Voretigene neparvovec for inherited retinal dystrophy due to RPE65 mutations: a scoping review of eligibility and treatment challenges from clinical trials to real practice.

Biallelic mutations in the RPE65 gene affect nearly 8% of Leber Congenital Amaurosis and 2% of Retinitis Pigmentosa cases. Voretigene neparvovec (VN) is the first gene therapy approach approved for their treatment. To date, real life experience has demonstrated functional improvements following VN treatment, which are consistent with the clinical trials outcomes. However, there is currently no consensus on the characteristics for eligibility for VN treatment. We reviewed relevant literature to explore whether recommendations on patient eligibility can be extrapolated following VN marketing. We screened 166 papers through six research questions, following scoping reviews methodology, to investigate: (1) the clinical and genetic features considered in VN treatment eligibility; (2) the psychophysical tests and imaging modalities used in the pre-treatment and follow-up; (3) the potential correlations between visual function and retinal structure that can be used to define treatment impact on disease progression; (4) retinal degeneration; (5) the most advanced testing modalities; and (6) the impact of surgical procedure on treatment outcomes. Current gaps concerning patients' eligibility in clinical settings, such as pre-treatment characteristics and outcomes are not consistently reported across the studies. No upper limit of retinal degeneration can be defined as the univocal factor in patient eligibility, although evidence suggested that the potential for function rescue is related to the preservation of photoreceptors before treatment. In general, paediatric patients retain more viable cells, present a less severe disease stage and show the highest potential for improvements, making them the most suitable candidates for treatment.

Anterior Vitreous Objective Assessment in Uveitis: An Anterior Segment Swept Source Optical Coherence Tomography Study.

PURPOSE: To assess inflammatory changes in the anterior vitreous (AV) using a swept source anterior segment optical coherence tomography (SS-ASOCT) and to correlate them with uveitis features and clinical grading of intraocular inflammation. METHODS: 140 eyes from 96 patients were included in this observational, cross-sectional study: 40 ACTIVE uveitis, 40 INACTIVE uveitis and 60 CONTROLS. All eyes underwent intraocular inflammation clinical grading (anterior chamber (AC) cells counting and vitreous haze evaluation) and AV imaging with SS-ASOCT. Cells seen in the AV on OCT were manually counted using imageJ. Vitreous reflectivity variation was indirectly measured by calculating the vitreous/iris pigment epithelium (VIT/IPE) relative intensity. These OCT-based parameters were compared across the groups and correlated with inflammation clinical grading. RESULTS: The mean [SD] number of AV OCT cells was significantly higher (both p < 0.001) in ACTIVE uveitis (12[9.8]) compared to INACTIVE uveitis (4.5[3.5]) and CONTROLS (4[3.1]). In ACTIVE uveitis the number of AV OCT cells was significantly and positively correlated with the AC cells (p = 0.04), the VIT/IPE relative intensity (p = 0.0002), the uveitis anatomical classification (INTERMEDIATE UVEITIS, p = 0.02) and the vitreous haze clinical grading (p < 0.0001). The mean[SD] VIT/IPE relative intensity of the AV increased from CONTROLS (0.12[0.01]) to INACTIVE uveitis (0.15[0.01]) to ACTIVE uveitis (0.17[0.02]), but with no statistically significant differences. CONCLUSIONS: We were able to visualize and objectively evaluate changes occurring in the AV in eyes with uveitis by means of a commercially available SS-ASOCT. OCT-cells in the AV could represent an adjunctive tool in the objective evaluation of intraocular inflammation.

Resolution of epiretinal membrane after anti-VEGF and photodynamic therapy of retinal hemangioblastoma.

