Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials.

BACKGROUND: Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy. METHODS: OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively. Patients were randomly assigned (2:2:1:1) by central web-based randomisation system to intravitreal 15 mg per 0·1 mL pegcetacoplan monthly or every other month, or sham monthly or every other month using stratified permuted block randomisation (stratified by geographic atrophy lesion area at screening, history or presence of active choroidal neovascularisation in the eye not under assessment, and block size of six). Study site staff, patients, reading centre personnel, evaluating physicians, and the funder were masked to group assignment. Sham groups were pooled for the analyses. The primary endpoint was the change from baseline to month 12 in the total area of geographic atrophy lesions in the study eye based on fundus autofluorescence imaging, in the modified intention-to-treat population (ie, all patients who received one or more injections of pegcetacoplan or sham and had a baseline and at least one post-baseline value of lesion area). Key secondary endpoints (measured at 24 months) were change in monocular maximum reading speed of the study eye, change from baseline in mean functional reading independence index score, change from baseline in normal luminance best-corrected visual acuity score, and change from baseline in the mean threshold sensitivity of all points in the study eye by mesopic microperimetry (OAKS only). Safety analyses included patients who were randomly assigned and received at least one injection of pegcetacoplan or sham. The now completed studies are registered with ClinicalTrials.gov, NCT03525613 (OAKS) and NCT03525600 (DERBY). FINDINGS: Between Aug 30, 2018, and July 3, 2020, 1258 patients were enrolled in OAKS and DERBY. The modified intention-to-treat populations comprised 614 (96%) of 637 patients in OAKS (202 receiving pegcetacoplan monthly, 205 pegcetacoplan every other month, and 207 sham) and 597 (96%) of 621 patients in DERBY (201 receiving pegcetacoplan monthly, 201 pegcetacoplan every other month, and 195 sham). In OAKS, pegcetacoplan monthly and pegcetacoplan every other month significantly slowed geographic atrophy lesion growth by 21% (absolute difference in least-squares mean -0·41 mm2, 95% CI -0·64 to -0·18; p=0·0004) and 16% (-0·32 mm2, -0·54 to -0·09; p=0·0055), respectively, compared with sham at 12 months. In DERBY, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth, although it did not reach significance, by 12% (-0·23 mm2, -0·47 to 0·01; p=0·062) and 11% (-0·21 mm2, -0·44 to 0·03; p=0·085), respectively, compared with sham at 12 months. At 24 months, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth by 22% (-0·90 mm2, -1·30 to -0·50; p<0·0001) and 18% (-0·74 mm2, -1·13 to -0·36; p=0·0002) in OAKS, and by 19% (-0·75 mm2, -1·15 to -0·34; p=0·0004) and 16% (-0·63 mm2, -1·05 to -0·22; p=0·0030) in DERBY, respectively, compared with sham. There were no differences in key secondary visual function endpoints at 24 months. Serious ocular treatment-emergent adverse events were reported in five (2%) of 213, four (2%) of 212, and one (<1%) of 211 patients in OAKS, and in four (2%) of 206, two (1%) of 208, and two (1%) of 206 patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. New-onset exudative age-related macular degeneration was reported in 24 (11%), 16 (8%), and four (2%) patients in OAKS, and in 27 (13%), 12 (6%), and nine (4%) patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. INTERPRETATION: Pegcetacoplan, the first treatment approved by the US Food and Drug Administration for geographic atrophy, slowed geographic atrophy lesion growth with an acceptable safety profile. FUNDING: Apellis Pharmaceuticals.

Progression of Polypoidal Lesions Associated with Exudative Recurrence in Polypoidal Choroidal Vasculopathy.

