Diagnosis and Management of Patients With Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Delphi Consensus Exercise.

Geographic atrophy (GA) is a progressive and irreversible retinal disease with no comprehensive recommendations for diagnosis or monitoring. We used a Delphi approach to determine consensus in key areas around diagnosis and management of GA. A steering committee of eight retina specialists developed two sequential online surveys administered to eye care professionals (ECPs). Consensus was defined as agreement by ≥ 75% of respondents. Up to 177 ECPs from eight countries completed one or both surveys. Consensus was achieved in several topics related to diagnostic imaging, including the use of optical coherence tomography, and the urgent need for treatments and beneficial interventions to reduce the associated burden. Currently, low-vision aids and smoking cessation are considered the most beneficial interventions. We demonstrate consensus for diagnosis and management of patients with GA including best practices in patient identification and monitoring, and unmet needs. [Ophthalmic Surg Lasers Imaging Retina 2023;54:589-598.].

Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), characterized by atrophic lesions that first start in the outer retina and progressively expand to cover the macula and the fovea, the center of the macula, leading to irreversible loss of vision over time. GA is distinct from wet or neovascular AMD (nAMD), the other form of advanced AMD. Neovascular AMD is characterized by new invading leaky blood vessels in the macula that can lead to acute vision loss. GA and nAMD may coexist in the same eye. The underlying pathophysiology of GA is complex and thought to involve chronic inflammation due to overactivation of the complement system that leads to the loss of photoreceptors, retinal pigment epithelium (RPE), and the underlying choriocapillaris. The disappearance of these structures appears as sharply demarcated atrophic lesions that are typical of GA. Researchers have reported about 1 million reported cases of GA in the United States, and about 160,000 cases occur per year. The most important risk factors for GA are increasing age and family history. Diagnosis of GA is usually made by using multimodal imaging techniques. Lesions associated with GA are highly heterogeneous, and the growth rate may differ from patient to patient. Despite the progressive nature of GA, the fovea may be spared until much later in the disease, thereby retaining central vision in patients. With time, atrophic lesions may progressively grow to involve the fovea, thereby severely impairing central vision. Vision loss can happen rapidly once the lesions reach the fovea. However, even without the involvement of the fovea, ongoing vision impairment impacting daily life may be present. Median time from GA not involving the center of the fovea (without subfoveal involvement) to GA with lesion boundary affecting the foveal center (subfoveal involvement) ranges from 1.4 to 2.5 years. GA can greatly impact patients' functioning and quality of life and limit their independence by interfering with activities of daily living, including difficulties with reading, driving, watching television, recognizing faces, and being unable to do household chores. No treatments have been available until intravitreal pegcetacoplan was recently approved by the US Food and Drug Administration for GA secondary to AMD. DISCLOSURES: Dr Bakri serves as a consultant to Apellis Pharmaceuticals, as well as AbbVie, Adverum, Eyepoint, iLumen, Iveric Bio, Genentech, Novartis, Outlook Therapeutics, Pixium, Regeneron, Roche, and Regenxbio. Drs Sharp, Luo, and Sarda are employees of Apellis Pharmaceuticals. Dr Bektas and Ms Khan are employees of RTI Health Solutions. Apellis developed and led the concept design of this publication, review and interpretation, approval, and decision to publish. This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. This supplement is to describe the disease of geographic atrophy and was funded by Apellis. Apellis Pharmaceuticals has developed Syfovre (pegcetacoplan), the first and only treatment for geographic atrophy.

The intraocular implant and visual rehabilitation improve the quality of life of elderly patients with geographic atrophy secondary to age-related macular degeneration.

INTRODUCTION: The objective of this prospective study was to evaluate the effects of intraocular macular lens implantation and visual rehabilitation on the quality of life of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). METHODS: Patients with bilaterally decreased near vision (not better than 0.3 logMAR with the best correction), pseudophakia, were included in the project. The Scharioth macula lens (SML) was implanted into the patients' better-seeing eye. Intensive visual rehabilitation of the ability to perform nearby activities was performed for 20 consecutive postoperative days. All subjects were examined before and after SML implantation ophthalmologically. The National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) was administered before and 6 months after surgery. RESULTS: Twenty eligible patients with mean age 81 years (63 to 92 years) were included in the project: 7 males and 13 females. Nineteen of them completed the 6-month follow-up. Near uncorrected visual acuity was 1.321 ± 0.208 logMAR before SML implantation and improved to 0.547 ± 0.210 logMAR after 6 months (dz = - 2.846, p < 0.001, BF10 = 3.29E + 07). In the composite score of the NEI VFQ-25, there was an improvement in the general score and the specific domains related to the implantation. Participants reported fewer difficulties in performing near activities (dz = 0.91, p = 0.001, BF10 = 39.718) and upturns in mental health symptoms related to vision (dz = 0.62, p = .014, BF10 = 3.937). CONCLUSION: SML implantation, followed by appropriate rehabilitation, improved near vision and increased the quality of life of visually handicapped patients with AMD in our project.

