meta-Analysis.

PURPOSE: Age-related macular degeneration (AMD) shares many of the same risk factors with atherosclerosis. There is a postulated role of lipid-lowering agents in preventing AMD. This meta-analysis investigates the possible role of statins in the prevention of AMD onset and progression. METHODS: MEDLINE, EMBASE, Cochrane CENTRAL, and the reference lists of included studies were systematically searched from inception to September 2020. Studies were included if they measured the risk of AMD development or progression with statin use. The primary outcomes assessed were AMD incidence and progression. Secondary outcomes were the incidence of early AMD, late AMD, choroidal neovascularization, and geographic atrophy. RESULTS: Twenty-one articles (1 randomized control trial and 20 observational studies) collectively reporting on 1,460,989 participants were included. The pooled risk ratios (95% confidence interval) for statin use on any, early, and late AMD incidence were 1.05 (0.85-1.29) (P = 0.44), 0.99 (0.88-1.11) (P = 0.86), and 1.15 (0.90-1.47) (P = 0.27), respectively. In patients with existing AMD, the respective risk ratios for statin use on incidence of AMD progression, choroidal neovascularization, and geographic atrophy were 1.04 (0.70-1.53) (P = 0.85), 0.99 (0.66-1.48) (P = 0.95), and 0.84 (0.58-1.22) (P = 0.36). CONCLUSION: This meta-analysis found that there was no significant difference in the incidence or progression of AMD based on statin use.

PREDICTING LESION SHRINKAGE IN EYES WITH MYOPIC CHOROIDAL NEOVASCULARIZATION FROM FEATURES ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To identify baseline morphological predictors of lesion shrinkage in eyes with myopic choroidal neovascularization (mCNV) treated with anti-vascular endothelial growth factor. METHODS: This retrospective study included 46 eyes (41 consecutive patients) with active mCNV receiving anti-vascular endothelial growth factor treatment. Optical coherence tomography angiography was performed at baseline and 1 year after treatment. Quantitative features were obtained from optical coherence tomography angiography images using AngioTool software. Eyes were classified as "high shrinkage" or "low shrinkage" according to the median relative change in lesion area. Baseline quantitative morphological features associated with mCNV shrinkage were identified in univariate and multivariate analyses. RESULTS: The mCNV area was significantly smaller after 1 year ( P = 0.013), with a median relative change of -16.5%. The relative change in mCNV area was -48.3% in high-shrinkage eyes (n = 23) and -5.2% in low-shrinkage eyes (n = 23). High-shrinkage eyes had a smaller mCNV area ( P = 0.013), shorter total vessel length ( P = 0.023), and higher end point density ( P < 0.001). Multivariate analysis showed significant associations of high shrinkage with end point density (ß = -0.037, P = 0.043) and previous anti-vascular endothelial growth factor treatment (ß = 0.216, P = 0.029). CONCLUSION: Morphological features of neovascularization detected by optical coherence tomography angiography can predict lesion shrinkage in eyes with mCNV receiving anti-vascular endothelial growth factor therapy. Higher end point density contributed to shrinkage, particularly of treatment-naive lesions.

Chorioretinal thickness and retinal pigment epithelial degeneration of fellow eyes in patients with unilateral neovascular age-related macular degeneration with subretinal drusenoid deposits.

BACKGROUND: We sought to investigate the chorioretinal thickness and retinal pigment epithelial (RPE) degenerative features of eyes with early age-related macular degeneration (AMD) and subretinal drusenoid deposits (SDDs) according to the presence of macular neovascularization (MNV) in the fellow eyes. METHODS: We classified 70 eyes into two groups of 47 eyes with non-neovascular AMD and 23 eyes with neovascular AMD, respectively, according to the presence of MNV in the fellow eyes. The mean macular retinal, ganglion cell-inner plexiform layer (GCIPL), and choroidal thickness values and RPE features of the 6-mm-diameter zone were compared. RPE degeneration was defined as a lesion with an incomplete RPE and outer retinal atrophy (iRORA) or attenuated RPE reflectivity with diffuse basal laminar deposits, which was defined as when the eye showed an attenuated RPE line with granular features and mixed reflectivity in combination with sub-RPE deposits with a lesion ≥ 1,000 µm in length. RESULTS: Mean retinal, GCIPL, and choroidal thickness values (286.69 ± 15.02 µm, 64.36 ± 4.21 µm, and 156.11 ± 33.10 µm) of the neovascular AMD group were greater than those (278.61 ± 13.96 µm, 61.44 ± 4.63 µm, and 133.59 ± 34.33 µm) of the non-neovascular AMD group (all P < 0.05). RPE degeneration was more prevalent in the neovascular AMD group (65.2%) than the non-neovascular AMD group (38.3%; P = 0.034). Greater mean GCIPL and choroidal thickness values and the presence of RPE degeneration were associated with type 3 MNV in fellow eyes (all P < 0.05). CONCLUSIONS: Different degenerative features according to MNV in fellow eyes of patients with AMD and SDDs suggest that variable degenerative features might be present during disease progression and have an association with the phenotype.