PURPOSE: To investigate the characteristics of the branching vascular network (BVN) and polypoidal lesions in polypoidal choroidal vasculopathy (PCV) to determine near-term indicators that may predict exudative recurrence. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with PCV receiving anti-vascular endothelial growth factor (VEGF) monotherapy or anti-VEGF plus photodynamic therapy were followed for at least 1 year using swept-source OCT angiography (SS-OCTA) imaging. METHODS: Patients were divided into 2 groups based on whether exudative recurrence occurred during follow-up. Multiple parameters were collected and compared between the 2 groups, such as age, gender, visual acuity, number of polypoidal lesions, lesion area at the first SS-OCTA visit, and total lesion area change from the first SS-OCTA visit to the last SS-OCTA visit. To evaluate the association between SS-OCTA imaging-based risk factors and the exudative recurrences, imaging features associated with PCV such as BVN growth and polypoidal lesion progression (enlargement, new appearance, and reappearance) at each follow-up visit were analyzed. The time intervals from the nonexudative visit with lesion progression to the corresponding exudative recurrence visit were documented to explore their association with exudative recurrences. Cox regression and logistic regression analyses were used. MAIN OUTCOME MEASURES: Association between BVN growth and polypoidal lesion progression with exudative recurrence. RESULTS: Thirty-one eyes of 31 patients (61% men) were included. Sixteen eyes had no recurrence of exudation, and 15 eyes had recurrence during follow-up. The average follow-up duration was 20.55 ± 6.86 months (range, 12-36 months). Overall, the recurrence group had worse best-corrected visual acuity (P = 0.019) and a greater increase in lesion area (P = 0.010). Logistical regression analysis showed that polypoidal lesion progression, including new appearance, enlargement, and reappearance of polypoidal lesions, was associated with exudative recurrences within 3 months (odds ratio, 26.67, 95% confidence interval, 3.77-188.54, P = 0.001). CONCLUSIONS: Growth of nonexudative BVN and progression of polypoidal lesions were found to be lesion characteristics associated with exudative recurrences, and progression of polypoidal lesions might serve as a stand-alone indicator for the near-term onset of exudation. In PCV, more frequent follow-up visits are recommended when polypoidal lesions show progression.

INTRAOCULAR INFLAMMATION INCIDENCE AFTER INTRAVITREAL BROLUCIZUMAB INJECTION FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: We evaluated the clinical outcomes of intraocular inflammation (IOI) of eyes with neovascular age-related macular degeneration (AMD) injected with brolucizumab in our tertiary referral center. METHODS: A retrospective case series for which clinical records of all eyes that received intravitreal brolucizumab at Bascom Palmer Eye Institute between December 1, 2019, and April 1, 2021, were reviewed. RESULTS: There were 345 eyes of 278 patients who received 801 brolucizumab injections. IOI was detected in 16 eyes of 13 patients (4.6%). In those patients, baseline Logarithm of Minimu Angle of Resolution (logMAR) best-corrected visual acuity was 0.32 0.2 (20/42), while it was 0.58 0.3 (20/76) at IOI presentation. The mean number of injections among eyes experiencing IOI was 2.4, and the interval between the last brolucizumab injection and IOI presentation was 20 days. There was no known case of retinal vasculitis. Management of IOI included topical steroids in seven eyes (54%), topical and systemic steroids in five eyes (38%), and observation in one eye (8%). Best-corrected visual acuity returned to baseline and inflammation resolved in all eyes by the last follow-up examination. CONCLUSION: Intraocular inflammation after brolucizumab injection for neovascular AMD was not uncommon. Inflammation resolved in all eyes by the last follow-up visit.

Longitudinal quantification of choriocapillaris flow deficits in persistent placoid maculopathy: a case report.

BACKGROUND: Persistent placoid maculopathy (PPM) is a rare idiopathic chorioretinopathy characterized by choriocapillaris (CC) hypoperfusion. In a case of PPM, we quantified CC flow deficits (FDs) over time and observed an increase in CC perfusion as the visual acuity and outer photoreceptor anatomy improved. CASE PRESENTATION: A 58-year-old man was diagnosed with PPM in both eyes based on the patient's clinical presentation and imaging. He presented with sudden-onset central scotomas in both eyes for about two months. On referral, the best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/100 in the left eye. Plaque-like yellowish macular lesions were observed bilaterally and autofluorescence imaging showed bilateral hyperautofluorescent lesions. Fluorescein angiography (FA) revealed early-phase hyper-fluorescent staining that intensified in the late phases, while indocyanine green angiography (ICGA) displayed persistent hypofluorescence in both eyes. Foveal centered swept source optical coherence tomography (SS-OCT) B-scans showed bilateral focal deposits on the level of retinal pigment epithelium (RPE) and disruption of outer photoreceptor bands. The CC FDs were quantified on SS-OCT angiography (SS-OCTA) images using a previously published algorithm that was validated. The CC FD% was 12.52% in the right eye and 14.64% in the left eye within a 5 mm circle centered on the fovea. After 5 months of steroid treatment, BCVA remained 20/20 in the right eye and improved to 20/25 in the left eye. On OCT imaging, the outer photoreceptor bands fully recovered in both eyes, while some focal deposits remained along the RPE in the left eye. The CC perfusion in both eyes improved, with CC FD% decreasing from 12.52% to 9.16% in the right eye and from 14.64% to 9.34% in the left eye. CONCLUSIONS: Significant impairment of macular CC perfusion was detected after the onset of PPM. Improvement in central macular CC perfusion corresponded with improvements in BCVA and outer retinal anatomy. Our findings suggest that imaging and quantification of CC FDs could serve as a valuable imaging strategy for diagnosing PPM and for following disease progression.