Long-term observations of macular thickness after subretinal implantation of a photovoltaic prosthesis in patients with atrophic age-related macular degeneration.

Objective. Subretinal prostheses electrically stimulate the residual inner retinal neurons to partially restore vision. We investigated the changes in neurosensory macular structures and it is thickness associated with subretinal implantation in geographic atrophy (GA) secondary to age-related macular degeneration (AMD).Approach. Using optical coherence tomography, changes in distance between electrodes and retinal inner nuclear layer (INL) as well as alterations in thickness of retinal layers were measured over time above and near the subretinal chip implanted within the atrophic area. Retinal thickness (RT) was quantified across the implant surface and edges as well as outside the implant zone to compare with the natural macular changes following subretinal surgery, and the natural course of dry AMD.Main results. GA was defined based on complete retinal pigment epithelium and outer retinal atrophy (cRORA). Based on the analysis of three patients with subretinal implantation, we found that the distance between the implant and the target cells was stable over the long-term follow-up. Total RT above the implant decreased on average, by 39 ± 12µm during 3 months post-implantation, but no significant changes were observed after that, up to 36 months of the follow-up. RT also changed near the temporal entry point areas outside the implantation zone following the surgical trauma of retinal detachment. There was no change in the macula cRORA nasal to the implanted zone, where there was no surgical trauma or manipulation.Significance. The surgical delivery of the photovoltaic subretinal implant causes minor RT changes that settle after 3 months, and then remain stable over long-term with no adverse structural or functional effects. Distance between the implant and the INL remains stable up to 36 months of the follow-up.

Cluster Analysis and Genotype-Phenotype Assessment of Geographic Atrophy in Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 25.

PURPOSE: To explore whether phenotypes in geographic atrophy (GA) secondary to age-related macular degeneration can be separated into 2 or more partially distinct subtypes and if these have different genetic associations. This is important because distinct GA subtypes associated with different genetic factors might require customized therapeutic approaches. DESIGN: Cluster analysis of participants within a controlled clinical trial, followed by assessment of phenotype-genotype associations. PARTICIPANTS: Age-Related Eye Disease Study 2 participants with incident GA during study follow-up: 598 eyes of 598 participants. METHODS: Phenotypic features from reading center grading of fundus photographs were subjected to cluster analysis, by k-means and hierarchical methods, in cross-sectional analyses (using 15 phenotypic features) and longitudinal analyses (using 14 phenotypic features). The identified clusters were compared by 4 pathway-based genetic risk scores (complement, extracellular matrix, lipid, and ARMS2). The analyses were repeated in reverse (clustering by genotype and comparison by phenotype). MAIN OUTCOME MEASURES: Characteristics and quality of cluster solutions, assessed by Calinski-Harabasz scores, unexplained variance, and consistency; and genotype-phenotype associations, assessed by t test. RESULTS: In cross-sectional phenotypic analyses, k-means identified 2 clusters (labeled A and B), whereas hierarchical clustering identified 4 clusters (C-F); cluster membership differed principally by GA configuration but in few other ways. In longitudinal phenotypic analyses, k-means identified 2 clusters (G and H) that differed principally by smoking status but in few other ways. These 3 sets of cluster divisions were not similar to each other (r ≤ 0.20). Despite adequate power, pairwise cluster comparison by the 4 genetic risk scores demonstrated no significant differences (P > 0.05 for all). In clustering by genotype, k-means identified 2 clusters (I and J). These differed principally at ARMS2, but no significant genotype-phenotype associations were observed (P > 0.05 for all). CONCLUSIONS: Phenotypic clustering resulted in GA subtypes defined principally by GA configuration in cross-sectional analyses, but these were not replicated in longitudinal analyses. These negative findings, together with the absence of significant phenotype-genotype associations, indicate that GA phenotypes may vary continuously across a spectrum, rather than consisting of distinct subtypes that arise from separate genetic causes.

