Stereotactic radiotherapy for neovascular age-related macular degeneration (STAR): a pivotal, randomised, double-masked, sham-controlled device trial.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity. METHODS: This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment. FINDINGS: 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483). INTERPRETATION: SRT can reduce ranibizumab treatment burden without compromising vision. FUNDING: Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

Age-Related Macular Degeneration: A Review.

Importance: Age-related macular degeneration (AMD) affects approximately 20 million people in the US and 196 million people worldwide. AMD is a leading cause of severe vision impairment in older people and is expected to affect approximately 288 million people worldwide by 2040. Observations: Older age, genetic factors, and environmental factors, such as cigarette smoking, are associated with development of AMD. AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision. The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD. The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older. The estimated heritability of late-stage AMD is approximately 71% (95% CI, 18%-88%). Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked. AMD is diagnosed primarily with clinical examination that includes a special lens that focuses light of the slit lamp through the pupil. Exudative neovascular AMD is best identified using angiography and by optical coherence tomography. Individuals with AMD who take nutritional supplements consisting of high-dose vitamin C, vitamin E, carotenoids, and zinc have a 20% probability to progress to late-stage AMD at 5 years vs a 28% probability for those taking a placebo. In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment. Conclusions and Relevance: The prevalence of AMD is anticipated to increase worldwide to 288 million individuals by 2040. Intravitreally administered anti-VEGF treatment is first-line therapy for exudative neovascular AMD.

Identifying the severity of diabetic retinopathy by visual function measures using both traditional statistical methods and interpretable machine learning: a cross-sectional study.

AIMS/HYPOTHESIS: To determine the extent to which diabetic retinopathy severity stage may be classified using machine learning (ML) and commonly used clinical measures of visual function together with age and sex. METHODS: We measured the visual function of 1901 eyes from 1032 participants in the Northern Ireland Sensory Ageing Study, deriving 12 variables from nine visual function tests. Missing values were imputed using chained equations. Participants were divided into four groups using clinical measures and grading of ophthalmic images: no diabetes mellitus (no DM), diabetes but no diabetic retinopathy (DM no DR), diabetic retinopathy without diabetic macular oedema (DR no DMO) and diabetic retinopathy with DMO (DR with DMO). Ensemble ML models were fitted to classify group membership for three tasks, distinguishing (A) the DM no DR group from the no DM group; (B) the DR no DMO group from the DM no DR group; and (C) the DR with DMO group from the DR no DMO group. More conventional multiple logistic regression models were also fitted for comparison. An interpretable ML technique was used to rank the contribution of visual function variables to predictions and to disentangle associations between diabetic eye disease and visual function from artefacts of the data collection process. RESULTS: The performance of the ensemble ML models was good across all three classification tasks, with accuracies of 0.92, 1.00 and 0.84, respectively, for tasks A-C, substantially exceeding the accuracies for logistic regression (0.84, 0.61 and 0.80, respectively). Reading index was highly ranked for tasks A and B, whereas near visual acuity and Moorfields chart acuity were important for task C. Microperimetry variables ranked highly for all three tasks, but this was partly due to a data artefact (a large proportion of missing values). CONCLUSIONS/INTERPRETATION: Ensemble ML models predicted status of diabetic eye disease with high accuracy using just age, sex and measures of visual function. Interpretable ML methods enabled us to identify profiles of visual function associated with different stages of diabetic eye disease, and to disentangle associations from artefacts of the data collection process. Together, these two techniques have great potential for developing prediction models using untidy real-world clinical data.

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.

UNITED KINGDOM DATABASE STUDY OF INTRAVITREAL DEXAMETHASONE IMPLANT (OZURDEX) FOR MACULAR EDEMA RELATED TO RETINAL VEIN OCCLUSION.

