Navigated Focal Laser of Macular Telangiectasia Type I (Adult-Onset Coats' Disease).

We aimed to evaluate the anatomical and functional outcome of selective photocoagulation of idiopathic macular telangiectasia type 1 by navigated focal laser (Navilas, OD-OS GmBH). Consecutive patients with idiopathic macular telangiectasia type 1 were included in the analysis. All patients were treated with navigated focal laser, planned on multimodal imaging. Seven eyes of seven patients were retrospectively analyzed. Navigated laser photocoagulation of idiopathic macular telangiectasia type 1 successfully occluded the microaneurysms, inducing regression of macular edema and exudation, significative improvement in best-corrected visual acuity at 3 (P = 0.035) and 6 months (P = 0.034) and a decrease in central macular thickness at 3 (P = 0.01) and 6 months (P = 0.01). Patients with idiopathic macular telangiectasia type 1 are ideal candidates for navigated laser treatment. Navigated focal treatment has been shown to be effective and safe in occluding aneurysmal dilations without any side effects. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Deep Learning for prediction of late recurrence of retinal detachment using preoperative and postoperative ultra-wide field imaging.

PURPOSE: To elaborate a deep learning (DL) model for automatic prediction of late recurrence (LR) of rhegmatogenous retinal detachment (RRD) using pseudocolor and fundus autofluorescence (AF) ultra-wide field (UWF) images obtained preoperatively and postoperatively. MATERIALS AND METHODS: We retrospectively included patients >18 years who underwent either scleral buckling (SB) or pars plana vitrectomy (PPV) for primary or recurrent RRD with a post-operative follow-up >2 years. Records of RRD recurrence between 6 weeks and 2 years after surgery served as a ground truth for the training of the deep learning (DL) models. Four separate DL models were trained to predict LR within the 2 postoperative years (binary outputs) using, respectively, UWF preoperative and postoperative pseudocolor images and UWF preoperative and postoperative AF images. RESULTS: A total of 412 eyes were included in the study (332 eyes treated with PPV and 80 eyes with SB). The mean follow-up was 4.0 ± 2.1 years. The DL models based on preoperative and postoperative pseudocolor UWF imaging predicted recurrence with 85.6% (sensitivity 86.7%, specificity 85.4%) and 90.2% accuracy (sensitivity 87.0%, specificity 90.8%) in PPV-treated eyes, and 87.0% (sensitivity 86.7%, specificity 87.0%) and 91.1% (sensitivity 88.2%, specificity 91.9%) in SB-treated eyes, respectively. The DL models using preoperative and postoperative AF-UWF imaging predicted recurrence with 87.6% (sensitivity 84.0% and specificity 88.3%) and 91.0% (sensitivity 88.9%, specificity 91.5%) accuracy in PPV eyes, and 86.5% (sensitivity 87.5%; specificity 86.2%) and 90.6% (sensitivity 90.0%, specificity 90.7%) in SB eyes, respectively. Among the risk factors detected with visualisation methods, potential novel ones were extensive laser retinopexy and asymmetric staphyloma. CONCLUSIONS: DL can accurately predict the LR of RRD based on UWF images (especially postoperative ones), which can help refine follow-up strategies. Saliency maps might provide further insight into the dynamics of RRD recurrence.

KESTREL and KITE Phase 3 Studies: 100-Week Results With Brolucizumab in Patients With Diabetic Macular Edema.

