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Abstract Purpose Offer a personal perspective on the scientific advances on macular telangiectasia type 2 (MacTel2) since the launch of the MacTel Project in 2005. Design Literature review and personal perspective. Methods Critical review of the peer-reviewed literature and personal perspective. Results Generous financial support from the Lowy Medical Research Institute laid the foundations of the MacTel Project. MacTel Project investigators used state of the art multimodal retinal imaging and advanced modern biological methods to unravel many of the mysteries surrounding MacTel2. Major accomplishments includes elucidation of the pathogenic role that low serine levels, elevated 1-deoxysphingolipids and other mechanisms induce mitochondrial dysfunction which lead to Müller cell and photoreceptor degeneration; the use of objective measures of retinal structures such as the area of ellipsoid zone disruption as an outcome measure in clinical trials; the demonstration that the ciliary neurotrophic factor slows down retinal degeneration and the development of a new severity scale classification based on multimodal imaging findings. Conclusions MacTel2 is a predominantly metabolic disease characterized by defects in energy metabolism. Despite relatively good visual acuities, MacTel2 patients experience significant visual disability. The Mac Tel Project has been instrumental in advancing MacTel2 knowledge in the past two decades.

Abstract Purpose To report eplerenone use by retina specialists worldwide for central serous chorioretinopathy (CSCR). Methods A self-reporting questionnaire was distributed to retina specialists worldwide to gather clinicians’ perspectives on CSCR cases treated, eplerenone dosage and duration, reasons to use it, and side effects. Results The survey included 241 retina specialists (122 Indian and 119 international) with an average experience of 15.69 ± 9.59 years. Oral eplerenone was used to treat CSCR by 149 (62%) participants. Only 6% (n = 9) had easy access to verteporfin dye and photodynamic therapy. 30 (20%) of the 149 respondents changed their treatment with eplerenone after VICI trial results. Eplerenone was prescribed mostly for chronic CSCR (n = 86, 58%), regardless of involvement laterality. 62% (n = 92) had fewer than 25% CSCR cases treated with eplerenone. 85 (57%) respondents used eplerenone only when other treatments failed, while 36 (24%) used it as first-line treatment. 73 (49%) respondents, prescribed eplerenone at a 50 mg daily dose and 137 (92%) retina specialists used eplerenone for 0–3 months. The drug’s efficacy dissatisfied 21 (14%) study participants. 124 (83%) study participants did not encounter any ocular or systemic side effects with eplerenone use. Eplerenone related kidney and electrolyte issues were noted by 11 (7%) study participants. Conclusion The treatment of CSCR varies around the world and is primarily influenced by the photodynamic therapy availability and the findings of VICI trial. Despite the limited benefit of eplerenone reported by the VICI trial, it is still used as evidenced by real-world experience. Trial Registration Number Not applicable.

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin–Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

Abstract Background AQUILA (NCT03470103) was a prospective, observational, 12-month cohort study evaluating treatment patterns, clinical effectiveness, and safety of intravitreal aflibercept (IVT-AFL) in patients from Latin America with neovascular age-related macular degeneration (nAMD). Methods Treatment-naïve and previously treated (switching to IVT-AFL) patients (aged ≥ 55 years) were enrolled from March 2018, with a primary completion date of September 2020, from Argentina, Colombia, Costa Rica, and Mexico. Patients received IVT-AFL in a routine clinical practice setting. Results Of 274 patients in the full analysis set, 201 were treatment-naïve and 73 had received previous treatment. The mean ± standard deviation number of IVT-AFL injections received by month 12 was 4.2 ± 1.9 (treatment-naïve) and 5.2 ± 2.7 (previously treated). The median duration from diagnosis to IVT-AFL treatment was 1.2 months (treatment-naïve) and 19.5 months (previously treated). Mean best-corrected visual acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) improved from baseline to month 12 by + 5.2 ± 18.3 (treatment-naïve; baseline: 48.2 ± 23.5) and + 3.1 ± 15.3 letters (previously treated; baseline: 47.7 ± 21.4). Conclusion AQUILA is the first study to assess the use of IVT-AFL in routine clinical practice in Latin America. Mean BCVA and other visual acuity outcomes improved in both treatment groups, despite many patients not receiving the IVT-AFL label-recommended regimen of three initial monthly doses, or seven or more injections in 12 months. Patients who did receive the label-recommended number of injections had numerically greater improvements in visual acuity outcomes. Patients with nAMD treated regularly and more frequently with IVT-AFL, therefore, have the potential to achieve outcomes consistent with those observed in interventional studies. Trial registration: Clinicaltrials.gov, NCT03470103. Registered February 5, 2018, https://clinicaltrials.gov/ct2/show/NCT03470103