Juxtapapillary Choroidal Neovascularization in a Young Woman with Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome with Onset in Pediatric Age.

We describe the unusual case of a young woman with tubulointerstitial nephritis and uveitis (TINU) with bilateral diffuse uveitis and optic nerve inflammatory involvement since she was a child in the 1990s. Imaging diagnostic tools such as fluorescein angiography, indocyanine green angiography, optical coherence tomography (OCT), and OCT angiography revealed inactive juxtapapillary choroidal neovascularization (CNV) after 25 years of follow-up. After treatment, uveitis went into remission with BCVA 20/20 in both eyes and CNV lesions became inactive. Although anterior uveitis is more frequently reported in TINU, posterior uveitis with inflammatory involvement of the optic nerve should be accurately investigated to rule out juxtapapillary CNV, both at the time of active uveitis and during follow-up, since TINU may be complicated by CNV even at the later stages of the inflammatory process.

CLINICAL FEATURES OF FLAT IRREGULAR PIGMENT EPITHELIAL DETACHMENT ASSOCIATED WITH CHOROIDAL NEOVASCULARIZATION IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To describe the multimodal imaging characteristics of flat irregular pigment epithelial detachment (FIPED) in patients with chronic central serous chorioretinopathy and determine the risk factors for vascularized FIPED and to explore the activity of vascularized FIPED before and after half-dose photodynamic therapy. METHODS: Multimodal imaging data of 185 eyes of 155 consecutive patients with chronic central serous chorioretinopathy included spectral domain optical coherence tomography, fluorescein angiography, and indocyanine green angiography. Optical coherence tomography angiography was available for 56 eyes. Flat irregular PED was classified into two types based on indocyanine green angiography or optical coherence tomography angiography findings: avascular FIPED and vascularized FIPED. RESULTS: The avascular FIPED and vascularized FIPED were detected in 127 (68.6%) and 42 (22.7%) eyes, respectively. Age (P = 0.001), visual acuity (P = 0.048), subfoveal choroidal thickness (P = 0.032), height (P < 0.001) and width (P < 0.001) of FIPED, choriocapillary thickness (P = 0.015), and maximum vessel diameter (P = 0.009) beneath the FIPED were significantly different between avascular and vascularized FIPEDs. Old age was an independent risk factor for vascularized FIPED. On optical coherence tomography angiography, all vascularized FIPEDs manifested the pattern of mature choroidal neovascularization (CNV). After half-dose photodynamic therapy, vascularized FIPED remained stable without the reaccumulation of subretinal fluid at the last follow-up. CONCLUSION: In chronic central serous chorioretinopathy, vascularized FIPED was closely associated with Type I CNV. Old age was an independent risk factor for vascularized FIPED. Vascularized FIPED is suggested as "quiescent" CNV, and half-dose photodynamic therapy may be recommended as the first-line therapy in chronic central serous chorioretinopathy complicated with quiescent CNV, except when the activity of CNV becomes evident.

Multimodal Imaging in a Case of Peripapillary Choroidal Neovascular Membrane Associated With Idiopathic Intracranial Hypertension.

ABSTRACT: Optical coherence tomography angiography is one of the latest noninvasive imaging modalities for visualizing the vasculature of retina and choroid. We describe its application in the diagnosis, treatment, and monitoring of a patient with peripapillary choroidal neovascular membrane in the setting of idiopathic intracranial hypertension, who responded well to a course of ranibizumab intravitreal injections.

Macular Atrophy Incidence and Progression in Eyes with Neovascular Age-Related Macular Degeneration Treated with Vascular Endothelial Growth Factor Inhibitors Using a Treat-and-Extend or a Pro Re Nata Regimen: Four-Year Results of the MANEX Study.