Purpose: To describe the clinical and multimodal imaging features in a case of resolution of pre-macular fibrosis after photodynamic therapy (PDT) of retinal hemangioblastoma (RH) not related to von-Hippel-Lindau (VHL). Observations: A 25-year-old man presenting with blurred vision and central metamorphopsia in his left eye (LE) due to macular epiretinal membrane secondary to a peripheral RH. The patient had a comprehensive ophthalmic examination, including best corrected visual acuity (BCVA), wide-field fundus photography and autofluorescence (FAF), wide-field optical coherence tomography (OCT) and OCT angiography (OCTA), fluorescein angiography (FA) and indocyanine green angiography (ICGA) and ocular ultrasound. Baseline BCVA was 20/200 in his LE, and it improved to 20/40 nineteen months after anti-VEGF and photodynamic therapy were performed. The treatment led to a progressive shrinkage of the tumor and associated intraretinal exudation, and to a progressive resolution of the epiretinal membrane. Conclusions and importance: Treatments performed on the peripheral retina may result in changes at the level of the vitreo-retinal interface in the macular region. In our patient, after an intravitreal anti-VEGF associated with PDT, a posterior vitreous detachment (PVD) was induced resulting in auto-peeling of the macular epiretinal membrane secondary to a peripheral RH. An accurate assessment of the macular area by OCT is highly recommended in the first days following treatments.

Immunomodulatory Treatment Versus Systemic Steroids in Inflammatory Choroidal Neovascularization Secondary to Idiopathic Multifocal Choroiditis.

PURPOSE: To evaluate the influence of immunomodulatory therapy (IMT) on visual and treatment outcomes of inflammatory choroidal neovascularization (iCNV) in patients affected by multifocal choroiditis (MFC), and to compare them to patients treated with steroids as needed. DESIGN: Multicenter retrospective matched cohort study. METHODS: Patients affected by MFC with iCNV were divided into a IMT group and a "steroids as needed" group and matched according to the time between diagnosis and beginning of systemic treatment. Visual acuity (VA), number of anti-vascular endothelial growth factor (VEGF) intravitreal injections, and number of iCNV reactivations during 2 years of follow-up after treatment initiation were compared between the 2 groups. RESULTS: A total of 66 eyes of 58 patients were included, equally divided into the 2 groups. Patients in the IMT group had a lower relative risk (RR) of iCNV reactivation (0.64, P = .04) and of anti-VEGF intravitreal injection retreatment (0.59, P = .02). Relapses of MFC-related inflammation were independently associated with a higher RRs of iCNV reactivation (1.22, P = .003). Final VA was higher in the IMT compared to the steroids as needed group (mean [SD], 69.1 [15.1] vs 77.1 [8.9] letters, P = .01), and IMT was associated with greater VA gains over time (+2.5 letters per year, P = .04). CONCLUSIONS: IMT was associated with better visual and treatment outcomes in MFC complicated by iCNV compared to steroids as needed. The better outcomes of the IMT group and the association between MFC-related inflammation and iCNV reactivations highlight the need for tighter control of inflammation to prevent iCNV relapses and visual loss.

Lesion area progression in eyes with neovascular age-related macular degeneration treated using a proactive or a reactive regimen.

BACKGROUND: To compare the change in lesion area over 4 years of follow-up in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) agents using either a proactive or a reactive regimen in routine clinical practice. METHODS: This was a multicentre, retrospective comparative study. Totally, 202 treatment-naïve nAMD eyes (183 patients) received anti-VEGF therapy according to a proactive (n = 105) or reactive (n = 97) regimen. Eyes were included if they had received anti-VEGF injections for a period of at least 4 years and had baseline fluorescein angiography and annual optical coherence tomography (OCT) imaging. Two masked graders independently delineated the lesion's margins from serial OCT images and growth rates were calculated. RESULTS: At baseline, the mean [SD] lesion area was 7.24 [5.6] mm2 in the proactive group and 6.33 [4.8] mm2 in the reactive group respectively (p = 0.22). After four years of treatment, the mean [SD] lesion area in the proactive group was 5.16 [4.5] mm2 showing a significant reduction compared to the baseline (p < 0.001). By contrast, the mean [SD] lesion area kept expanding in the reactive group during the follow-up and was 9.24 [6.0] mm2 at four years (p < 0.001). The lesion area at 4 years was significantly influenced by treatment regimen, baseline lesion area, and proportion of visits with active lesions. CONCLUSIONS: Eyes treated using a reactive strategy had an increased lesion area and worse visual outcomes at 4 years. By contrast, the proactive regimen was associated with fewer recurrences of active disease, shrinkage of the lesion area, and better vision at four years.