Abstract Background AQUILA (NCT03470103) was a prospective, observational, 12-month cohort study to understand treatment patterns and to evaluate the clinical effectiveness and safety of intravitreal aflibercept (IVT-AFL) in patients from Latin America with diabetic macular edema (DME). Methods Treatment-naïve and previously treated (switching to IVT-AFL) patients (aged ≥ 18 years) were enrolled from March 2018, with a primary completion date of September 2020, from Argentina, Colombia, Costa Rica and Mexico. Patients received IVT-AFL in a routine clinical practice setting. Results Of 258 patients in the full analysis set, 181 were treatment-naïve and 77 had received previous treatment. The mean ± standard deviation number of IVT-AFL injections by Month 12 was 3.7 ± 1.8 (treatment-naïve) and 4.0 ± 2.2 (previously treated). The median duration from diagnosis to IVT-AFL treatment was 1.8 months (treatment-naïve) and 16.0 months (previously treated). Mean best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letters) improved from baseline to Month 12 by + 8.1 ± 17.7 (treatment-naïve; baseline: 54.5 ± 19.4) and + 4.6 ± 15.4 letters (previously treated; baseline: 52.9 ± 18.6). Conclusion AQUILA is the first study to assess the use of IVT-AFL in routine clinical practice in Latin America. Despite few patients being treated with the label-recommended regimen of 5 initial monthly doses or receiving ≥ 8 injections in 12 months, functional and anatomic visual outcomes improved during 12 months of treatment with IVT-AFL. Patients receiving the label-recommended number of injections had numerically greater improvements in visual acuity outcomes. Patients with DME treated regularly and more frequently with IVT-AFL therefore have the potential to achieve outcomes consistent with those observed in interventional studies. Trial registration Clinicaltrials.gov, NCT03470103. Registered February 5, 2018, https://clinicaltrials.gov/ct2/show/NCT03470103

A wide spectrum of phenotypic manifestations characterizes age-related macular degeneration (AMD). Drusen is considered the hallmark of AMD and is located underneath the retinal pigment epithelium (RPE). In contrast, subretinal drusenoid deposits (SDDs), also known as reticular pseudodrusens, are located in the subretinal space, on top of the RPE. SDDs are poorly detected by clinical examination and color fundus photography. Multimodal imaging is required for their proper diagnosis. SDDs are topographically and functionally related to rods. SDDs cause a deep impairment in retinal sensitivity and dark adaptation. SDDs are dynamic structures that may grow, fuse with each other, or regress over time. An intermediate step in some eyes is the development of an acquired vitelliform lesion. The presence of SDD confers an eye a high risk for the development of late AMD. SDD leads to macular neovascularization, particularly type 3, geographic atrophy, and outer retinal atrophy.

We thank the comment written by Fernández-Vigo et al. [...]

Geographic atrophy (GA) affects around 5 million individuals worldwide. Genome-wide, histopathologic, in vitro and animal studies have implicated the activation of the complement system and chronic local inflammation in the pathogenesis of GA. Recently, clinical trials have demonstrated that an intravitreal injection of pegcetacoplan, a C3 inhibitor, and avacincaptad pegol, a C5 inhibitor, both statistically significantly reduce the growth of GA up to 20% in a dose-dependent fashion. Furthermore, the protective effect of both pegcetacoplan and avacincaptad appear to increase with time. However, despite these anatomic outcomes, visual function has not improved as these drugs appear to only slow down the degenerative process. Unexpected adverse events included conversion to exudative NV-AMD with both drugs. Occlusive retinal vasculitis and anterior ischemic optic neuropathy have been reported in pegcetacoplan-treated eyes.