PURPOSE: To study the treatment patterns, visual outcomes and safety profile of intravitreal dexamethasone implant (IDI) used for the treatment of macular edema secondary to retinal vein occlusion. METHODS: Up to 2 years of routinely collected anonymized data within electronic medical record systems were remotely extracted from 16 centers. The outcome measures include visual outcome, number of injections, and safety measures, including the rate of intraocular pressure (IOP) rise, frequency of IOP-lowering medication usage, and cataract surgery rates. RESULTS: The study included 688 eyes (44.4%) with central retinal vein occlusion and 862 eyes (55.6%) with branch retinal vein occlusion; 1,250 eyes (80.6%) were treatment naive and 28% (275/989) had high IOP or were on IOP-lowering medications before IDI use. It was found that 31% (476) of eyes received two injections, and 11.7% (182) and 3.7% (58) of eyes received three and four injections, respectively. The mean baseline Snellen visual acuity improved from 20/125 to 20/40 after the first injection. The probability of cataract surgery was 15% at 24 months. The proportion of eyes with ≥10 mmHg change from baseline was higher in phakic (14.2%) compared with pseudophakic eyes (5.4%, P = 0.004). Three eyes required IOP filtering surgery (0.2%). CONCLUSION: The visual results of IDI in eyes with macular edema secondary to retinal vein occlusion in the real world are comparable to those of clinical trial setting. Increased IOP in eyes with preexisting ocular hypertension or glaucoma can be controlled with additional medical treatment. Intraocular pressure rise with IDI may be more frequent in phakic than in pseudophakic eyes.

Treatment patterns and persistence rates with anti-vascular endothelial growth factor treatment for diabetic macular oedema in the UK: A real-world study.

INTRODUCTION: Anti-vascular endothelial growth factors (anti-VEGFs) are considered standard of care therapy for diabetic macular oedema (DME). This study examined treatment patterns and outcomes in patients with DME treated with anti-VEGF therapy. METHODS: Using anonymized electronic medical record data collected from three UK sites, this retrospective cohort study assessed rates of anti-VEGF intravitreal injections in adults with treatment-naïve DME who received their first treatment between 1 September 2010 and 31 July 2018. The proportion of patients with at least one interval of at least 12 weeks between injections; the distribution of injection intervals; the discontinuation rates; and the number of anti-VEGF injection-, injection-free- and total visits were assessed during the first and second years of treatment. RESULTS: Overall, 1606 patient eyes with DME were included, with no minimum follow-up. During the first and second year of treatment, 63.2% and 73.1% of eyes had at least one anti-VEGF injection interval of at least 12 weeks, respectively. In the first and second years of treatment, the mean (standard deviation) numbers of injections were 7.7 (1.9) and 5.6 (2.2), with 14.2 (5.7) and 13.4 (6.4) total clinic visits, and 6.6 (5.0) and 7.8 (5.8) injection-free visits, respectively. In total, 27.8% of patient eyes discontinued treatment during the first 2 years. CONCLUSIONS: The high number of clinic visits and high discontinuation rates demonstrate a significant unmet need for a treatment to enable sustainable extended injection intervals, while maintaining visual acuity. This could improve patient adherence and health-related quality of life for patients with DME.

EFFECT OF RETINAL THICKNESS VARIABILITY ON VISUAL OUTCOMES AND FLUID PERSISTENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Post Hoc Analysis of the HAWK and HARRIER Studies.

PURPOSE: To determine the association between central subfield thickness (CST) variability and visual outcomes in eyes with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapies. METHODS: In this post hoc, treatment-agnostic analysis, patients (N = 1,752) were grouped into quartiles of increasing CST variation. The association between CST variability and best-corrected visual acuity was measured from baseline, or from the end of the loading phase, until the end of the study using a multilevel modeling for repeated-measures model. The association between CST variability and the presence of retinal fluid was also assessed. RESULTS: Increased CST variability was associated with worse best-corrected visual acuity outcomes at the end of study, with a least-square mean difference in best-corrected visual acuity of 8.9 Early Treatment Diabetic Retinopathy Study letters between the quartiles with the lowest and highest CST variability at the final visit. Increased variability was also associated with a higher mean fraction of visits with the presence of fluid. CONCLUSION: More stable CST was associated with better visual outcomes at the end of treatment suggesting that CST variability may provide a more reliable prognostic marker of visual outcomes than the presence of fluid alone, with the potential to enhance the clinical care of neovascular age-related macular degeneration patients.