CORRELATION BETWEEN MICROPERIMETRY AND IMAGING IN EXTENSIVE MACULAR ATROPHY WITH PSEUDODRUSEN-LIKE APPEARANCE.

PURPOSE: To determine the correlation between microperimetry and imaging findings in extensive macular atrophy with pseudodrusen-like appearance (EMAP). METHODS: This cross-sectional, observational study included 44 consecutive patients with EMAP (88 eyes) and 30 healthy subjects (60 eyes). Both groups underwent visual acuity assessment, mesopic and scotopic microperimetry, fundus photography, autofluorescence, optical coherence tomography, and optical coherence tomography angiography. Retinal sensitivity was also subdivided in macular (0-4°) and paramacular areas (8-10°). Scotopic sensitivity loss was defined as the difference between scotopic and mesopic sensitivities for each tested point. Eyes with EMAP were further classified into the three stages described by Romano et al: 19 eyes in Stage 1, 31 in Stage 2, and 38 in Stage 3. RESULTS: Mesopic and scotopic retinal sensitivity were significantly reduced in patients with EMAP compared with controls, particularly in the macular area (all P < 0.001). Mesopic retinal sensitivity progressively declined in more advanced EMAP stages (all P < 0.01), but no scotopic differences were observed between Stages 2 and 3 ( P = 0.08). Remarkably, scotopic sensitivity loss was significantly higher in Stage 1 ( P < 0.05).On multivariate analysis, mesopic dysfunction was associated with larger atrophic areas ( P < 0.01), foveal involvement ( P = 0.03), and fibrosis ( P = 0.02). Conversely, no independent variable was associated with a reduced scotopic retinal sensitivity (all P > 0.05). CONCLUSION: The findings highlight that patients with EMAP suffer from a severe cone- and rod-mediated dysfunction on microperimetry. The predominant rod impairment in the early cases (Stage 1) emphasizes the importance of dark-adapted scotopic microperimetry as a clinical end point and suggests defective transportation across the RPE-Bruch membrane complex in its pathogenesis.

MULTIMODAL RETINAL IMAGING REVEALS NEW PATHOGENIC INSIGHTS IN CENTRAL AREOLAR CHOROIDAL DYSTROPHY: A CASE SERIES.

PURPOSE: To describe novel imaging findings in a family affected by central areolar choroidal dystrophy. METHODS: Case series with multimodal retinal imaging assessment. RESULTS: A 19-year-old asymptomatic woman was referred for bilateral macular defects of the retinal pigment epithelium. Blue-light autofluorescence of her right eye revealed a speckled pattern in the macular area with a ring of decreased autofluorescence using near-infrared autofluorescence. Multimodal assessment of her left eye disclosed a single parafoveal spot of decreased pigmentation that was clearly visible as hyperautofluorescent using blue-light autofluorescence and as hypoautofluorescent using near-infrared autofluorescence. Optical coherence tomography angiography revealed several tiny areas of flow voids in correspondence of the retinal pigment epithelium alterations of both eyes. Three family members were recently diagnosed with presumed age-related macular degeneration and demonstrated well-demarcated areas of retinal pigment epithelium atrophy surrounded by yellowish deposits and a hypopigmented halo. Next-generation genetic analysis for inherited macular dystrophies was performed on the index case and the affected family members and revealed a p.Arg172Gln missense mutation in PRPH2 gene, leading to the diagnosis of central areolar choroidal dystrophy. CONCLUSION: Multimodal imaging can reveal new pathogenic insights in central areolar choroidal dystrophy. Of notice, near-infrared autofluorescence and optical coherence tomography angiography are able to detect retinal pigment epithelium hypopigmentation and choriocapillaris rarefaction, respectively, since the earliest stages of the disease.

Case report: Surgical management of vitreous obstruction following PreserFlo ® MicroShunt implantation.