LONGITUDINAL ANALYSIS OF DIABETIC CHOROIDOPATHY IN PROLIFERATIVE DIABETIC RETINOPATHY TREATED WITH PANRETINAL PHOTOCOAGULATION USING WIDEFIELD SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Widefield swept-source optical coherence tomography (OCT) imaging was used to characterize choroidal thickness and vascularity at baseline in proliferative diabetic retinopathy (PDR) and longitudinally after panretinal photocoagulation (PRP). METHODS: Patients with treatment-naive PDR were imaged at baseline and at 1 week, 1 month, and 3 months after PRP. Previously validated algorithms were used to calculate the mean choroidal thickness (MCT) and choroidal vascularity index (CVI) in 5 regions of 12 mm × 12 mm scans. RESULTS: Fourteen PDR eyes were included. Baseline MCT in PDR eyes did not differ significantly from normal eyes, but CVI measurements in PDR eyes were lower in all regions (P < 0.001-0.008). After PRP, MCT measurements in PDR eyes were significantly lower at 1 month and 3 months in all regions (P < 0.001-0.005) except the fovea (P = 0.074). However, CVI measurements did not change over time in any region after PRP. CONCLUSION: The choroid in PDR eyes has a smaller CVI than that in normal eyes. After PRP, the choroidal thickness decreases outside the fovea, but the CVI remains constant, which suggests that a relative decrease in choroidal vascularity persists. These widefield swept-source OCT results are consistent with choroidal alterations found in histopathological reports of diabetic choroidopathy.

CHANGE IN CHORIOCAPILLARIS FLOW DEFICITS WITHIN TEARS OF THE RETINAL PIGMENT EPITHELIUM IMAGED WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: Choriocapillaris (CC) flow deficits (FDs) were measured in the areas exposed by tears of the retinal pigment epithelium (RPE) before and after their onset to determine their change over time. METHODS: Patients enrolled in a prospective, swept-source optical coherence tomography angiography (SS-OCTA) study were retrospectively reviewed for RPE tears, and scans were evaluated before and after RPE tear formation. Choriocapillaris flow deficits were measured within the bed of the tear and within a symmetric control region. RESULTS: Three patients with RPE tears were imaged before tear formation and for at least 16 months afterward. When the baseline and first posttear visit were compared, CC FDs decreased by 1.0% in the tear region and 1.7% in the control region ( P = 0.84). When the 16-month follow-up visits were compared with the first post-RPE tear visits, CC FDs decreased by 1.9% in tear regions and increased by 1.3% in control regions ( P = 0.37). CONCLUSION: No significant changes in CC FDs were observed before and after RPE tear formation and for 16 months afterward, suggesting that CC FDs can be reliably detected in the presence of an intact RPE and the absence of the RPE did not affect CC perfusion for at least 16 months.

SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY DETECTION OF BRUCH MEMBRANE AND CHORIOCAPILLARIS ABNORMALITIES IN SORSBY MACULAR DYSTROPHY.