PURPOSE: To report the 100-week outcomes from the KESTREL and KITE trials. DESIGN: Two phase 3, double-masked, active-controlled, randomized trials. METHODS: Patients with diabetic macular edema (DME) were randomized 1:1:1 to brolucizumab 3 mg/6 mg (BRO3/BRO6) or aflibercept 2 mg (AFL) in KESTREL (N = 566) or 1:1 to BRO6 or AFL in KITE (N = 360). BRO3/BRO6 arms received 5 loading doses every 6 weeks (q6w) followed by q12w dosing, with an option to adjust to q8w at predefined disease activity assessment visits. In KITE, at week 72, based on the disease stability assessment, treatment intervals could be extended by 4 weeks in the BRO6 arm. AFL arms received 5 monthly loading doses followed by fixed q8w dosing. RESULTS: At week 100, change from baseline in BCVA (letters) was +8.8 for BRO6 and +10.6 for AFL in KESTREL; and +10.9 for BRO6 and +8.4 for AFL in KITE. In both studies, fewer BRO6 subjects had intraretinal fluid and/or subretinal fluid than AFL subjects. Results were achieved with 32.9% (KESTREL) and 47.5% (KITE) of BRO6 subjects maintained on q12w and q12w/q16w dosing, respectively. Intraocular inflammation rates for BRO6 vs AFL were 4.2% vs 1.1% (KESTREL) and 2.2% vs 1.7% (KITE), of which retinal vasculitis rates were 0.5% vs 0% in KESTREL, with no cases in KITE. Retinal vascular occlusion rates were 1.6% vs 0.5% (KESTREL) and 0.6% in both treatment arms in KITE. CONCLUSIONS: Results show the long-term efficacy and durability of brolucizumab in improving visual and anatomical outcomes in DME; the overall safety profile of brolucizumab remained unchanged through year 2.

Refractive outcome in combined phacovitrectomy: Anterior segment changes and corrective factor for IOL power calculation improvement.

PURPOSE: To analyze differences in refractive outcome Δ (difference between postoperative and expected refractive error) and in anterior segment changes between cataract surgery patients and combined phacovitrectomy patients. We also aimed to provide a corrective formula allowing to minimise the refractive outcome Δ in combined surgery patients. METHODS: Candidates for phacoemulsification and combined phacovitrectomy (respectively PHACO and COMBINED groups) were prospectively enrolled in two specialised centres. Patients underwent best corrected visual acuity (BCVA) assessment, ultra-high speed anterior segment optical coherence tomography (OCT), gonioscopy, retinal OCT, slit lamp examination and biometry at baseline, 6 weeks postoperatively and 3 months postoperatively. RESULTS: No differences in refractive Δ, refractive error and anterior segment parameters were noted between PHACO and COMBINED group (109 and 110 patients respectively) at 6 weeks. At 3 months, COMBINED group showed a spherical equivalent of -0.29 ± 0.10 D versus -0.03 ± 0.15 D in PHACO group (p = 0.023). COMBINED group showed a significantly higher Crystalline Lens Rise (CLR), angle-to-angle (ATA) and anterior chamber width (ACW) and a significantly lower anterior chamber depth (ACD) and refractive Δ with all 4 considered formulas at 3 months. For IOL power lower than 15, a hyperopic shift was observed instead. CONCLUSIONS: Anterior segment OCT suggests anterior displacement of the effective lens position in patients undergoing phacovitrectomy. A corrective formula can be applied to IOL power calculation to minimize undesired refractive error.

Neuropathy, ataxia, retinitis pigmentosa: a case of a mother and two siblings.

AIM: We describe the ophthalmic manifestations of Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome in three related patients. METHODS: We examined a mother and her two children, who were carriers of the mt 8993T>G mutation. The mother, patient I, is the first known carrier within the family pedigree. Patients II and III are her children from a non-carrier father. NARP syndrome and the heteroplasmy levels were established prior to the first referral of the patients to the Ophthalmology department.We performed a visual acuity testing, followed by a biomicroscopic and fundus examination, as well as additional multimodal imaging testing: optical coherence tomography (OCT) and fundus autofluorescence (FAF), and functional testing: electroretinogram and visual field. RESULTS: All patients had the clinical manifestations of NARP syndrome, which were variably expressed symptomatically, on the fundus exams, electroretinogram, and visual fields. CONCLUSIONS: Once genetically established, NARP syndrome, as other mitochondrial disorders, has a very variable progression with different degrees of severity. A multimodal approach involving both neurological and ophthalmological diagnosis of NARP syndrome is necessary in order to establish the course of the disease and the measures to be taken.

The Impact of Diabetic Retinopathy on the Choriocapillaris in Neovascular AMD.