Long-term progression of geographic atrophy in age-related macular degeneration does the phakic status matter?

PURPOSE: To assess the long-term risk of geographic atrophy (GA) progression after cataract surgery. METHODS: Subjects with GA secondary to AMD followed for at least 1 year with fundus autofluorescence imaging and with at least two visits at our centre were included. Patients with wet AMD, disciform scar, past history of intravitreal injections or laser treatment, other maculopathies and with poor quality images were excluded. GA area at baseline and at follow-up visit was measured. Three study groups were defined according to their phakic status: (A) pseudophakia, (B) phakic and (C) phacoemulsification surgery performed during the study. Differences of GA area progression were compared between these study groups. In addition, comparison between GA progression rate in group (C) before and after the surgery was performed. The enlargement rate (ER) was calculated for lesion size after transforming the measurements to the square-root scale. RESULTS: A total of 92 eyes of 92 patients were enrolled. Median follow-up time was 4 [1-10] years. Regarding the eye's phakic status, 29 (31.5%) were pseudophakic and 63 (68.5%) were phakic; of these, 22 underwent phacoemulsification during the study. Overall, the median baseline and follow-up area of GA were 1.42 [0.04-32.10] mm2 and 6.48 [0.25-47.40] mm2, respectively. The ER was similar between phakic and pseudophakic eyes (0.18 [0.01-1.03] vs 0.15 [0.01-0.65] mm/year, p = 0.62). In patients that underwent cataract surgery during the study, the GA ER remained stable (0.13 [0.01-0.92] vs 0.14 [0.01-0.63] mm/year, p = 0.43). CONCLUSION: These results suggest that cataract surgery does not increase the risk of pre-existing GA progression. Therefore, cataract surgery seems safe and a potential therapeutic weapon to improve visual acuity and consequently quality of life in GA patients.

Effect of Human Central Nervous System Stem Cell Subretinal Transplantation on Progression of Geographic Atrophy Secondary to Nonneovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the effect of subretinally transplanted human central nervous system stem cells (HuCNS-SC) on the progression of geographic atrophy (GA) in patients with nonneovascular age-related macular degeneration (AMD). DESIGN: Multicenter, prospective, phase 1 open-label clinical trial. PARTICIPANTS: Fifteen patients with bilateral GA solely the result of AMD. METHODS: The eye with the worst best-corrected visual acuity from each patient was selected for treatment and was considered the study eye; fellow eyes served as controls. A total of 0.25 × 106 or 1.0 × 106 HuCNS-SCs were infused directly into the subretinal space, superotemporal to the fovea near the junctional zone, outside the area of GA. All patients underwent spectral-domain OCT and fundus autofluorescence imaging using the Spectralis HRA+OCT (Heidelberg Engineering, Inc., Heidelberg, Germany). Total GA area in both eyes was measured at baseline and month 12 by certified reading center graders using the Spectralis Region Finder software. Sectoral (clock hour) per directional radial GA progression rates with respect to the foveal center in both eyes were calculated using the polar transformation method in Image J software (National Institutes of Health, Bethesda, MD). To facilitate comparative analysis across the cohort, all eyes were transformed to a right-eye orientation. MAIN OUTCOME MEASURES: Total GA area and sectoral per directional GA progression rates were compared in both study and control eyes. RESULTS: No statistically significant difference was found in mean change in total GA area at month 12 between study and fellow eyes (1.07 ± 0.84 mm2 vs. 2.08 ± 1.97 mm2; P = 0.08). However, the month 12 sectoral per directional radial GA growth rate for the superotemporal region (i.e., the location of HuCNS-SC transplantation) showed a significantly slower progression rate in study eyes than in fellow eyes (0.29 ± 0.58 mm vs. 1.08 ± 0.65 mm; P = 0.007). The progression rate in the superotemporal quadrant of the study eye was significantly slower than in the other 3 quadrants combined (P = 0.04). CONCLUSIONS: In this small pilot study, HuCNS-SC transplantation seems to be associated with slower expansion of the GA lesion in the transplanted quadrant. Larger confirmatory studies are required. Sectoral or directional analysis of growth rates of GA may be a useful approach for assessing the efficacy of locally delivered therapies.