PURPOSE: Swept-source optical coherence tomography angiography (SS-OCTA) was used to analyze Bruch membrane (BM) and choriocapillaris (CC) abnormalities in undiagnosed family members with Sorsby macular dystrophy (SMD). METHODS: In a family with SMD ( TIMP3 Tyr191Cys), SS-OCTA imaging was performed using the 6 × 6 mm scan patter and previously validated algorithms to detect abnormalities in BM and the CC, as well as the presence of reticular pseudodrusen and macular neovascularization. Genetic analyses were performed for TIMP3 mutations. RESULTS: Of eight family members, two were previously diagnosed with SMD and six were asymptomatic. SS-OCTA imaging of the 33-year-old proband revealed type 1 macular neovascularization in the left eye and bilateral reticular pseudodrusen, thickening of BM, CC thinning, and increases in CC flow deficits. A TIMP3 mutation was confirmed. His niece, despite having no clinical evidence of SMD, showed BM thickening and CC thinning on SS-OCTA. A TIMP3 mutation was confirmed. The proband's younger nephew and niece also carried the TIMP3 mutation without clinical evidence of SMD. Two additional members had normal examinations, unremarkable SS-OCTA findings, and no TIMP3 mutation. CONCLUSION: Swept-source optical coherence tomography angiography imaging can detect BM and CC abnormalities in vivo in subjects unaware of their TIMP3 status in a family with SMD.

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial. DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA). SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246. INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period. MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity. RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy. CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

WIDE-FIELD SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF DIABETIC TRACTIONAL RETINAL DETACHMENTS BEFORE AND AFTER SURGICAL REPAIR.

PURPOSE: Wide-field (WF) swept-source (SS) optical coherence tomography angiography (SS-OCTA) was used to image diabetic tractional retinal detachments (TRDs) before and after pars plana vitrectomy. The clinical utility of SS-OCTA was assessed. METHODS: Patients with diabetic TRDs were imaged prospectively with SS-OCTA. Ultrawide-field imaging was obtained when possible. Postoperative WF SS-OCTA imaging was performed. RESULTS: From January 2018 through December 2019, 31 eyes of 21 patients with diabetic TRDs were imaged. Wide-field SS-OCTA en-face images captured all areas of TRD and fibrovascular proliferation within the posterior pole that were visualized on ultrawide-field imaging. Optical coherence tomography angiography B-scans revealed the vascularity of preretinal membranes and identified areas of vitreoretinal traction and posterior vitreous detachment. Ten eyes underwent pars plana vitrectomy. Postoperative SS-OCTA imaging demonstrated removal of fibrovascular membranes, relief of traction, and resolution of TRDs. Retinal ischemia before and after surgical repair appeared similar. CONCLUSION: All clinically relevant features of diabetic TRDs were identified at baseline and assessed longitudinally after pars plana vitrectomy using WF SS-OCTA, which showed resolution of vitreoretinal traction and no apparent change in the status of retinal perfusion after surgery. If the media are clear and fixation is adequate, WF SS-OCTA is likely the only imaging modality needed for the diagnosis and longitudinal evaluation of diabetic TRDs.

Vision Loss after Intravitreal Injection of Autologous "Stem Cells" for AMD.

Adipose tissue-derived "stem cells" have been increasingly used by "stem-cell clinics" in the United States and elsewhere to treat a variety of disorders. We evaluated three patients in whom severe bilateral visual loss developed after they received intravitreal injections of autologous adipose tissue-derived "stem cells" at one such clinic in the United States. In these three patients, the last documented visual acuity on the Snellen eye chart before the injection ranged from 20/30 to 20/200. The patients' severe visual loss after the injection was associated with ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, combined traction and rhegmatogenous retinal detachment, or lens dislocation. After 1 year, the patients' visual acuity ranged from 20/200 to no light perception.

Structural OCT Signs Suggestive of Subclinical Nonexudative Macular Neovascularization in Eyes with Large Drusen.