Purpose: To investigate the impact of diabetic retinopathy (DR) on morphological choriocapillaris (CC) modifications in eyes with type 1 macular neovascularization (MNV) secondary to AMD using optical coherence tomography angiography (OCTA). Methods: Eyes with AMD-related type 1 MNV with and without DR were prospectively included. We performed 3 × 3 mm OCTA scans at two visits: before the loading phase of intravitreal injections of aflibercept (T1) and 1 month after the last injection (T2). OCTA En face flow images of the CC were analyzed for flow deficit percentage (FD%), FD average area and FD number in a 500-µm-wide ring surrounding the dark halo (DH) around type 1 MNV. Results: A total of 65 eyes, out of which 30 eyes had mild DR, were included. In the group without diabetes, there was a gradual reduction in FD% in the CC ring around the DH after antiangiogenic therapy, indicating reperfusion of the CC (P = 0.003). However, in the DR group, there were no significant changes in CC parameters between the two study visits. Specifically, the FD% in the CC ring around the DH did not show a significant reduction at T2 compared with T1 values (P > 0.05). Furthermore, the comparison of the variation in FD% between the two groups was statistically significant. The nondiabetic group exhibited a gradual CC reperfusion after the loading phase of aflibercept, whereas the diabetic eyes did not show significant changes (P = 0.029). Conclusions: The CC surrounding the DH associated to type 1 MNV exhibited greater hypoperfusion in diabetic eyes compared with eyes without diabetes, both before starting therapy and after the loading phase. Hence, DR may be a potential risk factor in the development and progression of late-stage AMD and may also influence the response to antiangiogenic therapy.

Stargardt disease-associated in-frame ABCA4 exon 17 skipping results in significant ABCA4 function.

BACKGROUND: ABCA4, the gene implicated in Stargardt disease (STGD1), contains 50 exons, of which 17 contain multiples of three nucleotides. The impact of in-frame exon skipping is yet to be determined. Antisense oligonucleotides (AONs) have been investigated in Usher syndrome-associated genes to induce skipping of in-frame exons carrying severe variants and mitigate their disease-linked effect. Upon the identification of a STGD1 proband carrying a novel exon 17 canonical splice site variant, the activity of ABCA4 lacking 22 amino acids encoded by exon 17 was examined, followed by design of AONs able to induce exon 17 skipping. METHODS: A STGD1 proband was compound heterozygous for the splice variant c.2653+1G>A, that was predicted to result in in-frame skipping of exon 17, and a null variant [c.735T>G, p.(Tyr245*)]. Clinical characteristics of this proband were studied using multi-modal imaging and complete ophthalmological examination. The aberrant splicing of c.2653+1G>A was investigated in vitro in HEK293T cells with wild-type and mutant midigenes. The residual activity of the mutant ABCA4 protein lacking Asp864-Gly885 encoded by exon 17 was analyzed with all-trans-retinal-activated ATPase activity assay, along with its subcellular localization. To induce exon 17 skipping, the effect of 40 AONs was examined in vitro in WT WERI-Rb-1 cells and 3D human retinal organoids. RESULTS: Late onset STGD1 in the proband suggests that c.2653+1G>A does not have a fully deleterious effect. The in vitro splice assay confirmed that this variant leads to ABCA4 transcripts without exon 17. ABCA4 Asp864_Gly863del was stable and retained 58% all-trans-retinal-activated ATPase activity compared to WT ABCA4. This sequence is located in an unstructured linker region between transmembrane domain 6 and nucleotide-binding domain-1 of ABCA4. AONs were designed to possibly reduce pathogenicity of severe variants harbored in exon 17. The best AON achieved 59% of exon 17 skipping in retinal organoids. CONCLUSIONS: Exon 17 deletion in ABCA4 does not result in the absence of protein activity and does not cause a severe STGD1 phenotype when in trans with a null allele. By applying AONs, the effect of severe variants in exon 17 can potentially be ameliorated by exon skipping, thus generating partial ABCA4 activity in STGD1 patients.

Subretinal Pseudocysts: A Comprehensive Analysis of this Novel OCT Finding.