OPTICAL COHERENCE TOMOGRAPHY FEATURES OF POLYPOIDAL LESION CLOSURE IN POLYPOIDAL CHOROIDAL VASCULOPATHY TREATED WITH AFLIBERCEPT.

PURPOSE: To evaluate whether optical coherence tomography (OCT) can determine polypoidal lesion (PL) perfusion in polypoidal choroidal vasculopathy eyes after 12 months of aflibercept monotherapy. Polypoidal lesion perfusion status, assessed by indocyanine green angiography, is an important anatomical outcome in polypoidal choroidal vasculopathy management. METHODS: Post hoc data from a prospective randomized, open-label, study in eyes with polypoidal choroidal vasculopathy undergoing monotherapy with aflibercept evaluated PL perfusion status based on indocyanine green angiography (gold standard) and OCT features from baseline to 12 months. RESULTS: Individual PLs (110 in total) from 48 eyes (48 patients) showed at 12 months; 57/110 PLs (51.8%) were closed on indocyanine green angiography. At 12 months, eyes with closed PLs were more likely to have the following OCT features: 1) no subretinal fluid (67.1% vs. 32.9%), 2) smaller pigment epithelial detachment height (67.2 [±43.8] vs. 189.2 [±104.9] µm), 3) densely hyperreflective pigment epithelial detachment contents (84.0% vs. 16.0%), 4) an absence of a hyperreflective ring(64.0% vs. 36.0%), and a 5) indistinct overlying retinal pigment epithelial (71.4% vs. 28.6%) (all P < 0.05). The three highest performing OCT features that differentiated perfused from closed PLs were (1), (3), and (4) (area under the receiver operating characteristic curve 0.85, 0.73, and 0.70, respectively). A combination of these three features achieved an area under the receiver operating characteristic curve of 0.90. CONCLUSION: Polypoidal lesion closure, an important anatomical treatment outcome in polypoidal choroidal vasculopathy typically defined by indocyanine green angiography, can be accurately detected by specific OCT features.

Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In chronic central serous chorioretinopathy (CSCR), fluid accumulates in the subretinal space. CSCR is a common visually disabling condition that develops in individuals up to 60 years of age, and there is no definitive treatment. Previous research suggests the mineralocorticoid receptor antagonist, eplerenone, is effective for treating CSCR; however, this drug is not licensed for the treatment of patients with CSCR. We aimed to evaluate whether eplerenone was superior to placebo in terms of improving visual acuity in patients with chronic CSCR. METHODS: This randomised, double-blind, parallel-group, multicentre placebo-controlled trial was done at 22 hospitals in the UK. Participants were eligible if they were aged 18-60 years and had had treatment-naive CSCR for 4 months or more. Patients were randomly assigned (1:1) to either the eplerenone or the placebo group by a trial statistician through a password-protected system online. Allocation was stratified by best-corrected visual acuity (BCVA) and hospital. Patients were given either oral eplerenone (25 mg/day for 1 week, increasing to 50 mg/day for up to 12 months) plus usual care or placebo plus usual care for up to 12 months. All participants, care teams, outcome assessors, pharmacists, and members of the trial management group were masked to the treatment allocation. The primary outcome was BCVA, measured as letters read, at 12 months. All outcomes apart from safety were analysed on a modified intention-to-treat basis (participants who withdrew consent without contributing a post-randomisation BCVA measurement were excluded from the primary analysis population and from most secondary analysis populations). The trial is registered with ISRCTN, ISRCTN92746680, and is completed. FINDINGS: Between Jan 11, 2017, and Feb 22, 2018, we enrolled and randomly assigned 114 patients to receive either eplerenone (n=57) or placebo (n=57). Three participants in the placebo group withdrew consent without contributing a post-randomisation BCVA measurement and were excluded from the primary outcome analysis population. All patients from the eplerenone group and 54 patients from the placebo group were included in the primary outcome. Modelled mean BCVA at 12 months was 79·5 letters (SD 4·5) in the placebo group and 80·4 letters (4·6) in the eplerenone group, with an adjusted estimated mean difference of 1·73 letters (95% CI -1·12 to 4·57; p=0·24) at 12 months. Hyperkalaemia occurred in eight (14%) patients in each group. No serious adverse events were reported in the eplerenone group and three unrelated serious adverse events were reported in the placebo group (myocardial infarction [anticipated], diverticulitis [unanticipated], and metabolic surgery [unanticipated]). INTERPRETATION: Eplerenone was not superior to placebo for improving BCVA in people with chronic CSCR after 12 months of treatment. Ophthalmologists who currently prescribe eplerenone for CSCR should discontinue this practice. FUNDING: Efficacy and Mechanism Evaluation Programme, and National Institute for Health Research and Social Care.