PURPOSE: To further define the structural OCT features described as the "double-layer sign" suggestive of subclinical, nonexudative macular neovascularization (NE-MNV) in asymptomatic eyes with age-related macular degeneration (AMD). DESIGN: Cross-sectional observational study. PARTICIPANTS: Participants with large drusen (>125 µm) secondary to AMD in at least 1 eye. METHODS: Participants in a "discovery" cohort, with known NE-MNV identified on swept-source (SS) OCT angiography (OCTA) and the "double-layer sign" on structural spectral-domain OCT (SD-OCT) imaging, were used to identify characteristic features of this sign. These features were then assessed by masked grading in an "evaluation" cohort of AMD eyes with large drusen to determine the predictive values for NE-MNV. MAIN OUTCOME MEASURES: Description of OCT features associated with an increased risk of NE-MNV and their diagnostic and predictive performance. RESULTS: The discovery cohort of 4 eyes revealed that in retinal pigment epithelium (RPE) elevations with a greatest transverse linear dimension of 1000 µm or more, an irregular RPE layer with a height of predominantly less than 100 µm, and a nonhomogenous internal reflectivity as characteristic features of the double-layer sign when NE-MNV was present. We term these collective features as a shallow, irregular RPE elevation (SIRE). Features on OCT images from 233 eyes in the evaluation cohort that were associated significantly with NE-MNV when the RPE elevation was more than 1000 µm in length were: height of the RPE elevation, overall flat or variable morphologic features, RPE layer irregularity, and nonhomogeneous reflectivity (all P ≥ 0.032). Twenty-four eyes (10.3%) were identified with a SIRE. On SS-OCTA imaging, 6 of the 233 eyes were found to have definite NE-MNV, and all 6 graded positively for SIRE (sensitivity, 100%). The absence of SIRE was identified in 209 of 227 eyes without NE-MNV (specificity, 92.1%). The positive predictive value for SIRE was 25% and the negative predictive value was 100%. CONCLUSIONS: Eyes whose OCT images display a SIRE sign are at higher risk of having subclinical NE-MNV. SIRE can be used as a screening tool on routine structural OCT imaging. More frequent follow-up and diligent home monitoring is recommended for those with SIRE.

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial.

PURPOSE: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN: Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS: Two hundred forty-six patients with GA. METHODS: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.

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.

Presence or absence of choroidal hyper-transmission by SD-OCT imaging distinguishes inflammatory from neovascular lesions in myopic eyes.

PURPOSE: To compare the characteristics of choroidal transmission in punctate inner choroidopathy (PIC) with or without choroidal neovascularization (CNV) and myopic CNV (mCNV) using spectral domain optical coherence tomography (SD-OCT). METHODS: This retrospective observational case series includes 22 consecutive myopic patients (22 eyes) recruited from April 2016 until April 2018 who complained of acute blurring of vision and showed evidence of hyper-reflective material on SD-OCT imaging. Each patient underwent a comprehensive eye examination and imaging with fundus fluorescein angiography (FFA), SD-OCT, and SD-OCT angiography (SD-OCTA). Based on the results of SD-OCTA imaging and the color fundus imaging, the patients were divided into 2 groups: a group with myopic choroidal neovascularization (mCNV group, n = 10 eyes) and a group with PIC and no evidence of CNV at baseline (PIC group, n = 12 eyes). Four eyes diagnosed with PIC developed secondary PIC-CNV during follow-up. The characteristics of choroidal transmission in these eyes using SD-OCT imaging were compared. RESULTS: At baseline, none of the PIC lesions showed any evidence of blood flow within the lesions on OCTA imaging. However, all of the eyes with mCNV showed flow signals within the subretinal neovascularization on SD-OCTA and subretinal or intra-retinal fluid on SD-OCT imaging. These eyes with mCNV showed subretinal hyper-reflectivity associated with choroidal hypo-transmission accompanied by retinal pigment epithelium (RPE) and ellipsoid zone (EZ) disruption. In eyes with PIC inflammatory lesions, disruption of both the RPE and EZ were observed in 33% of the inflammatory lesions, and disruption of the EZ alone was observed in 67% of the lesions at the baseline. They all showed a hyper-reflective subretinal lesion located above RPE. Three cases (25%) showed evidence of choroidal hyper-transmission at the baseline, while the remaining had normal transmission within the first month after onset. Hyper-transmission then developed in all the lesions as the disease progressed. Four cases of PIC (33%) developed PIC-related CNV that showed choroidal hypo-transmission along with hyper-transmission with disruption of the RPE and EZ. In cases with PIC-related CNV, evidences of neovascularization on SD-OCTA imaging were all detected afterwards. No intra-retinal fluid was detected before secondary CNV occurred. CONCLUSION: SD-OCT imaging can noninvasively differentiate and track the progression of inflammatory lesions and myopic CNV by using the presence of choroidal hyper-transmission as a sign of just an inflammatory lesion and the presence hypo-transmission as a sign of a secondary CNV, which provides a convenient strategy for diagnosis and treatment of these lesions.

