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Background: To characterise early stages of geographic atrophy (GA) development in age-related macular degeneration (AMD) and to determine the prognostic value of structural precursor lesions in eyes with intermediate (i) AMD on the subsequent GA progression., Methods: Structural precursor lesions for atrophic areas (lesion size at least 0.5 mm² in fundus autofluorescence images) were retrospectively identified based on multimodal imaging and evaluated for association with the subsequent GA enlargement rates (square-root transformed, sqrt). A linear mixed-effects model was used to account for the hierarchical nature of the data with a Tukey post hoc test to assess the impact of the local precursor on the subsequent GA progression rate., Results: A total of 39 eyes with GA of 34 patients with a mean age of 74.4±6.7 (±SD) years were included in this study. Five precursor lesions (phenotypes 1-5) preceding GA development were identified: large, sub-retinal pigment epithelial drusen (n=19), reticular pseudodrusen (RPD, n=10), refractile deposits (n=4), pigment epithelial detachment (n=4) and vitelliform lesions (n=2). Precursor lesions exhibited a significant association with the subsequent (sqrt) GA progression rates (p=0.0018) with RPD (phenotype 2) being associated with the fastest GA enlargement (2.29±0.52 (±SE) mm/year., Conclusions: The results indicate the prognostic relevance of iAMD phenotyping for subsequent GA progression highlighting the role of structural AMD features across different AMD stages., Competing Interests: Competing interests: Non-financial support from Heidelberg Engineering to ST, MP; from CenterVue to ST, MP and MF; from Optos to ST, SS-V and MF. Grant from German Research Foundation (PF 950/1-1 to MP and FL 658/4-1 and Fl658/4-2 to MF); grant from Katairo to SS-V; from Acucela, CenterVue to SS-V and FGH; from Zeiss, Optos, NightStar X and Bioeq/Formycon to FGH. Personal fees from Heidelberg Engineering, Bayer and Novartis to ST; from Bioeq/Formycon, Galimedix to SS-V; from Pixium Vision, Lin Bioscience, Oxurion, Stealth Therapeutics, Kodiak to FGH. Patent pending: US20140303013A1 from MF., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: The prospective, non-interventional ORCA module of the OCEAN study (Observation of Treatment Patterns with Lucentis in Approved Indications) evaluated the qualiy of spectral domain-optical coherence tomography (SD-OCT) image interpretation and treatment decisions by clinicians in Germany and the impact on visual outcomes over 24 months in patients with neovascular age-related macular degeneration (nAMD)., Methods: 2286 SD-OCT scans of 205 eyes were independently evaluated by clinicians and reading centres (RCs) regarding signs of choroidal neovascularisation (CNV) activity, including presence of intraretinal fluid, subretinal fluid, and/or increase in pigment epithelial detachments. Agreement between clinicians and RCs was calculated. Treatment decisions by clinicians and the impact on treatment outcomes were evaluated., Results: CNV activity was detected by RCs on 1578 scans (69.0%) and by clinicians on 1392 scans (60.9%), with agreement in 74.9% of cases. Of the 1578 scans with RC detected CNV activity, anti-vascular endothelial growth factor injections were performed by clinicians in only 35.5% (560/1578). In 19.7% of cases (311/1578), lack of treatment was justified by patients request, termination criteria or chronic cystoid spaces without other signs for CNV activity. In 44.8% of cases (707/1578) with RC detected CNV activity, clinicians claimed no treatment was necessary despite having correctly detected CNV activity in about 2/3 of these cases. In 34% of cases with presumed undertreatment, visual acuity declined in the following visit., Conclusion: Although broad agreement on CNV activity parameters was observed between clinicians and RCs, correct identification of CNV activity did not always lead to the initiation of (re-)treatment. To preserve vision over time, correct interpretation of SD-OCT scans and careful retreatment decisions are required., Trial Registration Number: NCT02194803., Competing Interests: Competing interests: SL received personal fees from Novartis, Heidelberg Engineering, Carl Zeiss Meditec, Allergan, Bayer, and was member of an advisory board for Novartis. GS received personal fees from Bayer Healthcare, Novartis, Zeiss, OD-OS and Allergan Pharma. CKB has received grants from Heidelberg Engineering, Newtricious, Novartis, Zeiss Meditec; and personal fees from Heidelberg Engineering, Newtricious and Novartis. TS received personal fees from Novartis. FZ received grants and personal fees from Alimera, Allergan, Bayer Healthcare, Biogen and Roche, grants from Clearside, personal