Progression of macular atrophy in patients undergoing anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration.

PURPOSE: To assess differences in the progression of macular atrophy (MA) between neovascular age-related macular degeneration (AMD) subtypes and to identify the risk factors associated with the foveal involvement among patients with MA undergoing long-term anti-vascular endothelial growth factor (VEGF) treatment. METHODS: Eighty eyes of 80 patients with neovascular AMD who developed incident MA following anti-VEGF therapy were retrospectively included. Macular atrophy (MA) was quantified using autofluoresence (AF) images within 24 months after the onset of MA, and the enlargement rate was compared between neovascular AMD subtypes. Regression models were constructed to explore relationships between foveal involvement in MA and baseline characteristics. RESULTS: The growth rate of MA was 0.18 mm2 /year for type 1 neovascularization (NV), 0.24 mm2 /year for type 2 NV, and 1.21 mm2 /year for type 3 NV; differences between groups were significant (p = 0.022). Multivariate logistic regression analysis revealed that thin subfoveal choroidal thickness (p = 0.028), presence of subretinal drusenoid deposit (p = 0.005), type 2 or 3 NV (p = 0.023), and geographic atrophy in the fellow eye (p = 0.035) were significant risk factors for MA with foveal involvement. The number of injections showed no significant association with the progression or the foveal involvement in MA. CONCLUSIONS: The progression of MA in patients with neovascular AMD undergoing anti-VEGF treatment differed significantly depending on the subtype of neovascularization. The risk of foveal involvement in MA was associated with the baseline factors or phenotype of neovascular AMD rather than with injection frequency of anti-VEGF.

Plasma biomarkers of the amyloid pathway are associated with geographic atrophy secondary to age-related macular degeneration.

Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD), in which local inflammation and hyperactivity of the complement pathway have been implicated in its pathophysiology. This study explores whether any surrogate biomarkers are specifically associated with GA. Plasma from subjects with GA, intermediate dry AMD and non-AMD control were evaluated in 2 cohorts. Cohort 1 was assayed in a 320-analyte Luminex library. Statistical analysis was performed using non-parametric and parametric methods (Kruskal-Wallis, principal component analysis, partial least squares and multivariate analysis of variance (MANOVA) and univariate ANCOVAs). Bioinformatic analysis was conducted and identified connections to the amyloid pathway. Statistically significant biomarkers identified in Cohort 1 were then re-evaluated in Cohort 2 using individual ELISA and multiplexing. Of 320 analytes in Cohort 1, 273 were rendered measurable, of which 56 were identified as changing. Among these markers, 40 were identified in univariate ANCOVAs. Serum amyloid precursor protein (sAPP) was analyzed by a separate ELISA and included in further analyses. The 40 biomarkers, sAPP and amyloid-ß (Aß) (1-42) (included for comparison) were evaluated in Cohort 2. This resulted in 11 statistically significant biomarkers, including sAPP and Aß(1-40), but not Aß(1-42). Other biomarkers identified included serum proteases- tissue plasminogen activator, tumor-associated trypsinogen inhibitor, matrix metalloproteinases 7 and 9, and non-proteases- insulin-like growth factor binding protein 6, AXL receptor tyrosine kinase, omentin, pentraxin-3 and osteopontin. Findings suggest that there is a preferential processing of APP to Aß(1-40) over Aß(1-42), and a potential role for the carboxylase activity of the γ-secretase protein, which preferentially splices sAPPß to Aß(1-40). Other markers are associated with the breakdown and remodeling of the extracellular matrix, and loss of homeostasis, possibly within the photoreceptor-retinal pigment epithelium-choriocapillaris complex. These data suggest novel disease pathways associated with GA pathogenesis and could provide potential novel targets for treatment of GA.

Immunization Against Oxidized Elastin Exacerbates Structural and Functional Damage in Mouse Model of Smoke-Induced Ocular Injury.