A2E Distribution in RPE Granules in Human Eyes.

A2E (N-retinylidene-N-retinylethanolamine) is a major fluorophore in the RPE (retinal pigment epithelium). To identify and characterize A2E-rich RPE lipofuscin, we fractionated RPE granules from human donor eyes into five fractions (F1-F5 in ascending order of density) by discontinuous sucrose density gradient centrifugation. The dry weight of each fraction was measured and A2E was quantified by liquid chromatography/mass spectrometry (LC/MS) using a synthetic A2E homolog as a standard. Autofluorescence emission was characterized by a customer-built spectro-fluorometer system. A significant A2E level was detected in every fraction, and the highest level was found in F1, a low-density fraction that makes up half of the total weight of all RPE granules, contains 67% of all A2E, and emits 75% of projected autofluorescence by all RPE granules. This group of RPE granules, not described previously, is therefore the most abundant RPE lipofuscin granule population. A progressive decrease in autofluorescence was observed from F2 to F4, whereas no autofluorescence emission was detected from the heavily pigmented F5. The identification of a novel and major RPE lipofuscin population could have significant implications in our understanding of A2E and lipofuscin in human RPE.

Effect of Ciliary Neurotrophic Factor on Retinal Neurodegeneration in Patients with Macular Telangiectasia Type 2: A Randomized Clinical Trial.

PURPOSE: To test the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary neurotrophic factor (CNTF), on progression of macular telangiectasia type 2, a neurodegenerative disease with no proven effective therapy. DESIGN: Randomized sham-controlled clinical trial. PARTICIPANTS: Ninety-nine study eyes of 67 eligible participants were enrolled. METHODS: Single-masked randomized clinical trial of 24 months' duration conducted from May 2014 through April 2017 in 11 clinical centers of retinal specialists in the United States and Australia. Participants were randomized 1:1 to surgical implantation of intravitreal sustained delivery of human CNTF versus a sham procedure. MAIN OUTCOME MEASURES: The primary outcome was the difference in the area of neurodegeneration as measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral-domain (SD) OCT images at 24 months from baseline between the treated and untreated groups. Secondary outcomes included comparison of visual function changes between treatment groups. RESULTS: Among the 67 participants who were randomized (mean age, 62±8.9 years; 41 women [61%]; 58 white persons [86%]), 65 (97%) completed the study. Two participants (3 study eyes) died and 3 participants (4 eyes) were found ineligible. The eyes receiving sham treatment had 31% greater progression of neurodegeneration than the CNTF-treated eyes. The difference in mean area of photoreceptor loss was 0.05±0.03 mm2 (P = 0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were correlated highly with the changes in the area of photoreceptor loss (r = 0.86; P < 0.0001). The mean retinal sensitivity loss of the sham group was 45% greater than that of the treated group (decrease, 15.81±8.93 dB; P = 0.07). Reading speed deteriorated in the sham group (-13.9 words per minute) with no loss in the treated group (P = 0.02). Serious adverse ocular effects were found in 2 of 51 persons (4%) in the sham group and 2 of 48 persons (4%) in the treated group. CONCLUSIONS: In participants with macular telangiectasia type 2, a surgical implant that released CNTF into the vitreous cavity, compared with a sham procedure, slowed the progression of retinal degeneration. Further research is needed to assess longer-term clinical outcomes and safety.

Emixustat Hydrochloride for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Clinical Trial.