INTRODUCTION: In current clinical practice, several optical coherence tomography (OCT) biomarkers have been proposed for the assessment of severity and prognosis of different retinal diseases. Subretinal pseudocysts are subretinal cystoid spaces with hyperreflective borders and only a few single cases have been reported thus far. The aim of the study was to characterize and investigate this novel OCT finding, exploring its clinical outcome. METHODS: Patients were evaluated retrospectively across different centers. The inclusion criterion was the presence of subretinal cystoid space on OCT scans, regardless of concurrent retinal diseases. Baseline examination was set as the first time the subretinal pseudocyst was identified by OCT. Medical and ophthalmological histories were collected at baseline. OCT and OCT-angiography were performed at baseline and at each follow-up examination. RESULTS: Twenty-eight eyes were included in the study and 31 subretinal pseudocysts were characterized. Out of 28 eyes, 16 were diagnosed with neovascular age-related macular degeneration (AMD), 7 with central serous chorioretinopathy, 4 with diabetic retinopathy, and 1 with angioid streaks. Subretinal and intraretinal fluid were present in 25 and 13 eyes, respectively. Mean distance of the subretinal pseudocyst from the fovea was 686 µm. The diameter of the pseudocyst was positively associated with the height of the subretinal fluid (r = 0.46; p = 0.018) and central macular thickness (r = 0.612; p = 0.001). At follow-up, subretinal pseudocysts disappeared in most of the reimaged eyes (16 out of 17). Of these, two patients presented retinal atrophy at baseline examination and eight patients (47%) developed retinal atrophy at follow-up. Conversely, seven eyes (41%) did not develop retinal atrophy. CONCLUSION: Subretinal pseudocysts are precarious OCT findings, usually disclosed in a context of subretinal fluid, and are probably transient alterations within the photoreceptor outer segments and retinal pigment epithelium (RPE) layer. Despite their nature, subretinal pseudocysts have been associated with photoreceptor loss and incomplete RPE definition.

IMPACT OF RETINAL FLUID-FREE MONTHS ON OUTCOMES IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Treatment Agnostic Analysis of the HAWK and HARRIER Studies.

PURPOSE: To assess the effect of the total number of fluid-free months after loading on visual and anatomical outcomes in neovascular age-related macular degeneration patients receiving anti-vascular endothelial growth factor therapy. METHODS: This post hoc analysis pooled patient-level data from the brolucizumab 6 mg (n = 718) and aflibercept 2 mg (n = 715) arms of the HAWK and HARRIER randomized clinical trials. Based on data from Weeks 12 to 96, patients were assigned to one of five categories based on fluid-free visits (FFVs; the total number of monthly visits at which they were observed to be without retinal fluid). Three definitions of "fluid-free" were explored based on the location of the fluid observed. RESULTS: Patients allocated to Categories 4 (15-21 FFV) and 5 (22 FFV, always dry) consistently had the best visual and anatomical outcomes at Week 96, whereas patients allocated to Categories 1 (0 FFV, never dry) and 2 (1-7 FFV) consistently had the worst visual and anatomical outcomes. Variability in retinal thickness over time was lowest in Categories 4 and 5. CONCLUSION: Absence of retinal fluid at more visits after loading has a positive association with visual and anatomic outcomes in neovascular age-related macular degeneration patients, regardless of fluid type.

TRAMADOL-ASSOCIATED BILATERAL CYSTOID MACULAR EDEMA.

PURPOSE: To describe a case of bilateral cystoid macular edema in a patient with long-standing tramadol hydrochloride use. METHODS: Observational case report. RESULTS: A 73-year-old female patient was referred for progressive, bilateral decreased visual acuity. The patient was phakic with a best-corrected visual acuity at presentation was 20/50 on the right eye and 20/64 on the left eye. The patient had a history of low back pain and had been on tramadol hydrochloride 200 mg/day for 16 years. Bilateral cystoid macular edema was confirmed by means of multimodal imaging, including optical coherence tomography angiography. Tramadol intake was progressively reduced over one month and then completely interrupted. At 3 months follow-up, the cystoid macular edema had completely resolved and the best-corrected visual acuity improved in both eyes. CONCLUSION: Cystoid macular edema may be associated with longstanding treatment with tramadol hydrochloride. Tramadol hydrochloride-associated cystoid macular edema is described and its resolution on tramadol cessation.