Purpose: Age-related macular degeneration (AMD) is the leading cause of blindness in Western populations. While an overactive complement system has been linked to pathogenesis, mechanisms contributing to its activation are largely unknown. In aged and AMD eyes, loss of the elastin layer (EL) of Bruch's membrane (BrM) has been reported. Elastin antibodies are elevated in patients with AMD, the pathogenic significance of which is unclear. Here we assess the role of elastin antibodies using a mouse model of smoke-induced ocular pathology (SIOP), which similarly demonstrates EL loss. Methods: C57BL/6J mice were immunized with elastin or elastin peptide oxidatively modified by cigarette smoke (ox-elastin). Mice were then exposed to cigarette smoke or air for 6 months. Visual function was assessed by optokinetic response, retinal morphology by spectral-domain optical coherence tomography and electron microscopy, and complement activation and antibody deposition by Western blot. Results: Ox-elastin IgG and IgM antibodies were elevated in ox-elastin immunized mice following 6 months of smoke, whereas elastin immunization had a smaller effect. Ox-elastin immunization exacerbated smoke-induced vision loss, with thicker BrM and more damaged retinal pigment epithelium (RPE) mitochondria compared with mice immunized with elastin or nonimmunized controls. These changes were correlated with increased levels of IgM, IgG2, IgG3, and complement activation products in RPE/choroid. Conclusions: These data demonstrate that SIOP mice generate elastin-specific antibodies and that immunization with ox-elastin exacerbates ocular pathology. Elastin antibodies represented complement fixing isotypes that, together with the increased presence of complement activation seen in immunized mice, suggest that elastin antibodies exert pathogenic effects through mediating complement activation.

Safety and Efficacy of Subretinally Administered Palucorcel for Geographic Atrophy of Age-Related Macular Degeneration: Phase 2b Study.

PURPOSE: To evaluate safety and successful use of a novel subretinal delivery system and suprachoroidal surgical approach and safety and activity of human umbilical tissue-derived cells (palucorcel) via a novel delivery system in patients with geographic atrophy (GA). DESIGN: Multicenter, open-label phase 2b study. PARTICIPANTS: Participants were 55 to 90 years with GA secondary to age-related macular degeneration (AMD) and best-corrected visual acuity (BCVA) of 20/80 to 20/800. Exclusion criteria included neovascular AMD in the intervention eye, glaucoma with intraocular pressure of 25 mmHg or more, or other significant ophthalmologic conditions. METHODS: Participants received a subretinal injection of palucorcel, 3.0 × 105 cells in 50 µl, using the custom-designed delivery system and surgical procedure. MAIN OUTCOME MEASURES: Safety assessments included treatment-emergent adverse events (AEs), immunologic assessments, and ophthalmologic evaluations. Efficacy was evaluated as change in mean number of BCVA letters from baseline, proportion of participants gaining 15 BCVA letters or more, and growth rate of GA lesions at 12 months. RESULTS: Surgery and palucorcel administration were performed in 21 participants at 8 sites by 8 different surgeons. At baseline, median total area of GA was 13.4 mm2 and median BCVA was 43 letters in the intervention eye. Eye-related AEs occurred in 76% of participants (16/21), including conjunctival hemorrhage (n = 5), retinal hemorrhage (n = 4), and vitreous floaters (n = 4). Most AEs were mild and resolved within 1 month. No serious AEs, no retinal detachment or perforation, and no significant changes in intraocular pressure occurred. At month 12, mean change in BCVA from baseline was -5.9 letters correct (standard deviation, 13.0 letters correct) in the intervention eye and -3.7 letters correct (standard deviation, 9.0 letters correct) in the fellow eye. No participants showed improvement of 15 letters or more in the intervention eye, and 3 participants lost more than 15 letters by month 1. No apparent effect of treatment was observed. CONCLUSIONS: Palucorcel was delivered successfully to the targeted subretinal site using a novel delivery system and suprachoroidal approach for most participants; however, improvement in GA area, retardation of growth, or visual acuity were not demonstrated.

MACULAR ATROPHY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Pilot Post Hoc Analysis of Patients With Pigment Epithelial Detachments.