Purpose: To describe a clinical case of lumen obstruction a few days after implantation of the PreserFlo® Microshunt which has been resolved by anterior vitrectomy. Observation: A 76-year-old patient with advanced and progressing primary open-angle glaucoma (POAG) presented ten days after PreserFlo® Microshunt implantation in his left eye with an intraocular pressure (IOP) of 24 mmHg because of vitreous obstruction. Anterior vitrectomy with 25 Gauge vitrector was performed to remove the vitreous using a bimanual technique with two corneal accesses. The surgery was successful in lowering uncontrolled IOP without device repositioning. A free lumen and a IOP in the low range of tens was observed during follow-up. Conclusions and importance: PreserFlo ® MicroShunt obstruction by vitreous in pseudophakic patient is a possible complication. Anterior vitrectomy without the need of tube repositioning was successful in lowering uncontrolled IOP.

Towards a Long-Read Sequencing Approach for the Molecular Diagnosis of RPGRORF15 Genetic Variants.

Sequencing of the low-complexity ORF15 exon of RPGR, a gene correlated with retinitis pigmentosa and cone dystrophy, is difficult to achieve with NGS and Sanger sequencing. False results could lead to the inaccurate annotation of genetic variants in dbSNP and ClinVar databases, tools on which HGMD and Ensembl rely, finally resulting in incorrect genetic variants interpretation. This paper aims to propose PacBio sequencing as a feasible method to correctly detect genetic variants in low-complexity regions, such as the ORF15 exon of RPGR, and interpret their pathogenicity by structural studies. Biological samples from 75 patients affected by retinitis pigmentosa or cone dystrophy were analyzed with NGS and repeated with PacBio. The results showed that NGS has a low coverage of the ORF15 region, while PacBio was able to sequence the region of interest and detect eight genetic variants, of which four are likely pathogenic. Furthermore, molecular modeling and dynamics of the RPGR Glu-Gly repeats binding to TTLL5 allowed for the structural evaluation of the variants, providing a way to predict their pathogenicity. Therefore, we propose PacBio sequencing as a standard procedure in diagnostic research for sequencing low-complexity regions such as RPGRORF15, aiding in the correct annotation of genetic variants in online databases.

Unveiling the Hidden: Early Manifestations of Extensive Macular Atrophy with Pseudodrusen-like appearance.

PURPOSE: To describe novel microperimetry and imaging findings in two patients affected by extensive macular atrophy with pseudodrusen-like appearance (EMAP) without signs of retinal pigment epithelium (RPE) atrophy. METHODS: Case series. Both patients underwent mesopic and dark-adapted two-color scotopic microperimetry, followed by multimodal imaging assessment including ultra-widefield photography, fundus autofluorescence (AF), high-resolution optical coherence tomography (Hi-Res OCT), OCT angiography and high-magnification module (HMM). RESULTS: Albeit normal visual acuity, both patients had a significant reduction of retinal sensitivity - especially under scotopic cyan conditions. One patient had macular pigment abnormalities, while the combination of blue and near-infrared AF modalities highlighted different patterns of pseudodrusen-like lesions.Of notice, Hi-Res OCT revealed a marked separation between the RPE and Bruch's membrane, containing a hyperreflective material with two different reflectivities. OCT angiography excluded the presence of macular neovascularization and documented several choriocapillaris flow voids. HMM images showed severe alteration of photoreceptors' mosaic in the perifovea. CONCLUSIONS: Our comprehensive assessment of two stage 1 EMAP patients revealed a predominant damage of perifoveal rods over areas of RPE-Bruch's membrane separation. These findings underscore the importance of basal laminar deposits in the initial stages of EMAP, contributing to a deeper understanding of its underlying mechanisms.

Clinical, Genotypic, and Imaging Characterization of the Spectrum of ABCA4 Retinopathies.