Diagnostic Accuracy of Monitoring Tests of Fellow Eyes in Patients with Unilateral Neovascular Age-Related Macular Degeneration: Early Detection of Neovascular Age-Related Macular Degeneration Study.

PURPOSE: To evaluate the diagnostic accuracy of routinely used tests of visual function and retinal morphology compared with fundus fluorescein angiography (FFA) to detect onset of active macular neovascularization in unaffected fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD). DESIGN: Prospective diagnostic accuracy cohort study conducted in 24 eye clinics in the United Kingdom over 3 years. PARTICIPANTS: Older adults (>50 years) with recently diagnosed unilateral nAMD with a fellow (study) eye free of nAMD. METHODS: Self-reported vision, Amsler, clinic-measured visual acuity (VA), fundus assessment, and spectral domain OCT. The reference standard is FFA. MAIN OUTCOME MEASURES: Sensitivity and specificity of the 5 index tests. RESULTS: Of 552 participants monitored for up to 3 years, 145 (26.3%) developed active nAMD in the study eye, of whom 120 had an FFA at detection and constituted the primary analysis cohort. Index test positives at nAMD detection in those confirmed by FFA were self-reported vision much worse (5), distortion on Amsler (33), 10-letter decrease in acuity from baseline (36), fundus examination (64), and OCT (110). Percentage index test sensitivities were: self-reported vision 4.2 (95% confidence interval [CI], 1.6-9.8); Amsler 33.7 (95% CI, 25.1-43.5); VA 30.0 (95% CI, 22.5-38.7); fundus examination 53.8 (95% CI, 44.8-62.5); and OCT 91.7 (95% CI, 85.2-95.6). All 5 index test specificities were high at 97.0 (95% CI, 94.6-98.5), 81.4 (95% CI, 76.4-85.5), 66.3 (95% CI, 61.0-71.1), 97.6 (95% CI, 95.3-98.9), and 87.8 (95% CI, 83.8-90.9), respectively. The combination of OCT with one other index test that was a secondary outcome measure increased sensitivity marginally and decreased specificity for all combinations except fundus examination. CONCLUSIONS: Tests of self-reported change in vision, unmasking of new distortion, measurements of acuity, and fundus checks to diagnose active nAMD performed poorly in contrast to OCT. Our findings support a change to guidelines in clinical practice to monitor for onset of nAMD.

Polypoidal Choroidal Vasculopathy: Consensus Nomenclature and Non-Indocyanine Green Angiograph Diagnostic Criteria from the Asia-Pacific Ocular Imaging Society PCV Workgroup.

PURPOSE: To develop consensus terminology in the setting of polypoidal choroidal vasculopathy (PCV) and to develop and validate a set of diagnostic criteria not requiring indocyanine green angiography (ICGA) for differentiating PCV from typical neovascular age-related macular degeneration (nAMD) based on a combination of OCT and color fundus photography findings. DESIGN: Evaluation of diagnostic test results. PARTICIPANTS: Panel of retina specialists. METHODS: As part of the Asia-Pacific Ocular Imaging Society, an international group of experts surveyed and discussed the published literature regarding the current nomenclature and lesion components for PCV, and proposed an updated consensus nomenclature that reflects our latest understanding based on imaging and histologic reports. The workgroup evaluated a set of diagnostic features based on OCT images and color fundus photographs for PCV that may distinguish it from typical nAMD and assessed the performance of individual and combinations of these non-ICGA features, aiming to propose a new set of diagnostic criteria that does not require the use of ICGA. The final recommendation was validated in 80 eyes from 2 additional cohorts. MAIN OUTCOME MEASURES: Consensus nomenclature system for PCV lesion components and non-ICGA-based criteria to differentiate PCV from typical nAMD. RESULTS: The workgroup recommended the terms polypoidal lesion and branching neovascular network for the 2 key lesion components in PCV. For the diagnosis of PCV, the combination of 3 OCT-based major criteria (sub-retinal pigment epithelium [RPE] ring-like lesion, en face OCT complex RPE elevation, and sharp-peaked PED) achieved an area under the receiver operating characteristic curve of 0.90. Validation of this new scheme in a separate subset 80 eyes achieved an accuracy of 82%. CONCLUSIONS: We propose updated terminology for PCV lesion components that better reflects the nature of these lesions and is based on international consensus. A set of practical diagnostic criteria applied easily to spectral-domain OCT results can be used for diagnosing PCV with high accuracy in clinical settings in which ICGA is not performed routinely.