PURPOSE: To determine optical coherence tomography signs associated with macular atrophy (MA) in eyes with neovascular age-related macular degeneration and pigment epithelial detachments treated with vascular endothelial growth factor inhibitors. METHODS: Optical coherence tomography scans from a subgroup of the pigment epithelial detachment cohort of the HARBOR study were analyzed for MA. Two groups were formed based on MA presence/absence at Month 24. Then, optical coherence tomography scans from each baseline visit were graded with standard reading center grading parameters including ellipsoid zone disruption, intraretinal cysts, subretinal fluid, and MA or nascent MA in the study and fellow eyes. RESULTS: Twenty-eight eyes from 28 patients were included in the analysis. Fourteen eyes had optical coherence tomography-based MA at Month 24 and 14 did not. Macular atrophy at Month 24 was significantly associated with 1) MA/nascent MA at baseline (P = 0.0136), 2) intraretinal cysts at baseline (P = 0.0048), and 3) collapse of pigment epithelial detachments in the study eye (P = 0.0025). Macular atrophy was not associated with ellipsoid zone disruption or subretinal fluid in the study eye at baseline. CONCLUSION: This study suggests that some optical coherence tomography findings in eyes of patients with neovascular age-related macular degeneration were present before the start of anti-vascular endothelial growth factor therapy and may predict the development of MA.

Direct Ophthalmic Healthcare Resource Use among Patients with Geographic Atrophy in a Large Cohort from the United Kingdom.

PURPOSE: To estimate the direct ophthalmic healthcare resource use in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective analysis of anonymized data derived from electronic medical records (EMRs) acquired at 10 clinical sites in the United Kingdom. PARTICIPANTS: Patients aged ≥50 years with ≥1 eye with a clinical record of GA or, for comparison, bilateral early/intermediate AMD. Four subgroups were identified: GA in both eyes (GA:GA); GA in 1 eye, choroidal neovascularization (CNV) in the fellow eye (GA:CNV); GA in 1 eye with early or intermediate AMD in the fellow eye (GA:E); and early/intermediate AMD in both eyes (E:E). METHODS: The EMRs were analyzed to derive the median number of visits over the first 2 years after diagnosis of GA or early/intermediate AMD. Clinical tests recorded at visits were used to calculate estimated costs (payer perspective) of monitoring. Analyses were restricted to patients with an initial diagnosis on or after January 1, 2011, to represent present day monitoring and costs associated with AMD. MAIN OUTCOME MEASURES: Median number of visits and estimated monitoring costs per patient (in £) over the first 2 years among patients with ≥2 years of follow-up and in the individual subgroups. Intravitreal treatment costs in the GA:CNV group were excluded. RESULTS: For all 3 GA subgroups (n = 1080), the median number of visits over the first 2 years was 5, and monitoring costs were £460.80 per patient. The GA:CNV subgroup (n = 355) had the highest number of visits (median, 15), with a cost of £1581, compared with the GA:E subgroup (n = 283; median 4 visits; cost ∼£369) and the GA:GA subgroup (n = 442; median 3 visits; cost ∼£277). Ophthalmic tests were conducted most frequently in the GA:CNV subgroup. Visits and costs in the E:E subgroup (n = 6079) were lower. CONCLUSIONS: Resource use in patients with GA varies considerably and is strongly influenced by the concomitant presence of CNV and lack of monitoring strategies for GA.

Systemic Levels of Interleukin-6 Correlate With Progression Rate of Geographic Atrophy Secondary to Age-Related Macular Degeneration.

Purpose: Geographic atrophy (GA) is a clinical phenotype of late age-related macular degeneration (AMD) with no current treatment available. In this study, we investigated markers of chronic inflammation in plasma of patients with GA and how these relate to progression rate. Methods: We prospectively included 42 patients with GA, 41 patients with neovascular AMD, and 27 healthy controls. We quantified levels of interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF) receptor 2, and C-reactive protein (CRP). We adapted an inflammation summary score to cluster conceptually related markers of chronic inflammation. Enlargement rate of the atrophic lesion was measured from fundus autofluorescence images performed at baseline and after 1 year. Results: Patients with GA showed an increase in proinflammatory markers of IL-6 (P = 0.009), TNF receptor 2 (P = 0.013), and CRP (P = 0.017) compared to healthy controls. We found that IL-8 levels were markedly higher in patients with GA when compared to patients with neovascular AMD (P = 0.013). The inflammation summary score was high in patients with neovascular AMD (P = 0.024), but even higher in patients with GA (<0.001), when compared to healthy controls. GA enlargement was measured in 36 patients, who completed follow-up. Plasma levels of IL-6 had a moderate but significant correlation with GA enlargement rate (R2 = 0.23, P = 0.0035). Conclusions: Markers of chronic inflammation strongly associates with presence of GA secondary to AMD. Plasma IL-6 possesses predictive ability of progression and constitutes the first known plasma biomarker of disease activity in GA. These findings shed light into a poorly understood clinical phenotype of AMD and highlights the important role of chronic inflammation in GA.