PURPOSE: To determine whether emixustat hydrochloride (emixustat) reduces the rate of enlargement of geographic atrophy (GA) compared with placebo in subjects with age-related macular degeneration (AMD) and to evaluate the safety and tolerability of emixustat over 24 months of treatment. DESIGN: Multicenter, randomized, double-masked, placebo-controlled, phase 2b/3 clinical trial. PARTICIPANTS: Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.25 to 18 mm2 were enrolled. METHODS: Subjects were randomized (1:1:1:1) to emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for 24 months. Visits included screening, baseline, and months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, and 25. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean annual growth rate of total GA area in the study eye, as measured by a central reading center using fundus autofluorescence (FAF) images. The change from baseline in normal luminance best-corrected visual acuity (NL-BCVA) was a secondary efficacy end point. RESULTS: Of 508 randomized subjects, 320 completed the study. Demographics and baseline characteristics were comparable between treatment groups. On average, GA lesions in the study eye grew at a similar rate in each group (emixustat: 1.69 to 1.84 mm2/year; placebo: 1.69 mm2/year; P ≥ 0.81). Changes in NL-BCVA were also comparable between groups. Subjects with a larger low luminance deficit (LLD) at baseline (≥20 letters) demonstrated a more rapid growth of GA over 24 months. No relationship was observed between the risk-allele status of the AMD-associated single-nucleotide polymorphisms tested and the growth rate of GA. The most common adverse events in emixustat-treated subjects were delayed dark adaptation (55%), chromatopsia (18%), visual impairment (15%), and erythropsia (15%). CONCLUSIONS: Emixustat did not reduce the growth rate of GA in AMD. The most common adverse events were ocular in nature and likely related to the drug's mechanism of action. Data gained from this study over a 2-year period add to the understanding of the natural history of GA and the baseline characteristics affecting the growth rate of GA.

Natural History of Subclinical Neovascularization in Nonexudative Age-Related Macular Degeneration Using Swept-Source OCT Angiography.

PURPOSE: Swept-source (SS) OCT angiography (OCTA) was used to determine the prevalence, incidence, and natural history of subclinical macular neovascularization (MNV) in eyes with nonexudative age-related macular degeneration (AMD). DESIGN: Prospective, observational, consecutive case series. PARTICIPANTS: Patients with intermediate AMD (iAMD) or geographic atrophy (GA) secondary to nonexudative AMD in 1 eye and exudative AMD in the fellow eye. METHODS: All patients were imaged using both the 3×3 mm and 6×6 mm SS OCTA fields of view (PLEX Elite 9000; Carl Zeiss Meditec, Inc, Dublin, CA). The en face slab used to detect the MNV extended from the outer retina to the choriocapillaris, and projection artifacts were removed using a proprietary algorithm. MAIN OUTCOME MEASURES: Prevalence of subclinical MNV and time to exudation with Kaplan-Meier cumulative estimates of exudation at 1 year. RESULTS: From August 2014 through March 2017, 160 patients underwent SS OCTA (110 eyes with iAMD and 50 eyes with GA). Swept-source OCTA identified subclinical MNV at the time of first imaging in 23 of 160 eyes, for a prevalence of 14.4%. Six eyes demonstrated subclinical MNV during the follow-up. Of 134 eyes with follow-up visits, a total of 13 eyes demonstrated exudation, and of these 13 eyes, 10 eyes were found to have pre-existing subclinical MNV. By 12 months, the Kaplan-Meier cumulative incidence of exudation for all 134 eyes was 6.8%. For eyes with subclinical MNV at the time of first SS OCTA imaging, the incidence was 21.1%, and for eyes without subclinical MNV, the incidence was 3.6%. There was no difference in the cumulative incidence of exudation from pre-existing MNV in eyes with iAMD or GA (P = 0.847, log-rank test). After the detection of subclinical MNV, the risk of exudation was 15.2 times (95% confidence interval, 4.2-55.4) greater compared with eyes without subclinical MNV. CONCLUSIONS: By 12 months, the risk of exudation was greater for eyes with documented subclinical MNV compared with eyes without detectable MNV. For eyes with subclinical MNV, recommendations include more frequent follow-up and home monitoring. Intravitreal therapy is not recommended until prospective studies are performed.

Progression of Geographic Atrophy in Age-related Macular Degeneration: AREDS2 Report Number 16.

PURPOSE: To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. DESIGN: Prospective cohort study within a controlled clinical trial. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years. METHODS: Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. MAIN OUTCOME MEASURES: (1) Presence or development of GA; (2) change in the square root of GA area over time. RESULTS: At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes. CONCLUSIONS: Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.