POLYPOIDAL CHOROIDAL VASCULOPATHY FEATURES VARY ACCORDING TO SUBFOVEAL CHOROIDAL THICKNESS.

PURPOSE: To evaluate associations between choroidal thickness and features of polypoidal choroidal vasculopathy (PCV) lesions based on multimodal imaging. METHODS: This cross-sectional analysis included treatment-naive PCV eyes from a prospectively recruited observational cohort. Associations between of subfoveal choroidal thickness (SFCT) and qualitative and quantitative morphologic features of PCV lesions on color fundus photographs, indocyanine green and fluorescein angiography, and spectral-domain optical coherence tomography were evaluated. RESULTS: We included 100 eyes with indocyanine green angiography-proven PCV. Subfoveal choroidal thickness showed a bimodal distribution with peaks at 170 µm and 350 µm. There was a significant linear increase in the total lesion area (P-trend = 0.028) and the polypoidal lesion area (P-trend = 0.030 and P-continuous = 0.037) with increasing SFCT. Pairwise comparisons between quartiles showed that the total lesion area (4.20 ± 2.61 vs. 2.89 ± 1.43 mm2, P = 0.024) and the polypoidal lesion area (1.03 ± 1.01 vs. 0.59 ± 0.45 mm2, P = 0.042) are significantly larger in eyes in Q4 (SFCT ≥ 350 µm) than eyes in Q1 (SFCT ≤ 170 µm). Although there was no significant linear trend relating SFCT to best-corrected visual acuity, pairwise comparisons showed that eyes in Q4 (SFCT ≥ 350 µm) have significantly worse vision (0.85 ± 0.63 vs. 0.55 ± 0.27 logMAR, P = 0.030) than eyes in Q2 (SFCT 170-260 µm). CONCLUSION: Total lesion areas and polypoidal lesion areas tend to be larger in eyes with increasing SFCT. Choroidal background may influence the phenotype or progression pattern of PCV.

USING MICROPERIMETRY AND LOW-LUMINANCE VISUAL ACUITY TO DETECT THE ONSET OF LATE AGE-RELATED MACULAR DEGENERATION: A LEAD Study Report.

PURPOSE: To evaluate the performance of microperimetry and low-luminance visual acuity for detecting late age-related macular degeneration (AMD) onset. METHODS: Two hundred ninety-two individuals with bilateral large drusen in the Laser Intervention in the Early Stages of AMD study underwent best-corrected visual acuity, low-luminance visual acuity, and microperimetry testing as well as multimodal imaging to detect late (neovascular or atrophic) AMD onset. The performance of the change in the measurement from baseline of each of visual function test for detecting late AMD onset was compared. RESULTS: The area under the receiver operating characteristic curve for detecting neovascular and atrophic AMD onset was not significantly different for low-luminance visual acuity (area under the receiver operating characteristic curve = 0.71 and 0.56, respectively) and microperimetry (area under the receiver operating characteristic curve = 0.82 and 0.62, respectively) compared with best-corrected visual acuity (area under the receiver operating characteristic curve = 0.57 and 0.56, respectively; P ≥ 0.126 for all). There was also only a fair degree of agreement between the three visual function measures for detecting the onset of neovascular and atrophic AMD (κ ≥ 0.24). CONCLUSION: Microperimetry, low-luminance visual acuity, and best-corrected visual acuity demonstrate limited performance for detecting the earliest onset of late AMD. It remains to be established whether they perform better than current methods designed to enable self-detection of neovascular AMD onset, such as Amsler grid testing.