Choroidal and Sub-Retinal Pigment Epithelium Caverns: Multimodal Imaging and Correspondence with Friedman Lipid Globules.

PURPOSE: To survey Friedman lipid globules by high-resolution histologic examination and to compare with multimodal imaging of hyporeflective caverns in eyes with geographic atrophy (GA) secondary to age-related macular (AMD) and other retinal diseases. DESIGN: Histologic survey of donor eyes with and without AMD. Clinical case series with multimodal imaging analysis. PARTICIPANTS: Donor eyes (n = 139; 26 with early AMD, 13 with GA, 40 with nAMD, 52 with a healthy macula, and 8 with other or unknown characteristics) and 41 eyes of 28 participants with GA (n = 16), nAMD (n = 8), Stargardt disease (n = 4), cone dystrophy (n = 2), pachychoroid spectrum (n = 6), choroidal hemangioma (n = 1), and healthy eyes (n = 4). METHODS: Donor eyes were prepared for macula-wide epoxy resin sections through the foveal and perifoveal area. In patients, caverns were identified as nonreflective spaces on OCT images. Multimodal imaging included color and red-free fundus photography; fundus autofluorescence; fluorescein and, indocyanine green angiography; OCT angiography; near-infrared reflectance; and confocal multispectral (MultiColor [Spectralis, Heidelberg Engineering, Germany]) imaging. MAIN OUTCOME MEASURES: Presence and morphologic features of globules, and presence and appearance of caverns on multimodal imaging. RESULTS: Globules were found primarily in the inner choroidal stroma (91.0%), but also localized to the sclera (4.9%) and neovascular membranes (2.1%). Mean diameters of solitary and multilobular globules were 58.9±37.8 µm and 65.4±27.9 µm, respectively. Globules showed morphologic signs of dynamism including pitting, dispersion, disintegration, and crystal formation. Evidence for inflammation in the surrounding tissue was absent. En face OCT rendered sharply delimited hyporeflective areas as large as choroidal vessels, frequently grouped around choroid vessels or in the neovascular tissue. Cross-sectional OCT revealed a characteristic posterior hypertransmission. OCT angiography showed absence of flow signal within caverns. CONCLUSIONS: Based on prior literature documenting OCT signatures of tissue lipid in atheroma and nAMD, we speculate that caverns are lipid rich. Globules, with similar sizes and tissue locations in AMD and healthy persons, are candidates for histologic correlates of caverns. The role of globules in chorioretinal physiologic features, perhaps as a lipid depot for photoreceptor metabolism, is approachable through clinical imaging.

Predictive models of long-term anatomic outcome in age-related macular degeneration treated with as-needed Ranibizumab.

BACKGROUND: To analyze predictors and develop predictive models of anatomic outcome in neovascular age-related macular degeneration (AMD) treated with as-needed ranibizumab after 4 years of follow-up. METHODS: A multicenter consecutive case series non-interventional study was performed. Clinical, funduscopic and OCT characteristics of 194 treatment-naïve patients with AMD treated with as-needed ranibizumab for at least 2 years and up to 4 years were analyzed at baseline, 3 months and each year until the end of the follow-up. Baseline demographic and angiographic characteristics were also evaluated. R Statistical Software was used for statistical analysis. Main outcome measure was final anatomic status. RESULTS: Factors associated with less probability of preserved macula were diagnosis in 2009, older age, worse vision, presence of atrophy/fibrosis, pigment epithelium detachment, and geographic atrophy/fibrotic scar/neovascular AMD in the fellow eye. Factors associated with higher probability of GA were presence of atrophy and greater number of injections, whereas male sex, worse vision, lesser change in central macular thickness and presence of fibrosis were associated with less probability of GA as final macular status. Predictive model of preserved macula vs. GA/fibrotic scar showed sensibility of 77.78% and specificity of 69.09%. Predictive model of GA vs. fibrotic scar showed sensibility of 68.89% and specificity of 72.22%. CONCLUSIONS: We identified predictors of final macular status, and developed two predictive models. Predictive models that we propose are based on easily harvested variables, and, if validated, could be a useful tool for individual patient management and clinical research studies.