fees from Boehringer Ingelheim, Novartis, NovoNordisk and MSD Sharp & Dohme. JV and MK are employees of Novartis. BK received grants from Novartis and personal fees from Novartis, Pfizer and Bayer. FGH received grants from Acucela, Alcon, Allergan, Bayer, Genentech, Heidelberg Engineering, Novartis, Ophthotech, Roche and personal fees from Allergan, Bayer, Genentech, Novartis, Ophthotech; he was a member of advisory boards for Acucela, Allergan, Avalanche, Bayer, Genentech, Heidelberg Engineering, Johnson & Johnson, Novartis, Ophthotech and Roche. DP received grants from Novartis, Ophthotech, Acucela, Genentech, Roche, Bayer and personal fees from Novartis, Bayer, Allergan; he was a member of advisory boards for Novartis, Bayer and Allergan. SS-V received grants and non-financial research funding from Acucela, Alcon/Novartis, Allergan, Bayer, Bioeq/Formycon, Centervue, Galimedix, Genentech/Roche, Heidelberg Engineering, Optos, Carl Zeiss MediTec, and personal fees and honoraria from Alcon/Novartis, Bayer, Genentech/Roche and Carl Zeiss MediTec., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: Prospective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity., Methods: SAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed., Results: One hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of -30.75 µm (95% CI -59.50,-20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0-≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified., Conclusion: Switching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab., Competing Interests: Competing interests: RPG: consultancy, educational grants and institutional research grants for Novartis and Bayer; IP: speakers’ fees, consulting fees and travel support from Novartis and Bayer; NE: grant/research support from Novartis and Bayer; speakers’ honoraria from: Novartis, Bayer, Allergan and Heidelberg Engineering; Advisory board member for: Novartis, Bayer, Allergan, Bausch and Lomb, Alimera Sciences and Roche; consultancy fees from Bayer; FG: consultant for Novartis and Bayer; advisory board member for Novartis and Bayer; speakers’ fees and research support from Bayer; FGH: financial support from: Acucela, Allergan, Bayer, Bioeq, CenterVue, Hoffmann-La Roche/Genentech, Heidelberg Engineering, Novartis, and Zeiss; Consultant for Acucela, Alcon, Bayer, Boehringer-Ingelheim, Hoffmann-La Roche/Genentech, Grayburg Vision, Heidelberg Engineering, Lin Bioscience, Novartis, Stealth Biotherapeutics, and Zeiss; SS-V: financial support from: Acucela, Alcon/Novartis, Allergan, Bayer, Bioeq/Formycon, Carl Zeiss MedicTec, CenterVue, Hoffman-La Roche/Genentech, Heidelberg Engineering, Katairo and Optos; consultant for: Alcon/Novartis, Bioeq/Formycon and Galimedix Therapeutics; recipient of gifts, honoraria, travel reimbursement, patent royalties and/or any other financial compensation from: Alcon/Novartis, Allergan, Bayer, Carl Zeiss MedicTec and Hoffmann-La Roche/Genentech; KB: travel grants and speakers’ fees from: Novartis, Bayer, Alimera, Topcon and Heidelberg Engineering; research grants from Novartis and Bayer; BJLB: advisory board and international conference attendance sponsored by Novartis and Bayer; SD: principal investigator on trials sponsored by: Novartis, Bayer, Roche, and Ely Lilly; speakers’ honoraria from: Novartis, Bayer, Roche and/or Eli Lilly; conference and travel support from Novartis and Eli Lilly; consultant for Hakko Kyowa and Circadian Therapeutics; grant/research support from Novartis; HE: travel grants and speakers’ fees from Novartis; advisory board member for Novartis; SG: speakers’ fees from Hoffman-La Roche and Novartis; advisory board member for, and travel grants from Bayer; DFG: travel grants from Novartis and Bayer; speakers’ fees from Novartis; RH: research support and travel grants from, and advisory board member for Novartis, Bayer, Allergan, and Ellex; AL: travel support to attend educational meetings from Bayer; NP: grant support and travel grants from Novartis and Bayer; PP: none declared; CS: speakers’ fees, consulting fees, conference and travel support from Novartis and Bayer; ST: travel grant and conference registration from Bayer; DV: travel grants from Novartis, Bayer and Allergan; Advisory board member for: Allergan, Novartis, Bayer, Alcon and Polyphotonix; investigator on clinical trials sponsored or funded by: Novartis, Bayer, Hoffmann-La Roche and Allergan; Speakers’ fees from Bayer and Novartis; GW: advisory board member for, and support to attend conferences from Novartis and Bayer; MAW: travel grants from Novartis, Bayer and Allergan; recipient of grant to develop medical education material on ophthalmology; AW: consulting fees from Novartis and Bayer; speakers’ fees from Novartis; advisory board member for Novartis; travel