PURPOSE: To investigate the clinical and genotypic differences in the spectrum of ABCA4-associated retinopathies (ABCA4Rs). DESIGN: Observational, cross sectional case series. PARTICIPANTS: Sixty-six patients (132 eyes) carrying biallelic ABCA4 variants. METHODS: Patients underwent visual acuity measurement and multimodal imaging. Clinical records were reviewed for age at onset, presenting symptoms, genetic variants, and electroretinogram (ERG). Each eye was assigned to a phenotype based on age at onset, imaging and ERG: cone dystrophy-bull's-eye maculopathy (CD-BEM, 40 eyes), cone-rod dystrophy (CRD, 12 eyes), Stargardt disease (SD, 28 eyes), late-onset SD (LO-SD, 38 eyes), and fundus flavimaculatus (14 eyes). Images were analyzed for: peripapillary sparing, retinal pigment epithelium (RPE) atrophy (definitely decreased autofluorescence, DDAF), flecks patterns using autofluorescence; type of atrophy according to Classification of Atrophy Meeting reports, macular and choroidal thickness on OCT; and choriocapillaris flow deficits on OCT angiography. MAIN OUTCOME MEASURES: Primary outcome was to report the demographic, genotypic, and imaging characteristics of the different ABCA4R phenotypes. Secondary objectives included the assessment of imaging biomarkers as outcome measures for clinical trials. RESULTS: Age at onset was lower in CRD (12 ± 8 years) and higher in patients with LO-SD (59 ± 9 years) (all P < 0.01). Central vision loss was a common presenting symptom in CD-BEM and SD, whereas patients with LO-SD primarily complained of difficult dark adaptation. Missense variants were more frequent in CD-BEM, and splice site in CRD and LO-SD (P < 0.05). Peripapillary sparing was absent in 3 eyes with LO-SD (8%). Cone dystrophy-bull's-eye maculopathy eyes typically had complete outer retinal atrophy alterations (98%), whereas CRD and SD eyes showed both complete outer retinal atrophy and complete RPE and outer retinal atrophy (cRORA) (71%-100%). Patients with LO-SD had larger areas of DDAF (100% cRORA) and of choriocapillaris flow deficits (all P < 0.01). Repeatability of DDAF measurements was low for some phenotypes (CD-BEM and CRD) and atrophic areas <7.5 mm2. Resorbed flecks were significantly associated with CRD and LO-SD (P < 0.01). CONCLUSIONS: This research provides a thorough evaluation of the spectrum of ABCA4R. Our findings suggest that certain phenotypes show preferential photoreceptor degeneration (e.g., CD-BEM), whereas others have substantial RPE and choriocapillaris alterations (e.g., LO-SD). We recommend that clinical trial end points take into consideration these imaging features to improve the interpretation of their results. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial.

BACKGROUND: Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth. METHODS: GATHER2 is a randomised, double-masked, sham-controlled, 24-month, phase 3 trial across 205 retina clinics, research hospitals, and academic institutions globally. To be eligible, patients had to be aged 50 years or older with non-centrepoint-involving geographic atrophy and best corrected visual acuity between 20/25 and 20/320 in the study eye. Eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 µL intravitreal injection or sham for the first 12 months. Randomisation was performed using an interactive response technology system with stratification by factors known to be of prognostic importance in age-related macular degeneration. Patients, investigators, study centre staff, sponsor personnel, and data analysts were masked to treatment allocation. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. Efficacy and safety analyses were done in the modified intention-to-treat and safety populations, respectively. This trial is registered with ClinicalTrials.gov, NCT04435366. FINDINGS: Between June 22, 2020, and July 23, 2021, 1422 patients were screened for eligibility, of whom 448 were enrolled and randomly assigned to avacincaptad pegol 2 mg (n=225) or sham (n=223). One patient in the sham group did not receive study treatment and was excluded from analyses. There were 154 (68%) female patients and 71 (32%) male patients in the avacincaptad pegol 2 mg group, and 156 (70%) female patients and 66 (30%) male patients in the sham group. From baseline to month 12, the mean rate of square-root-transformed geographic atrophy area growth was 0·336 mm/year (SE 0·032) with avacincaptad pegol 2 mg and 0·392 mm/year (0·033) with sham, a difference in growth of 0·056 mm/year (95% CI 0·016-0·096; p=0·0064), representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group. Ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) in the sham group. There were no endophthalmitis, intraocular inflammation, or ischaemic optic neuropathy events over 12 months. To month 12, macular neovascularisation in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and nine (4%) in the sham group, with exudative macular neovascularisation occurring in 11 (5%) in the avacincaptad pegol 2 mg group and seven (3%) in the sham group. INTERPRETATION: Monthly avacincaptad pegol 2 mg was well tolerated and showed significantly slower geographic atrophy growth over 12 months than sham treatment, suggesting that avacincaptad pegol might slow disease progression and potentially change the trajectory of disease for patients with geographic atrophy. FUNDING: Iveric Bio, An Astellas Company.