Association between retinal thickness variation and visual acuity change in neovascular age-related macular degeneration.

BACKGROUND: To assess the association between variation in retinal central subfield thickness (CSFT) with best-corrected visual acuity (BCVA) change in patients receiving vascular endothelial growth factor (VEGF) inhibitor therapy for neovascular age-related macular degeneration (nAMD). METHODS: CSFT measurements were obtained from 141 eyes (total 1300 scans). SD of CSFT was calculated. The eyes were categorised into CSFT variation tertiles. Multiple linear regression was used to examine the association between the CSFT tertiles and BCVA change at 12 mo, adjusting for differences in baseline demographic and clinical characteristics. RESULTS: At 12 mo, the mean BCVA of the high CSFT variation group (50.6 letters) was significantly lower than the low and moderate CSFT variation groups (57.5 and 59.8 letters, respectively), P = .02. The adjusted mean BCVA gains were +1.7, +7.2, and +7.8 letters in the high, moderate and low CSFT variation groups, respectively (P = .03). CONCLUSIONS: A greater variation in retinal thickness during VEGF inhibitor therapy for nAMD is associated with a less favourable visual outcome. CSFT stability is useful in prognosticating visual outcomes in VEGF inhibitor therapy for nAMD.

Long-term Visual Outcomes after Release from Protocol in Patients who Participated in the Inhibition of VEGF in Age-related Choroidal Neovascularisation (IVAN) Trial.

PURPOSE: To describe visual outcomes, frequency of treatment and monitoring visits, and anti-vascular endothelial growth factor drugs used in usual care in participants who exited a trial in which treatment for neovascular age-related macular degeneration (nAMD) was initiated with bevacizumab or ranibizumab. DESIGN: Multicenter cohort study up to 7 years after trial exit. PARTICIPANTS: Patients enrolled in the Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial; after excluding participants from 2 sites and who died or withdrew during the trial, 537 were included in this follow-up cohort. METHODS: Data were collected between May 26, 2016, and August 24, 2017. Distance visual acuity (DVA) (letters read) in both eyes and treatments for nAMD administered to either eye at all usual care visits were extracted from medical records of all participants until the point of data collection (duration of study eye monitoring). MAIN OUTCOME MEASURES: Rate of change of DVA during active surveillance of the study eye (study eye monitoring), estimated using a multivariable linear random effects model. Other outcome measures were visit and treatment frequency and switches in anti-vascular endothelial growth factor (VEGF) drug. RESULTS: Data were obtained for 99% (532/537) of eligible participants. The median duration of study eye monitoring after IVAN exit was 3.3 years (interquartile range [IQR], 1.3-4.7), and median DVA was 58.0 letters (IQR, 34.0-73.0). Study eye DVA deteriorated by 4.3 (95% confidence interval [CI], 3.7-4.9) letters per year. Injection rate did not influence the rate of change in DVA after adjusting for key covariates. After IVAN exit, 174 participants (32%) received no treatment; 332 of 358 (93%) were treated first with ranibizumab, 78 (23%) of whom switched to aflibercept. The DVA was similar among participants who switched or did not switch at the end of study monitoring. CONCLUSIONS: Approximately 5 years after the IVAN study finished, with unprecedented completeness of follow-up for such a trial, the trajectory of functional decline in the study eye was shown to be greater than that previously reported for incomplete trial cohorts. Anti-VEGF injection rates and treatment switches were not important factors in determining visual acuity outcomes.

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4.

PURPOSE: To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression. DESIGN: Consensus meeting. PARTICIPANTS: Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists. METHODS: As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA. MAIN OUTCOME MEASURES: Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. RESULTS: OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. CONCLUSIONS: An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavors, acknowledging that the classification will be refined as new data are generated.

Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration Data: Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group.