Abstract Background To compare the functional and anatomic outcomes at 24 months of eyes with a primary macular hole that failed to close after a prior surgery and were treated with either an autologous transplantation of internal limiting membrane (AT-ILM) or the retina expansion (RE) technique. Methods Retrospective, single center, comparative study of 28 eyes with a macular hole that failed to close after a prior vitrectomy. All eyes had a size of ≥ 500 μm. Participants were divided into two groups according to the type of intervention performed: AT-ILM group (n = 14) and RE group (n = 14). Main outcomes measured were the MH closure rate assessed by spectral-domain optical coherence tomography (SD-OCT) and the best-corrected visual acuity (BCVA) at 24 months after surgery. Results Patients in the AT-ILM group experienced a statistically significantly improved post-operative BCVA (median 49.50 letters, range 20–66 letters) over the pre-operative BCVA (median 39 letters, range 18–52 letters) (p-value = 0.006 Wilcoxon paired sample test). In contrast, patients in the RE group did not achieve a statistically significant improvement (p-value = 0.328, Wilcoxon paired sample test). The median pre-operative BCVA was 35 letters (range 18–52 letters), whereas the median post-operative BCVA was 39 letters (range 16–66 letters). At 24 months of follow-up, 85.7% of patients in the AT-ILM group achieved closure compared to 57.1% in the RE group (p-value = 0.209, Fisher’s exact test). Multivariate analysis showed that MH size and baseline BCVA were important determinants of post-operative BCVA. The baseline MH size was the only significant pre-operative factor that influenced MH closure. Conclusions This study demonstrates similar closure rates for both groups however better visual outcomes were obtained with the AT-ILM.

BackgroundMany artificial intelligence (AI) studies have focused on development of AI models, novel techniques, and reporting guidelines. However, little is understood about clinicians' perspectives of AI applications in medical fields including ophthalmology, particularly in light of recent regulatory guidelines. The aim for this study was to evaluate the perspectives of ophthalmologists regarding AI in 4 major eye conditions: diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD) and cataract.MethodsThis was a multi-national survey of ophthalmologists between March 1st, 2020 to February 29th, 2021 disseminated via the major global ophthalmology societies. The survey was designed based on microsystem, mesosystem and macrosystem questions, and the software as a medical device (SaMD) regulatory framework chaired by the Food and Drug Administration (FDA). Factors associated with AI adoption for ophthalmology analyzed with multivariable logistic regression random forest machine learning.ResultsOne thousand one hundred seventy-six ophthalmologists from 70 countries participated with a response rate ranging from 78.8 to 85.8% per question. Ophthalmologists were more willing to use AI as clinical assistive tools (88.1%, n = 890/1,010) especially those with over 20 years' experience (OR 3.70, 95% CI: 1.10–12.5, p = 0.035), as compared to clinical decision support tools (78.8%, n = 796/1,010) or diagnostic tools (64.5%, n = 651). A majority of Ophthalmologists felt that AI is most relevant to DR (78.2%), followed by glaucoma (70.7%), AMD (66.8%), and cataract (51.4%) detection. Many participants were confident their roles will not be replaced (68.2%, n = 632/927), and felt COVID-19 catalyzed willingness to adopt AI (80.9%, n = 750/927). Common barriers to implementation include medical liability from errors (72.5%, n = 672/927) whereas enablers include improving access (94.5%, n = 876/927). Machine learning modeling predicted acceptance from participant demographics with moderate to high accuracy, and area under the receiver operating curves of 0.63–0.83.ConclusionOphthalmologists are receptive to adopting AI as assistive tools for DR, glaucoma, and AMD. Furthermore, ML is a useful method that can be applied to evaluate predictive factors on clinical qualitative questionnaires. This study outlines actionable insights for future research and facilitation interventions to drive adoption and operationalization of AI tools for Ophthalmology.

In this paper, we compare the post-operative macular microvascular parameters (vascular density and foveal avascular zone) in eyes with refractory macular hole (MH) that underwent pars plana vitrectomy and autologous retinal transplant (ART) with the fellow unoperated eye. We conducted a retrospective case control study of six consecutive patients who underwent pars plana vitrectomy and ART with at least six months of post-operative follow-up. Pre-operatively, all eyes underwent SD-OCT (Spectral Domain Optical Coherence Tomography) examination. Post-operative OCT-A analyses included vascular density (VD) and the foveal avascular zone (FAZ) area. Six patients with a mean age of 63.7 ± 14.3 years were included. The mean follow-up was 24 months (range 6–30 months). The pre-operative BCVA (best-corrected visual acuity) was 0.99 ± 0.46 logMAR and 1.02 ± 0.23 logMAR at the last post-operative visit (p = 1.00). The mean MH diameter was 966 ± 620 µm. VD in the MH group was 28.1 ± 7.3% compared to 20.2 ± 2.9% in the fellow eyes group (p < 0.05). The mean post-operative FAZ area in the MH group was 109.8 ± 114.6 mm2 compared to 41.5 ± 10.4 mm2 in the control group (p < 0.05). In all six eyes, MH closure was obtained. The post-operative visual acuity did not improve after ART. Eyes with a closed MH showed a bigger FAZ with a higher VD compared to the fellow healthy eye.