Lens-Iris diaphragm retropulsion syndrome: Risk factors and management. A prospective study.

PURPOSE: The lens-iris diaphragm retropulsion syndrome (LIDRS) corresponds to an acute deepening of the anterior chamber during phacoemulsification. LIDRS is painful for the patient and sometimes causes intraoperative complications. This study was designed to assess the preoperative risk factors of LIDRS and its outcome. SETTING: Monocentric study in the university department of ophthalmology, Intercommunal Hospital Center, Creteil, France. DESIGN: Prospective observational study. METHODS: Preoperative parameters of consecutive patients who underwent cataract surgery were recorded. LIDRS occurrence was evaluated during surgery and classified into 3 stages. Except for the first patient, a simple and rapid maneuver to separate the iris from the capsule was performed in all patients with LIDRS. RESULTS: LIDRS occurred in 101 out of 205 included eyes: mild in 73.2%, marked in 16.8%, and severe in 9.9%. LIDRS patients were younger, and had a longer axial length and a thinner lens than the control group (p < 0.01 for all). Univariate logistic regression showed that the main predictive factors of LIDRS were long axial length and decreased lens thickness. LIDRS occurred in 83% (5/6) of eyes with prior vitrectomy. Complications occurred (zonular dehiscence, lens or IOL dislocation), especially in vitrectomized eyes. The maneuver separating the iris from the capsule allowed almost all eyes to restore normal chamber depth and prevent complications. CONCLUSIONS: Myopia and prior vitrectomy were the main risk factors of LIDRS. The maneuver separating the iris from the capsule allowed almost all eyes to resolve LIDRS. Analysis of preoperative factors can help the surgeon identify patients at risk and prevent patient pain and intraoperative complications associated with LIDRS.

NEW ARTIFICIAL INTELLIGENCE ANALYSIS FOR PREDICTION OF LONG-TERM VISUAL IMPROVEMENT AFTER EPIRETINAL MEMBRANE SURGERY.

PURPOSE: To predict improvement of best-corrected visual acuity (BCVA) 1 year after pars plana vitrectomy for epiretinal membrane (ERM) using artificial intelligence methods on optical coherence tomography B-scan images. METHODS: Four hundred and eleven (411) patients with Stage II ERM were divided in a group improvement (IM) (≥15 ETDRS letters of VA recovery) and a group no improvement (N-IM) (<15 letters) according to 1-year VA improvement after 25-G pars plana vitrectomy with internal limiting membrane peeling. Primary outcome was the creation of a deep learning classifier (DLC) based on optical coherence tomography B-scan images for prediction. Secondary outcome was assessment of the influence of various clinical and imaging predictors on BCVA improvement. Inception-ResNet-V2 was trained using standard augmentation techniques. Testing was performed on an external data set. For secondary outcome, B-scan acquisitions were analyzed by graders both before and after fibrillary change processing enhancement. RESULTS: The overall performance of the DLC showed a sensitivity of 87.3% and a specificity of 86.2%. Regression analysis showed a difference in preoperative images prevalence of ectopic inner foveal layer, foveal detachment, ellipsoid zone interruption, cotton wool sign, unprocessed fibrillary changes (odds ratio = 2.75 [confidence interval: 2.49-2.96]), and processed fibrillary changes (odds ratio = 5.42 [confidence interval: 4.81-6.08]), whereas preoperative BCVA and central macular thickness did not differ between groups. CONCLUSION: The DLC showed high performances in predicting 1-year visual outcome in ERM surgery patients. Fibrillary changes should also be considered as relevant predictors.

Effects of Photobiomodulation in Patients Presenting with Reticular Pseudodrusen: A Retrospective Observational Case Series Study.