grants from Bayer; research support from Novartis and Bayer; RHZ: none declared; FI: employee of Novartis Pharmaceuticals UK Ltd; FA: employee of Novartis Pharmaceuticals UK Ltd., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: To analyse the retest reliability of visual field indices and to describe patterns of visual field deficits in mesopic and dark-adapted two-colour fundus-controlled perimetry (FCP) in macular diseases., Methods: Seventy-seven eyes (30 eyes with macular diseases and 47 normal eyes) underwent duplicate mesopic and dark-adapted two-colour FCP (Scotopic Macular Integrity Assessment, CenterVue). Non-weighted (mean defect, loss variance), variability-weighted (mean deviation, pattern standard deviation (PSD)) and graphical (cumulative defect (Bebie) curves) indices were computed. Reproducibility (coefficient of repeatability, CoR) of these indices was assessed. Cluster analysis was carried out to identify patterns of visual field deficits., Results: The intrasession reproducibility was lower for the mean defect as compared with the mean deviation (CoR (dB) 2.67 vs 2.57 for mesopic, 1.71 vs 1.45 for dark-adapted cyan, 1.94 vs 1.87 for dark-adapted red testing) and lower for the square-root loss variance as compared with the PSD (CoR (dB) 1.48 vs 1.34, 0.77 vs 0.65, 1.23 vs 1.03). Hierarchical cluster analysis of the indices disclosed six patterns of visual field deficits (approximately unbiased P value>0.95) with varying degrees of global versus focal defect and rod versus cone dysfunction. These were also reflected by the cumulative defect curves., Conclusion: FCP with mesopic and dark-adapted two-colour testing allows for reproducible assessment of different types of retinal sensitivity, whereby mean deviation and PSD exhibited the better retest reliability of the tested indices. Distinct patterns of retinal dysfunction can be identified using this setup, reflecting variable degrees of rod and cone dysfunction in different macular diseases. Dark-adapted two-colour FCP provides additional diagnostic information and allows for refined structure-function correlation in macular diseases., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background/aims: To evaluate predictive factors for the treatment success of ocriplasmin and to use these factors to generate a multivariate model to calculate the individual probability of successful treatment., Methods: Data were collected in a retrospective, multicentre cohort study. Patients with vitreomacular traction (VMT) syndrome without a full-thickness macular hole were included if they received an intravitreal injection (IVI) of ocriplasmin. Five factors (age, gender, lens status, presence of epiretinal membrane (ERM) formation and horizontal diameter of VMT) were assessed on their association with VMT resolution. A multivariable logistic regression model was employed to further analyse these factors and calculate the individual probability of successful treatment., Results: 167 eyes of 167 patients were included. Univariate analysis revealed a significant correlation to VMT resolution for all analysed factors: age (years) (OR 0.9208; 95% CI 0.8845 to 0.9586; p<0.0001), gender (male) (OR 0.480; 95% CI 0.241 to 0.957; p=0.0371), lens status (phakic) (OR 2.042; 95% CI 1.054 to 3.958; p=0.0344), ERM formation (present) (OR 0.384; 95% CI 0.179 to 0.821; p=0.0136) and horizontal VMT diameter (µm) (OR 0.99812; 95% CI 0.99684 to 0.99941, p=0.0042). A significant multivariable logistic regression model was established with age and VMT diameter., Conclusion: Known predictive factors for VMT resolution after ocriplasmin IVI were confirmed in our study. We were able to combine them into a formula, ultimately allowing the calculation of an individual probability of treatment success with ocriplasmin in patients with VMT syndrome without FTHM., Competing Interests: Competing interests: HH reports personal fees from Allergan, personal fees from Alcon, personal fees from Bayer, personal fees from Heidelberg Engineering, personal fees from Novartis, personal fees from Alimera, outside the submitted work; NF reports personal fees and non-financial support from Allergan, personal fees and non-financial support from Bayer, personal fees from Heidelberg Engineering, personal fees and non-financial support from Novartis, personal fees and non-financial support from Alimera, outside the submitted work; JW reports personal fees from Allergan, personal fees from Bayer, personal fees from Novartis, personal fees from Alcon, outside the submitted work; HK reports personal fees from Abbott Medical Optics, personal fees from Alimera Sciences, personal fees from Alcon, personal fees from Allergan, personal fees from Carl Zeiss Meditec AG, personal fees from Dres. Schlegel + Schmidt, personal fees from Ellex, personal fees from Geuder, personal fees from Novartis, personal fees from Oculentis, personal fees from Oertli Instrumente AG, personal fees from Polytech Domilens, personal fees from Topcon Medical, outside the submitted work; SM reports personal fees from Bayer healthcare, personal fees from Novartis, outside the submitted work; MJK reports personal fees from Allergan, personal fees from Allimera, personal fees from Bayer, personal fees from Insight Instruments, personal fees from Novartis, outside the submitted work; SF reports personal fees from Roche, outside the submitted work; MMM reports personal fees from Allergan, personal fees from Bayer, personal fees from Novartis, personal fees from Heidelberg Engineering, personal fees from Alcon, personal fees from Zeiss, outside the submitted work; RGS reports personal fees from Allergan, personal fees from Novartis, outside the submitted work; SM has nothing to disclose. PC reports personal fees from Novartis, outside the submitted work; PS has nothing to disclose. AL reports personal fees from Alcon, personal fees from Bayer, outside the submitted work; TB reports personal fees from Alcon, personal fees from Novartis, personal fees from Alimera, personal fees from Bayer, personal fees from Heidelberg, outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background/aims: To analyse appearance, development over 2 years and characteristic patterns of reticular drusen (RDR) in eyes with high-risk characteristics for progression to late-stage age-related macular degeneration (AMD) (age-related eye disease study stages 3 and 4)., Methods: 98 eyes of 98 patients (median age 73.4 years, IQR [69-78]) participating in the Molecular Diagnostic of Age-related Macular Degeneration study were included. Simultaneous combined confocal scanning laser ophthalmoscopy (cSLO) and spectral-domain optical coherence tomography (SD-OCT) imaging as well as colour-fundus imaging was performed at baseline and at 24 months. Two independent graders determined the presence of different RDR phenotypes (cSLO modalities: 'dot', 'target', 'ribbon'; SD-OCT: 'spike' and 'wave') at both visits., Results: At baseline, RDR were detected in 44% (κ 0.96). They were always visible in near-infrared reflectance images. Detection rate was 42% using fundus autofluorescence (FAF), 39% on SD-OCT (waves: 100%; spikes: 90%) and 26% on blue reflectance (BR). 'Dots' were more frequently detected in all imaging compared with 'targets'. The 'ribbon' pattern was most frequently observed in colour images, BR images and FAF images. In 8 of the 48 eyes with no signs of RDR in any imaging modality at baseline, the development of RDR lesions was observed at 24 months (16.6%, κ 0.42)., Conclusions: Careful and meticulous analysis using three-dimensional in vivo imaging reveals distinct characteristic RDR patterns underlying detectable dynamic changes over a period of 2 years. RDR in eyes with early or intermediate AMD are a common observation but appear to be overall less common compared with eyes with geographic atrophy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aim: To evaluate near-infrared (NIR) autofluorescence (AF) in patients with geographic atrophy (GA) secondary to age-related macular degeneration and to investigate the origin of the signal by in vivo and histological analysis in rats and in a human donor eye., Methods: Confocal scanning laser ophthalmoscopy in vivo imaging, including blue (excitation: 488 nm, emission 500-700 nm) and NIR (excitation: 790 nm, emission >810 nm) AF was performed in 21 eyes of 18 GA patients. Pigmented and albino rats underwent with the same device both in vivo and post-mortem imaging. For the latter, cryostat prepared retinal cross-sections were imaged using an additional customised magnification lens. Finally, cross-sections of a 49-year old human donor eye were recorded., Results: Atrophic areas in GA were characterised by low NIR AF intensities. In the junctional zone of atrophy, focal areas of increased intensity were seen which appeared to seldom correlate to blue AF findings. Confocal live scanning in pigmented rats identified the maximum of the NIR AF signal in the outer retina, with histological confirmation of the signal origin localised to the retinal pigment epithelium and sclera in both animals and human donor eye. No NIR AF was found in the retina of young non-pigmented rats., Discussion: This study further underscores the assumption that melanin is the main source of NIR AF in the healthy retina. Increased NIR AF intensities in the junctional zone in GA may represent accumulation of melanolipofuscin, which may reflect disease activity and thus may allow for early identification of patients at high-risk of GA enlargement.