The aim of this study was to evaluate the effectiveness and safety of a yellow subthreshold laser (STL) for the treatment of chronic central serous chorioretinopathy delivered in a fovea-sparing pattern and to analyze the post-laser changes in the choroidal structure by Swept-Source Optical Coherence Tomography. This study was a prospective case series of 43 eyes corresponding to 37 patients. Data were recorded at 6, 12 and 24 weeks after the STL treatment. The best-corrected visual acuity improved in 93% of the patients and remained stable in 7%. The subretinal fluid was completely reabsorbed in 27.9%, 32.6% and 69.8% of the patients at 6, 12 and 24 weeks, respectively. There were reductions in the choroidal thickness of 13.1% and 25.3% at 12 and 24 weeks, which corresponded to reductions of 17.5% and 45.9% in the choriocapillaris and Sattler layer and reductions of 12.2% and 21.2% in the Haller layer at 12 and 24 weeks, respectively (p < 0.05). This might account for the effect of the laser on the inner choroidal vasculature, the dysregulation of which is believed to be at the core of central serous chorioretinopathy. No laser-related complications were detected. Overall, the fovea-sparing STL was safe and effective in this series of patients.

There is a wide spectrum of macular conditions that are characterized by an irregular foveal contour caused by a break in the inner fovea. These include full-thickness macular hole (FTMH), foveal pseudocyst, lamellar macular hole (LMH) and macular pseudohole (MPH). Clinical examination of vitreomacular interface disorders is notoriously poor in differentiating these conditions. These conditions were initially described with slit-lamp biomicroscopy, and the main goal was to distinguish an FTMH from the others. The introduction of optical coherence tomography (OCT) has revolutionized our understanding of the foveal microstructural anatomy and has facilitated differentiating these conditions from an FTMH. However, the definitions of the other conditions, particularly LMH, has evolved over the past two decades. Initially the term LMH encompassed a wide spectrum of clinical conditions. As OCT became more widely used and observations became more refined, two different phenotypes of LMH became apparent, raising the question of different pathogenic mechanisms for each phenotype. Tractional and degenerative pathological mechanisms were proposed. Epiretinal membranes (ERMs) associated with each phenotype were identified. Typical ERMs were associated with a tractional mechanism, whereas an epiretinal proliferation was associated with a degenerative mechanism. Epiretinal proliferation represents Müller cell proliferation as a reactive process to retinal injury. These two types of ERM were differentiated by their characteristics on SD-OCT. The latest consensus definitions take into account this phenotypic differentiation and classifies these entities into LMH, MPH and ERM foveoschisis. The initial event in both ERM foveoschisis and LMH is a tractional event that disrupts the Müller cell cone in the foveola or the foveal walls. Depending on the extent of Müller cell disruption, either a LMH or an ERM foveoschisis may develop. Although surgical intervention for LMH remains controversial and no clear guidelines exist for pars plana vitrectomy (PPV), eyes with symptomatic, progressive ERM foveoschisis and LMH may benefit from surgical intervention.

Purpose To ascertain the anatomic factors that help achieve non-surgical sealing in full thickness macular hole (FTMH). Methods Retrospective collaborative study of FTMH that closed without surgical intervention. Results A total of 78 patients (mean age 57.9 years) included 18 patients with blunt ocular trauma, 18 patients that received topical or intravitreal therapies and 42 patients with idiopathic FTMH. Mean±SD of the initial corrected visual acuity (VA) in logMAR improved from 0.65±0.54 to 0.34±0.45 (p<0.001) at a mean follow-up of 33.8±37.1 months. FTMH reopened in seven eyes (9.0%) after a mean of 8.6 months. Vitreomacular traction was noted in 12 eyes (15.8%), perifoveal posterior vitreous detachment in 42 (53.8%), foveal epiretinal membrane in 10 (12.8%), cystoid macular oedema (CME) in 49 (62.8%) and subretinal fluid (SRF) in 20 (25.6%). By multivariate analysis, initial VA correlated to the height (p<0.001) and narrowest diameter of the hole (p<0.001) while final VA correlated to the basal diameter (p<0.001). Time for closure of FTMH (median 2.8 months) correlated to the narrowest diameter (p<0.001) and the presence of SRF (p=0.001). Mean time for closure (in months) was 1.6 for eyes with trauma, 4.3 for eyes without trauma but with therapy for CME, 4.4 for eyes without trauma and without therapy in less than 200 µm in size and 24.7 for more than 200 µm. Conclusion Our data suggest an observation period in new onset FTMH for non-surgical closure, in the setting of trauma, treatment of CME and size <200 µm. [ABSTRACT FROM AUTHOR]