Background and Objectives: The purpose of this study is to describe the effects of photobiomodulation on drusen regression with patients presenting with reticular pseudodrusen (RPD). Materials and Methods: This study is a retrospective observational case series study including patients presenting with RPD who underwent treatment by photobiomodulation. All patients underwent a complete ophthalmic examination and multimodal imaging prior to treatment, including spectral-domain optical coherence tomography (SD-OCT). Eyes were treated two times per week for six consecutive weeks. Best corrected-visual acuity (BVCA) was measured prior and after treatment for all patients. The number of RPD on the SD-OCT scans centered on the macula and stages of RPD was noted at baseline and 6 months after the first treatment session. Results: Five eyes of five patients were included in the study. Mean BCVA did not change 6 months after treatment compared to baseline. Mean number of RPD per eye was 112.60 +/- 48.33 RPD at baseline and 111.6 +/- 49.29 in the same area 6 months after treatment. Changes in RPD distribution according to RPD classification were observed before and after treatment with photobiomodulation. Changes in distribution mostly concerned stages 1 and 3 RPD: Total number of stage 1 RPD was 289 and increased to 324 after treatment. Total number of stage 3 RPD was 97 at baseline and decreased to 67 6 months after treatment. Percentage of stage 1 RPD increased from 46% to 56% after treatment. Percentage of stage 3 RPD decreased from 20% to 13% after treatment. Conclusions: Changes in RPD distribution were observed before and after treatment with photobiomodulation. The number of stage 3 reticular pseudodrusen decreased while number of stage 1 reticular pseudodrusen increased after treatment.

Comparison of Multimodal Imaging for the Characterization of Geographic Atrophy.

Purpose: The purpose of this study was to compare the performances of infrared (IR), fundus autofluorescence (FAF), and multicolor (MC) imaging in the characterization of geographic atrophy, with a focus on the possibility to detect incomplete retinal pigmented and outer retinal atrophy (iRORA) on en face imaging. Methods: The ground truth was established by two graders evaluating atrophy on spectral-domain optical coherence tomography (SD-OCT) images. A score for visibility of foveal sparing and margins of atrophy was attributed. Measurement of the atrophic area and the fovea-to-margin distance were performed. Accuracy of detection of foveal sparing was evaluated through comparison with B-scan images ground truth, with/without the inclusion of patients with foveal iRORA. Results: Seventy patients were included in this study. Foveal sparing and atrophy's margins subjective visibility were significantly higher rated on MC images compared to IR and FAF (P < 0.005 and P < 0.001). Agreement with OCT B-scan assessed foveal sparing revealed a significantly higher area under receiver operating characteristic curves (AUROC) for MC images at the analysis performed both with (0.876) and without (0.853) inclusion of patients with foveal iRORA (P < 0.001 and P = 0.006). Quantitative measurements revealed lower atrophy extension (P = 0.026) and fovea-to-margin distance (P = 0.019) with MC imaging. Conclusions: MC imaging performed better at foveal sparing assessment, especially in the setting of foveal iRORA. MC also resulted in higher visibility of atrophy's margins, lower atrophy extension measurements, and lower distance from the fovea to atrophy's margins compared to both FAF and IR. Translational Relevance: MC rated significantly higher in foveal sparing and atrophy detection, higher visibility of atrophy's margins, lower atrophy extension measurements, and lower distance from the fovea to atrophy's margins, compared to FAF and IR.

Deep learning to distinguish Best vitelliform macular dystrophy (BVMD) from adult-onset vitelliform macular degeneration (AVMD).