PURPOSE: To establish a process to evaluate and standardize a state-of-the-art nomenclature for reporting neovascular age-related macular degeneration (AMD) data. DESIGN: Consensus meeting. PARTICIPANTS: An international panel of retina specialists, imaging and image reading center experts, and ocular pathologists. METHODS: During several meetings organized under the auspices of the Macula Society, an international study group discussed and codified a set nomenclature framework for classifying the subtypes of neovascular AMD and associated lesion components. MAIN OUTCOME MEASURES: A consensus classification of neovascular AMD. RESULTS: The study group created a standardized working definition of AMD. The components of neovascular AMD were defined and subclassified. Disease consequences of macular neovascularization were delineated. CONCLUSIONS: The framework of a consensus nomenclature system, a definition of AMD, and a delineation of the subtypes of neovascular AMD were developed. Establishing a uniform set of definitions will facilitate comparison of diverse patient groups and different studies. The framework presented is modified and updated readily, processes that are anticipated to occur on a periodic basis. The study group suggests that the consensus standards outlined in this article be used in future reported studies of neovascular AMD and clinical practice.

Prevalence and Pattern of Geographic Atrophy in Asia: The Asian Eye Epidemiology Consortium.

PURPOSE: Although there have been many population-based studies of age-related macular degeneration (AMD), only limited information is available in Asia on the epidemiology of geographic atrophy (GA). We aimed to determine the prevalence and patterns of GA through an analysis of multiple studies conducted within the Asian Eye Epidemiology Consortium (AEEC). DESIGN: Cross-sectional meta-analyses. PARTICIPANTS: A total of 97 213 individuals aged 40 years and older. METHODS: Data from 22 population-based studies from countries belonging to the AEEC were included. In all studies, AMD was defined on the basis of standardized grading systems. Geographic atrophy was defined as an area of pallor in the fundus with visibility of the underlying choroidal blood vessels and sharply defined borders. Random-effects meta-analysis was performed to estimate overall and age-, gender-, and region-specific pooled prevalence of GA. MAIN OUTCOME MEASURES: Prevalence of GA per 1000 persons. RESULTS: The mean age was 60.8 ± 10.0 years, and 42 673 (43.9%) were male. Overall, a total of 223 individuals (0.2%) had GA. The pooled overall prevalence of GA was 1.57 per 1000 persons (95% confidence interval [CI], 1.04-2.10), which was 3 times less than that of neovascular AMD of 5.20 per 1000 persons (95% CI, 3.97-6.43). Compared with those aged 50 to 59 years, the prevalence of GA increased from 0.34 per 1000 persons (95% CI, 0.07-0.62) to 2.90 per 1000 persons (95% CI, 1.55-4.25) in those aged ≥70 years. The GA prevalence per 1000 persons was similar between urban (2.22; 95% CI, 1.22-3.23) and rural residents (1.33; 95% CI, 0.70-1.96). Geographic atrophy was more prevalent in South Asia (based on studies from India and Nepal, 3.82 per 1000 persons; 95% CI, 1.72-5.93) compared with East Asia (based on studies from China, Korea, Hong Kong, Taiwan, and Japan, and the Singapore Chinese Eye Study, 0.76 per 1000 persons; 95% CI, 0.31-1.22, P = 0.005). CONCLUSIONS: Geographic atrophy is uncommon in Asian populations compared with those of European ancestry. Even within Asia, geographic differences in GA prevalence were seen. The findings of this meta-analysis suggest that better dissection of risk factors in the Asian population for GA may provide insights into the biological pathways that drive these late-stage manifestations, thus suggesting better targets for prevention.

Plasma level of lipocalin 2 is increased in neovascular age-related macular degeneration patients, particularly those with macular fibrosis.