Retromode Imaging Technology for Detecting Drusen-Like Deposits in Healthy Adults.

PURPOSE: To investigate the ability of retromode imaging technology to visualize drusen-like deposits (DLDs) in the macular region of healthy individuals without retinal diseases. Additionally, the correlation between subject age and the density of DLDs was assessed and their topographic distribution was evaluated. DESIGN: Prospective, observational, cross-sectional study SUBJECTS: Healthy volunteers (aged ≥ 35 years) without macular diseases. METHODS: This study evaluated macular images in healthy adults using color fundus photography (FP) and retromode imaging. Two masked graders counted the number of DLDs identifiable with each modality. The standardized ETDRS concentric rings were adopted to divide DLDs based on their topographic distribution. MAIN OUTCOME MEASURES: Comparison of the number of DLDs detected with each imaging modality. The association between DLDs and age. The topographic distribution of macular DLDs with retromode imaging. RESULTS: The study included 91 eyes of 52 healthy volunteers (mean ± standard deviation age, 57.9 ± 10.9 years; range, 36-82 years). Overall, at least 1 DLD was present in 63.74% of eyes on color FP and 96.71% on retromode. Retromode imaging allowed detection of significantly more DLDs compared with color FP within the ETDRS grid (median [interquartile range], 4 [1-14] vs. 0 [0-0] respectively; P < 0.001). The density of DLDs was higher in the outer and inner rings compared with the central subfield (relative risk [RR], 16.70; 95% confidence interval [CI], 10.3-27.3 vs. RR 17.1; 95% CI, 10.5-27.6, respectively). Age was significantly correlated with DLDs density in all 3 sectors (all P < 0.05). CONCLUSIONS: Retromode technology allowed the detection of a significantly higher number of DLDs compared with FP in the macula of healthy individuals. This noninvasive imaging modality could be used to investigate the effect of the aging process on the macula, fostering a better understanding of the pathophysiology of age-related macular diseases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

[The population affected by neovascular age-related macular degeneration and treated with anti-Vegf through Italian administrative healthcare data.] / La popolazione con degenerazione maculare neovascolare correlata all'età trattata con anti-Vegf attraverso i dati amministrativi sanitari.

INTRODUCTION: The neo-vascular age-related macular degeneration (nAmd) is a frequent cause of vision loss, although the intravitreal (Ivt) injections of anti-Vegf (vascular endothelial growth factor) have improved functional outcomes. This study has assessed the healthcare and economic burden on the Italian national health service (Inhs) for patients with nAmd and new users of anti-Vegf. METHODS: From the database of Fondazione Ricerca e Salute (ReS), people aged ≥55 and with an in-hospital diagnosis of nAmd and/or an injection of anti-Vegf (aflibercept, ranibizumab, pegaptanib; index date) in 2018 are selected. Those with other conditions treated with anti-Vegf and with an Ivt injection before 2018 are excluded. New users of anti-Vegf are analyzed by sex, age, comorbidities, Ivt administrations, switch of anti-Vegf, local outpatient specialist services (with some focuses) and direct healthcare costs charged to the Inhs Results. In 2018, of 8125 inhabitants aged ≥55 with nAmd (4.6x1000 inhab.; mean age 76±9; F: 50%), 1513 (19%) are new users of Ivt anti-Vegf (mean age 74±9), whose incidence (0.9x1000) increased with age until 84 years old. A proportion of 60.7% had ≥2 comorbidities (mainly hypertension, dyslipidemia and diabetes). Within the 2nd follow-up year, only 598 patients are still treated (60% were lost). On average, 4.8 Ivt injections in the first and 3.1 in the second year are registered. On average, the total cost charged to the Inhs per new user of anti-Vegf was € 6726 (Ivt anti-Vegf accounted for the 76%) and € 3282 (hospitalizations for causes different from nAmd accounted for the 47%), during the first and the second year, respectively. CONCLUSIONS: This analysis suggests that in Italy people with nAmd and new users of anti-Vegf are elderly, affected by many comorbidities, treated with Ivt anti-VEGF less than what is required and authorized to achieve a benefit, undergo very few follow-up outpatient specialist visits and tests and, within the 2nd year, their hospitalizations for causes different from nAmd mainly weighs on the total expenditure charged to the Inhs.