Initial stages of Best vitelliform macular dystrophy (BVMD) and adult vitelliform macular dystrophy (AVMD) harbor similar blue autofluorescence (BAF) and optical coherence tomography (OCT) features. Nevertheless, BVMD is characterized by a worse final stage visual acuity (VA) and an earlier onset of critical VA loss. Currently, differential diagnosis requires an invasive and time-consuming process including genetic testing, electrooculography (EOG), full field electroretinogram (ERG), and visual field testing. The aim of our study was to automatically classify OCT and BAF images from stage II BVMD and AVMD eyes using a deep learning algorithm and to identify an image processing method to facilitate human-based clinical diagnosis based on non-invasive tests like BAF and OCT without the use of machine-learning technology. After the application of a customized image processing method, OCT images were characterized by a dark appearance of the vitelliform deposit in the case of BVMD and a lighter inhomogeneous appearance in the case of AVMD. By contrast, a customized method for processing of BAF images revealed that BVMD and AVMD were characterized respectively by the presence or absence of a hypo-autofluorescent region of retina encircling the central hyperautofluorescent foveal lesion. The human-based evaluation of both BAF and OCT images showed significantly higher correspondence to ground truth reference when performed on processed images. The deep learning classifiers based on BAF and OCT images showed around 90% accuracy of classification with both processed and unprocessed images, which was significantly higher than human performance on both processed and unprocessed images. The ability to differentiate between the two entities without recurring to invasive and expensive tests may offer a valuable clinical tool in the management of the two diseases.

Comparative Efficacy of Brolucizumab in the Treatment of Neovascular Age-Related Macular Degeneration: A Systematic Literature Review and Network Meta-Analysis.

INTRODUCTION: A systematic literature review (SLR) and network meta-analysis (NMA) were conducted to evaluate the comparative efficacy of brolucizumab relative to other anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration (nAMD) at 1 and 2 years, and overall safety and injection frequency of each treatment. METHODS: An SLR identifying randomized controlled trials (RCTs) published before June 2021 according to a pre-specified protocol was followed by a Bayesian NMA to compare brolucizumab (6 mg q12w/q8w) against sham and all relevant anti-VEGF regimens. Pooled mean injection frequency, serious adverse ocular events, and discontinuation rates were estimated for each treatment regimen. RESULTS: Nineteen RCTs were included in NMA base-case analysis. Brolucizumab (6 mg q12w/q8w) with loading-phase (LP) demonstrated superior best-corrected visual acuity (BCVA) gains to sham both at year 1 (mean difference 16.8 [95%CrI 13.3, 20.4]) and year 2 (mean difference 21.2 [95%CrI 17.4, 25.0]) and was comparable to other anti-VEGFs. Brolucizumab (6 mg q12w/q8w) also showed superior retinal thickness reduction to most comparators including ranibizumab (0.5 mg q4w; year 1 mean difference - 50.1 [95%CrI - 70.3, - 29.8]; year 2 mean difference - 49.5 [95%CrI - 70.8, - 28.6]), aflibercept (2 mg q8w; year 1 mean difference - 39.7 [95%CrI - 52.9, - 26.4]; year 2 mean difference - 35.0 [95%CrI - 49.1, - 21.4]), and faricimab (6 mg q16w/q8w; year 1 mean difference - 27.6 [95%CrI - 42.3, - 12.8]). Brolucizumab (6 mg q12w/q8w) showed similar rates of treatment discontinuation and serious and overall adverse events (both years). At year 2, pooled annualized injection frequency was lowest for brolucizumab (6 mg q12w/q8w) and highest for ranibizumab (0.5 mg q4w) at 5.7 and 11.5 injections annually, respectively. CONCLUSION: Among all licensed anti-VEGF treatments, brolucizumab showed superior reduction in retinal thickness and comparable BCVA gains and discontinuation rates, despite having the lowest injection frequency. The current study provides the most up-to-date, robust comparison of treatments for nAMD.

Anti-Vascular Endothelial Growth Factor Treatment Discontinuation and Interval in Neovascular Age-Related Macular Degeneration in the United States.