PURPOSE: To compare the incidence and progression of macular atrophy (MA) in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) agents using either a treat-and-extend (T&E) or a pro re nata (PRN) regimen over 4 years in a real-world setting. DESIGN: Four-year, multicenter, retrospective comparative study. PARTICIPANTS: Two hundred sixty-four patients with treatment-naive nAMD. METHODS: Consecutive patients with nAMD received anti-VEGF therapy according to a T&E (n = 163) or PRN (n = 101) regimen. Eyes were included if they had received anti-VEGF injections for a period of at least 4 years and had undergone annual fundus autofluorescence (FAF) and OCT imaging using Heidelberg Spectralis. Two masked graders independently delineated areas of MA from serial FAF images using Heidelberg region finder software, and growth rates were calculated. Incident MA was assessed using proportional hazard ratios. MAIN OUTCOMES MEASURES: Macular atrophy incidence and progression over 4 years, association between treatment strategies, and number of injections. RESULTS: At baseline, MA was present in 24% and 20% of study eyes in T&E and PRN groups, respectively (P = 0.45). At year 4, 27% (34/124) and 25% (20/81) of eyes without baseline MA showed detectable MA in the T&E and PRN groups, respectively. In those with MA at baseline, the mean square root area of MA progressed by a rate of 0.4 ± 0.2 mm/year and 0.4 ± 0.1 mm/year in the T&E and PRN groups, respectively (P = 0.23). Multivariate analysis for baseline predictors of MA growth demonstrated that older age, poorer baseline visual acuity, and presence of retinal angiomatous proliferation had a higher risk of greater MA progression (P = 0.03). Regression analysis demonstrated no association between T&E and PRN treatment strategies with the risk of new MA developing during the 4 years of follow-up or the progression of pre-existing MA at year 4 (P = 0.692). CONCLUSIONS: Over 4 years, neither incidence nor progression of MA in eyes with nAMD treated with anti-VEGF injections was influenced by the treatment regimen and injection frequency. Eyes treated with a T&E regimen received more injections and achieved better visual outcomes compared with those treated with a PRN approach.

Incidence of Macular Atrophy after Untreated Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study Report 40.

PURPOSE: To report the natural history of untreated neovascular age-related macular degeneration (nAMD) regarding subsequent macular atrophy. DESIGN: Prospective cohort within a randomized, controlled trial of oral micronutrient supplements. PARTICIPANTS: Age-Related Eye Disease Study (AREDS) participants (55-80 years) who demonstrated nAMD during follow-up (1992-2005), prior to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Color fundus photographs were collected at annual study visits and graded centrally for late age-related macular degeneration (AMD). Incident macular atrophy after nAMD was examined by Kaplan-Meier analysis and proportional hazards regression. MAIN OUTCOME MEASURES: Incident macular atrophy after nAMD. RESULTS: Of the 4757 AREDS participants, 708 eyes (627 participants) demonstrated nAMD during follow-up and were eligible. The cumulative risks of incident macular atrophy after untreated nAMD were 9.6% (standard error, 1.2%), 31.4% (standard error, 2.2%), 43.1% (standard error, 2.6%), and 61.5% (standard error, 4.3%) at 2, 5, 7, and 10 years, respectively. This corresponded to a linear risk of 6.5% per year. The cumulative risk of central involvement was 30.4% (standard error, 3.2%), 43.4% (standard error, 3.8%), and 57.0% (standard error, 4.8%) at first appearance of atrophy, 2 years, and 5 years, respectively. Geographic atrophy (GA) in the fellow eye was associated with increased risk of macular atrophy (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.17-2.49; P = 0.006). However, higher 52-single nucleotide polymorphism AMD genetic risk score was not associated with increased risk of macular atrophy (HR, 1.03; 95% CI, 0.90-1.17; P = 0.67). Similarly, no significant differences were observed according to SNPs at CFH, ARMS2, or C3. CONCLUSIONS: The rate of incident macular atrophy after untreated nAMD is relatively high, increasing linearly over time and affecting half of eyes by 8 years. Hence, factors other than anti-VEGF therapy are involved in atrophy development, including natural progression to GA. Comparison with studies of treated nAMD suggests it may not be necessary to invoke a large effect of anti-VEGF therapy on inciting macular atrophy, although a contribution remains possible. Central involvement is present in one third of eyes at the outset (similar to pure GA) and increases linearly to half at 3 years.

Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration: Results from the Prospective Proxima A and B Clinical Trials.