Choroidal Neovascularization and Geographic Atrophy are Potential Complications of Early Onset Large Colloid Drusen.

The authors report a case of large colloid drusen (LCD) complicated by choroidal neovascularization (CNV) and geographic atrophy (GA). A 54-year-old man was referred to the authors' department with diagnosis of early onset retinal drusen. Multimodal imaging led to a diagnosis of LCD complicated by GA in the right eye and CNV in the left eye. The patient received a single injection of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) in the left eye. Six months later, best-corrected visual acuity improved to 20/25, and spectral-domain optical coherence tomography still showed absence of subretinal and intraretinal fluid. GA and CNV are possible complications of LCD, and contrary to previous beliefs, it should therefore not be considered as a benign condition. Intravitreal aflibercept could be considered as a useful treatment in cases complicated by CNV. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:586-590.].

Experience With a Subretinal Cell-based Therapy in Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration.

PURPOSE: To evaluate the safety and tolerability of and clinical response to a single, subretinal dose of human umbilical tissue-derived cells (palucorcel [CNTO-2476]) in the eyes of adults aged ≥50 years with bilateral geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Phase 1/2a, multicenter, open-label, dose-escalation, fellow-eye-controlled study. METHODS: In the phase 1 portion, eyes were assigned to receive a single, subretinal dose of palucorcel (ranging from 6.0 × 104 to 5.6 × 105 viable cells). In the phase 2a portion, eyes were assigned to one of 2 palucorcel doses (6.0 × 104 or 3.0 × 105 cells) determined during the phase 1 portion. The intervention eye was the eye with worse baseline visual acuity. RESULTS: A total of 35 eligible subjects underwent at least a partial surgical procedure. Palucorcel was administered in 33 eyes. Overall, 17.1% (6/35) of subjects experienced retinal detachments and 37.1% (13/35) experienced retinal perforations. No episodes of immune rejection or tumor formation were observed. At 1 year, ≥10- and ≥15-letter gains in best-corrected visual acuity were observed in 34.5% (10/29) and 24.1% (7/29) of eyes receiving palucorcel, respectively, and in 3.3% (1/30; for both) of fellow eyes. CONCLUSIONS: The subretinal delivery procedure in this study was associated with a high rate of retinal perforations (n = 13) and retinal detachments (n = 6). When cells were sequestered in the subretinal space, palucorcel was well tolerated and may be associated with improvements in visual acuity. Larger randomized controlled studies are required to confirm these results. Future studies would require a modified surgical approach.

Implications of the anatomical classification of the neovascular form of age-related macular degeneration. / Implicaciones de la clasificación anatómica de la forma neovascular de la degeneración macular asociada a la edad.

OBJECTIVE: To present the clinical relevance of the anatomical classification of the neovascular form of Age-Related Macular Degeneration (AMD). METHODS: Critical analysis of the current situation in the management of patients with neovascular AMD, by reviewing the available scientific evidence with regards to the classification of the types of neovascular lesion by angiography and optical coherence tomography (OCT). RESULTS: The classification of the neovascular lesion type secondary to AMD by OCT in type 1 lesions (under the pigment epithelium), type 2 (subretinal), and type 3 (retinal angiomatous proliferation), provides an added value in allowing to establish a long-term visual prognosis, an estimate of the number of treatments that a certain case may require, and a stratification of the risk for secondary geographic atrophy. CONCLUSIONS: Incorporating OCT to the initial qualitative analysis of cases with neovascular AMD offers an added value superior to that provided by the angiography, with the relevant clinical implications.

Risk of geographic atrophy in age-related macular degeneration patients treated with intravitreal anti-VEGF agents.

Anti-vascular endothelial growth factor (VEGF) intravitreal agents are the only successful treatment for wet age-related macular degeneration (AMD). However, there are emerging signals that anti-VEGF treatment can potentially increase development of geographic atrophy (GA). Histopathologic, animal, and clinical studies support this hypothesis although direct proof of a relationship between GA and use of anti-VEGF agents in neovascular AMD is not yet established. This review presents current evidence supporting an association between anti-VEGF therapy and progression of geographic atrophy. The need of exploring alternative methods of treating AMD is indirectly but clearly emphasized.