PURPOSE: To assess the association between treatment interval and likelihood of anti-vascular endothelial growth factor (anti-VEGF) discontinuation among patients with neovascular age-related macular degeneration (nAMD) in a real-world setting in the United States. DESIGN: Retrospective clinical cohort study. METHODS: Health insurance claims data from the IBM MarketScan Commercial and Medicare Supplemental databases were retrospectively reviewed to identify adults with nAMD who received anti-VEGF for the first time between July 1, 2011, and June 30, 2017. The proportion of discontinued patients was analyzed using Kaplan-Meier curves. Cox proportional hazards models were used to examine the association between treatment intervals at 24 months and anti-VEGF discontinuation. RESULTS: The analysis included 8167 patients on continuous, unilateral anti-VEGF treatment for at least 24 months. Baseline demographics and clinical characteristics were well balanced between treatment interval groups. The overall rate of discontinuation from 24 months until 60 months after treatment initiation was 30.4%. At 60 months, patients on shorter treatment intervals were more likely to remain on treatment than those on longer intervals, ranging from 76.8% (4-week interval group) to 60.6% (>12-week interval group) and corresponding to a 28% lower likelihood (HR [SE] 0.72 [0.12], P < .01) and 55% higher likelihood of discontinuing treatment (HR [SE] 1.55 [0.07], P < .01), respectively, compared with the 8-week group. CONCLUSIONS: nAMD patients on longer anti-VEGF treatment intervals at 24 months had consistently higher discontinuation rates than patients on shorter intervals in the following years. This highlights the need to support and educate patients on long treatment intervals to continue with their treatment.

Neovascular age-related macular degeneration: advancement in retinal imaging builds a bridge between histopathology and clinical findings.

PURPOSE: To provide a review of the salient histological and imaging features in neovascular age-related macular degeneration (AMD) that will be integrated in order to have a better comprehension of the pathogenesis and clinical aspects of this disease. METHODS: A literature review of histology and imaging features in neovascular AMD was conducted. RESULTS: Histology has granted a detailed characterization of neovascular AMD ex vivo. In details, histological features in these eyes have offered important insights into the pathogenesis of neovascular AMD. In addition, histology donated a detailed characterization of the different types of macular neovascularization (MNV) that may complicate AMD. The introduction of optical coherence tomography angiography (OCTA) has enormously amplified our knowledge of neovascular AMD through in vivo assessment of the anatomical and pathological characteristics of this disease. New insights elucidating the morphological features of the choriocapillaris confirmed that this vascular structure plays a crucial role in the pathogenesis of neovascular AMD. OCTA also offered a detailed visualization of MNV complicating neovascular AMD. CONCLUSIONS: New imaging technologies offer a remarkable chance to build a bridge between histology and clinical findings in neovascular AMD.

KESTREL and KITE: 52-Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular Edema.

PURPOSE: To compare the efficacy and safety of brolucizumab with aflibercept in patients with diabetic macular edema (DME). DESIGN: Double-masked, 100-week, multicenter, active-controlled, randomized trials. METHODS: Subjects were randomized 1:1:1 to brolucizumab 3 mg/6 mg or aflibercept 2 mg in KESTREL (n = 566) or 1:1 to brolucizumab 6 mg or aflibercept 2 mg in KITE (n = 360). Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed by 12-week (q12w) dosing, with optional adjustment to every 8 weeks (q8w) if disease activity was identified at predefined assessment visits; aflibercept groups received 5 doses every 4 weeks (q4w) followed by fixed q8w dosing. The primary endpoint was best-corrected visual acuity (BCVA) change from baseline at Week 52; secondary endpoints included the proportion of subjects maintained on q12w dosing, change in Diabetic Retinopathy Severity Scale score, and anatomical and safety outcomes. RESULTS: At Week 52, brolucizumab 6 mg was noninferior (NI margin 4 letters) to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2 letters vs +10.5 letters; KITE: +10.6 letters vs +9.4 letters; P < .001), more subjects achieved central subfield thickness (CSFT) <280 µm, and fewer had persisting subretinal and/or intraretinal fluid vs aflibercept, with more than half of brolucizumab 6 mg subjects maintained on q12w dosing after loading. In KITE, brolucizumab 6 mg showed superior improvements in change of CSFT from baseline over Week 40 to Week 52 vs aflibercept (P = .001). The incidence of ocular serious adverse events was 3.7% (brolucizumab 3 mg), 1.1% (brolucizumab 6 mg), and 2.1% (aflibercept) in KESTREL; and 2.2% (brolucizumab 6 mg) and 1.7% (aflibercept) in KITE. CONCLUSION: Brolucizumab 6 mg showed robust visual gains and anatomical improvements with an overall favorable benefit/risk profile in patients with DME.