BACKGROUND: Previously, we and others have reported higher populations of circulating neutrophils in patients with neovascular age-related macular degeneration (nAMD). Neutrophil gelatinase-associated lipocalin (NGAL, also known as lipocalin-2, LCN2), an important innate immune mediator, is known to be critically involved in sterile inflammation-mediated organ failure, fibrosis, cancer progression and retinal degeneration. This study investigated the plasma levels of LCN2, matrix metalloproteinase 9 (MMP9) and LCN2/MMP9 complex in different types of nAMD and examined whether the levels were related to patients' responsiveness to anti-VEGF therapy. RESULTS: One hundred and seventy-four nAMD patients, including 108 with choroidal neovascularisation (CNV), 32 with retinal angiomatous proliferation (RAP), 23 with polypoidal choroidal vasculopathy (PCV) and 11 unclassified patients, and 43 healthy controls were recruited to this case-control study. Fifty-eight nAMD patients had macular fibrosis and 110 patients did not. Out of the 174 nAMD patients, 80 patients responded completely, 90 responded partially, and 4 did not respond to the anti-VEGF therapy. The plasma levels of LCN2 in nAMD patients (181.46 ± 73.62 ng/ml) was significantly higher than that in healthy controls (152.24 ± 49.55 ng/ml, P = 0.047). However, the difference disappeared after adjusting for age. A positive correlation between plasma level of LCN2 and age was observed in nAMD patients (r = 0.29, P = 0.0002) but not in healthy controls. The plasma level of LCN2 was also positively correlated with circulating neutrophils in nAMD patients (r = 0.34, p = 0.0007) but not in healthy controls (r = 0.057, p = 0.77). No correlation was observed between age and circulating neutrophils. Further analysis of nAMD subtypes uncovered a significantly higher level of LCN2 in patients with macular fibrosis even after adjusting for age. No relationship was observed between plasma levels of LCN2 and patients' responsiveness to anti-VEGF therapy. The plasma levels of MMP9 and LCN2/MMP9 complex were comparable between nAMD and controls. CONCLUSIONS: Our results suggest that higher plasma levels of LCN2 in nAMD are related to ageing and increased population of circulating neutrophils. Our results also suggest that higher levels of LCN2 may increase the risk of macular fibrosis in nAMD.

Intralesional Macular Atrophy in Anti-Vascular Endothelial Growth Factor Therapy for Age-Related Macular Degeneration in the IVAN Trial.

PURPOSE: To report on the development and progression of macular atrophy (MA) and its relationship with morphologic and functional measures in study and fellow eyes in the Inhibition of vascular endothelial growth factor (VEGF) in Age-related Choroidal Neovascularisation trial. DESIGN: Reading center analysis of data from a randomized controlled trial. PARTICIPANTS: Participants with previously untreated neovascular age-related macular degeneration (nAMD) in the study eye. METHODS: Color, fluorescein angiography (FA) and OCT images acquired at baseline and during the 2-year follow-up were graded systematically for presence of MA. Regression models were constructed to explore relationships between MA and lesion morphology and vision measures (best-corrected distance and near acuity, reading speed and index, contrast sensitivity). MAIN OUTCOME MEASURES: Primary outcome was development of intralesional MA (≥175 µm greatest linear dimension of choroidal vessels seen on FA and/or color, aided by OCT) lying within the maximum footprint of the neovascular lesion. RESULTS: Study eye data were available for 594 of 610 participants; 57 (9.6%) showed intralesional MA at baseline. Incident intralesional MA occurred in 24.4% by the final visit and extralesional MA in only 1.54%. In fellow eyes, an established nAMD lesion was present at baseline in 248 of whom 42 (16.9%) showed intralesional MA at baseline and 32 (12.9%) developed incident intralesional MA. The odds of incident intralesional MA by final visit were lower in study eyes that had ≥50% classic CNV at baseline (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.19-0.80; P = 0.010), subretinal fluid at final visit (OR, 0.41; 95% CI, 0.25-0.76; P = 0.004), or pigment epithelial detachment at final visit (OR, 0.40; 95% CI, 0.21-0.74; P = 0.004). Secondary analyses of incident or progressed intralesional MA in study eyes supported these findings, with odds increasing if the fellow eye had baseline intralesional MA (OR, 2.43; 95% CI, 1.09-5.44; P = 0.030). No significant associations were observed between development of intralesional MA and any other morphologic or visual function measure. CONCLUSIONS: Macular atrophy frequently develops within an nAMD lesion in eyes receiving anti-VEGF therapy over 2 years. No associations between incident MA and drug or treatment frequency or visual function were detected, providing some reassurance to clinicians; however, the longer-term effects remain unknown.