PURPOSE: To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD). DESIGN: Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials. PARTICIPANTS: Eligible patients were aged ≥50 years. Patients in Proxima A had bilateral GA without choroidal neovascularization (CNV) in either eye (N = 295). Patients in Proxima B had GA without CNV in the study eye and CNV±GA in the fellow eye (fellow eye CNV cohort, n = 168) or GA without CNV in the study eye, no CNV/GA in the fellow eye (fellow eye intermediate AMD cohort, n = 32). METHODS: Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics. MAIN OUTCOME MEASURES: Prespecified end points included change in GA area from baseline, best-corrected visual acuity (BCVA) score assessed by Early Treatment Diabetic Retinopathy Study (ETDRS), and visual acuity under low-luminance (LLVA). RESULTS: At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mm2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm2 in the fellow eye intermediate AMD cohort (Proxima B). Progression of GA was greater in patients with baseline nonsubfoveal (vs. subfoveal) GA lesions and tended to increase as baseline low-luminance deficit increased (all patients). Conversion to GA or CNV in the fellow eye occurred in 30% and 6.7% of participants, respectively, in the Proxima B intermediate AMD cohort at month 12. Adjusted mean (standard error) changes in BCVA and LLVA (ETDRS letters) in the study eye from baseline to 24 months were -13.88 (1.40) and -7.64 (1.20) in Proxima A, -9.49 (1.29) and -7.57 (1.26) in Proxima B fellow eye CNV cohort, and -11.48 (3.39) and -8.37 (3.02) in Proxima B fellow eye intermediate AMD cohort, respectively. CONCLUSIONS: The prospective Proxima A and B studies highlight the severe functional impact of GA and the rapid rate of GA lesion progression over a 2-year period, including in patients with unilateral GA at baseline.

USE OF CHOROIDAL VASCULARITY INDEX FOR CHOROIDAL STRUCTURAL EVALUATION IN CENTRAL SEROUS CHORIORETINOPATHY WITH CHOROIDAL NEOVASCULARIZATION.

PURPOSE: To evaluate choroidal vascular structure in eyes with central serous chorioretinopathy (CSC) by assessing the choroidal vascular index (CVI). METHODS: We retrospectively analyzed the medical records of 117 eyes with CSC. Subjects were divided into 4 groups according to clinical characteristics: 1) acute CSC (N = 29), 2) non-neovascularized chronic CSC without flat irregular pigment epithelial detachment (N = 49), 3) non-neovascularized chronic CSC with flat irregular pigment epithelial detachment (N = 21), and 4) chronic CSC with choroidal neovascularization (N = 18). Subfoveal choroidal area (1,500 mm) of swept source optical coherence tomography scans were divided into luminal and stromal areas by the image binarization technique. The CVI was defined as the ratio of the luminal to the total subfoveal choroidal area. RESULTS: The CVI was significantly lower in eyes of Group 4 than those of other groups (all P < 0.05). The subfoveal choroidal thickness was significantly lower in Group 4 than in Groups 1 and 2 (P < 0.05), but regression analysis showed no association with the CVI. CONCLUSION: Decreased CVI may reflect choroidal vascular structure changes in eyes with choroidal neovascularization complicating CSC. These findings suggest that the CVI could be useful for evaluating choroidal vascular changes in eyes with CSC.

REAL-COLOR VERSUS PSEUDO-COLOR IMAGING OF FIBROTIC SCARS IN EXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To compare the morphological characteristics of subretinal fibrosis in late age-related macular degeneration using multicolor (MC) imaging, color fundus photography (CFP), and ultra-widefield CFP (UWFCFP). METHODS: Thirty-two eyes of 31 patients diagnosed with subretinal fibrosis complicating exudative age-related macular degeneration were included. Included eyes were imaged by MC, CFP, and UWFCFP. The overall ability to visualize fibrosis, its margins, and dissimilarity with surrounding atrophy was graded using a score (0: not visible, 1: barely visible, 2: mostly visible, and 3: fully visible) by two readers. Area of fibrosis was calculated. Scaling, lesion colocalization on all three imaging techniques, and area measurements were performed using ImageJ. RESULTS: Ninety-six images of 32 eyes were graded. The average area of fibrosis was 14.59 ± 8.94 mm for MC, 13.84 ± 8.56 mm for CFP, and 13.76 ± 8.79 mm for UWFCFP. Fibrosis was fully visible in 87.5% of cases using MC and 50% using CFP and UWFCFP. Fibrosis' margins were sharply defined in 40.6% of eyes with MC, 15.6% and 9.4% with CFP and UWFCFP, respectively. Multicolor imaging provided superior distinction between fibrosis and atrophy (100% for MC vs. 13.4% for CFP and 33.3% for UWFCFP). The inter- and intra-reader agreement was high for all measurements (P < 0.0001). CONCLUSION: Multicolor technology allows for improved visualization and analysis of subretinal fibrosis when compared with CFP and UWFCFP, especially when surrounding atrophy is present.