Utility of Anterior Segment OCT in the Management of Uveitic Cataract Surgery: A Fibrinoid Syndrome Case Treated with rtPA.

PURPOSE: To highlight the importance of swept-source anterior segment optical coherence tomography (SS-ASOCT) in the peri-surgical management of cataract in uveitis. To describe a case of fibrinoid syndrome in uveitis treated with recombinant tissue plasminogen activator (rtPA). METHODS: SS-ASOCT was performed at each follow-up before and after cataract surgery to assess anterior chamber inflammation and assist the clinical management of the patient. RESULTS: A patient with idiopathic autoimmune uveitis was scheduled for cataract surgery. SS-ASOCT allowed to correctly plan the surgery timing. The patient developed a severe fibrinoid syndrome. Postsurgical SS-ASOCT allowed to distinguish between anterior chamber cells and fibrin thus guiding the timing for rtPA intracameral injection. Visual acuity improved from 20/400 the day after the surgery to 20/40. CONCLUSION: SS-ASOCT allowed a precise assessment of the inflammatory components (cellular vs fibrinoid) after cataract surgery. Intracameral rtPA was safe and effective in the treatment fibrinoid syndrome in uveitis.

Ten-Year Incidence of Fibrosis and Risk Factors for Its Development in Neovascular Age-Related Macular Degeneration.

PURPOSE: To report the incidence and risk factors for fibrosis at 10 years in a large cohort of persons with neovascular age-related macular degeneration (nAMD). DESIGN: Retrospective, multicenter, cohort study. METHODS: We included 225 naive nAMD eyes that underwent intravitreal anti-vascular endothelial growth factor treatment over 10 years of follow-up at two Italian referral centers. Demographic and clinical data were reviewed at baseline and on an annual basis. Onset of fibrosis was defined by clinically assessing photographs, fundus descriptions, or fluorescein angiograms. Optical coherence tomography (OCT) scans of fibrosis were inspected by an external reading center and graded as subretinal pigment epithelium (RPE), mixed, or subretinal. RESULTS: The mean age at baseline was of 72.1 ± 6.9 years. The incidence rate of fibrosis was estimated to be 8.9 per 100 person-years, with a cumulative incidence of 62.7% at 10 years. Fibrotic lesions were sub-RPE in 46.1%, mixed in 29.8%, and subretinal in 22.7%. Independent factors associated with fibrosis included the following: larger central subfield thickness variation (P < .001), submacular hemorrhages (P = .008), higher number of injections (P = .01), and worse baseline visual acuity (VA) (P = .03). Type 2 macular neovascularization was significantly associated with mixed and subretinal fibrosis. VA significantly declined over 10 years (-16.4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters), particularly in eyes with mixed and subretinal fibrosis (P < .001). CONCLUSIONS: We identified a 62.7% cumulative incidence of fibrosis in a large nAMD cohort at 10 years. Fibrosis was more common with frequent reactivations and lower baseline VA; its onset had a significant impact on final VA. This supports the hypothesis that nAMD patients should be promptly treated with proactive regimens.