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Diabetic retinopathy in the pediatric population: Pathophysiology, screening, current and future treatments.
Invernizzi, A, Chhablani, J, Viola, F, Gabrielle, PH, Zarranz-Ventura, J, Staurenghi, G
Pharmacological research. 2023;:106670
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Abstract
Diabetic retinopathy (DR) is a sight threatening complication of diabetes mellitus (DM). The incidence of DR in the pediatric population has increased in the last two decades and it is expected to further rise in the future, following the increase in DM prevalence and obesity in youth. As early stages of the retinal disease are asymptomatic, screening programs are of extreme importance to guarantee a prompt diagnosis and avoid progression to more advanced, sight threatening stages. The management of DR comprises a wide range of actions starting from glycemic control, continuing with systemic and local medical treatments, up to para-surgical and surgical approaches to deal with the more aggressive complications. In this review we will describe the pathophysiology of DR trying to understand all the possible targets for currently available or future treatments. We will briefly consider the impact of screening techniques, screening strategies and their social and economic impact. Finally a large part of the review will be dedicated to medical and surgical treatments for DR including both currently available and under development therapies. Most of the available data in the literature on DR are focused on the adult population. The aim of our work is to provide clinicians and researchers with a comprehensive overview of the state of the art regarding DR in the pediatric population, considering the increasing numbers of this diseases in youth and the inevitable consequences that such a chronic disease could have if poorly managed in children.
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NATURAL COURSE AND CLASSIFICATION OF EXTENSIVE MACULAR ATROPHY WITH PSEUDODRUSEN-LIKE APPEARANCE.
Romano, F, Cozzi, M, Monteduro, D, Oldani, M, Boon, CJF, Staurenghi, G, Salvetti, AP
Retina (Philadelphia, Pa.). 2023;(3):402-411
Abstract
PURPOSE To describe the imaging characteristics and topographic expansion of retinal pigment epithelium (RPE) and outer retinal atrophy in extensive macular atrophy with pseudodrusen-like appearance. METHODS Three-year, prospective, observational study. Nine patients with extensive macular atrophy with pseudodrusen-like appearance (17 eyes; 6 women) with no other ocular conditions were annually examined; one eye was excluded because of macular neovascularization. Best-corrected visual acuity measurement, fundus photographs, blue-light autofluorescence, and optical coherence tomography were performed at each visit. Formation of atrophy was analyzed on optical coherence tomography at foveal and extrafoveal areas following the Classification of Atrophy Meeting recommendations. Spatial enlargement throughout four sectors was assessed on blue-light autofluorescence after placing an Early Treatment for Diabetic Retinopathy Study grid centered on the foveola. RESULTS Mean age was 53.0 ± 2.1 years at baseline with a follow-up of 36.6 ± 0.7 months. Thinning of the outer nuclear layer and disruption of the ellipsoid zone initially appeared above areas of RPE-Bruch membrane separation and preceded RPE atrophy. Subfoveal fibrosis was seen in 65% of the eyes. Superior sector involvement was found in all patients at baseline and was significantly larger than the other sectors at any time point ( P < 0.001). Best-corrected visual acuity declined from 68.0 ± 15.7 letters to 44.8 ± 14.9 letters during the follow-up and was significantly associated with subfoveal atrophy ( P < 0.001) and fibrosis ( P = 0.02). CONCLUSION Our findings suggest that primary alterations in patients with extensive macular atrophy with pseudodrusen-like appearance are present at the outer segment-RPE interface, with the superior Early Treatment for Diabetic Retinopathy Study sector being the most vulnerable, which progresses to extensive atrophy of the RPE and outer retinal layers. Accordingly, we propose a three-stage disease classification.
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COVID-19-Related Retinal Micro-vasculopathy - A Review of Current Evidence.
Teo, KY, Invernizzi, A, Staurenghi, G, Cheung, CMG
American journal of ophthalmology. 2022;:98-110
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Abstract
PURPOSE To evaluate the occurrence of retinal microvasculopathy in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and who developed coronavirus disease (COVID-19). DESIGN Systematic review and meta-analysis. METHODS The Pubmed and Embase databases were comprehensively searched to identify studies that reported retina vascular changes in eyes with COVID-19. Two independent reviewers selected papers and extracted data for analysis. Data of interest were extracted and analyzed in RevMan Web versions 3.3. Quality of evidence was assessed using the National Institute of Health quality assessment tool for a case-control study. RESULTS Thirty-one studies reporting on 1373 subjects (972 COVID-19 and 401 controls) were included. Only case-control studies were included in the pooled analysis. There was a significantly higher likelihood of retinal microvasculopathy in subjects with COVID-19 compared to controls (odds ratio [95% confidence interval], 8.86 [2.54-27.53], P < .01). Optical coherence tomography angiography (OCTA) revealed reduced vessel density and enlarged foveal avascular zone in subjects with COVID-19 compared to controls. CONCLUSIONS The results suggested that COVID-19-related retinal microvasculopathy is a significant ocular manifestation of COVID-19 and may herald future retinal complications. These microvascular impairments might have occurred antecedent to clinically visible changes and could be detected earlier by OCTA. These findings are significant, due to the large numbers with COVID-19, and need to be recognized by ophthalmologists as a potential long-term sequalae of the disease.
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EXTENDED FIELD IMAGING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FOR THE STUDY OF RETINAL AND CHOROIDAL CHANGES AFTER RADIATION THERAPY FOR CHOROIDAL MELANOMA: Comparison With Wide-Field Angiography.
Preziosa, C, Corvi, F, Staurenghi, G, Pellegrini, M
Retina (Philadelphia, Pa.). 2021;(2):373-380
Abstract
PURPOSE Radiation retinopathy is a common side effect of ocular radiotherapy with no long-term effective therapy. Optical coherence tomography angiography (OCTA) and wide-field fluorescein angiography (FA) are widely used for the study of radiation maculopathy and peripheral nonperfusion, respectively. We investigated the role of extended field imaging (EFI-OCTA) for the study of retinal and choroidal alterations after radiotherapy for choroidal melanoma. METHODS Cross-sectional observational study of 20 eyes of 20 patients diagnosed with radiation retinopathy. All patients underwent a complete imaging evaluation including FA and indocyanine green angiography (ICGA) with 55° and 102° lens (Spectralis Heidelberg Engineering, Heidelberg, Germany). Optical coherence tomography angiography imaging was performed with the Zeiss PlexElite 9000 Swept Source OCTA (Carl Zeiss Meditec, Dublin, CA) using a 12 × 12-mm volume scan pattern centered on the fovea and a +20.00-diopter lens specifically designed to obtain EFI examination. The imaging methods were then compared in terms of visible field of view, extension of nonperfused areas, and vessel density. RESULTS The mean extension ratio of EFI-OCTA compared to OCTA without EFI, FA/ICGA 55° and FA/ICGA 102° was, respectively, 1.98 ± 0.02, 1.21 ± 0.01 and 0.36 ± 0.003. The mean extension of retinal and choroidal nonperfused areas evaluated by EFI-OCTA (63.03 ± 48.21 and 38.63 ± 30.83 mm2) were significantly higher than with OCTA without EFI (40.40 ± 34.87 and 24.26 ± 21.82 mm2, P < 0.001) but lower than with FA/ICGA 102° (140.7 ± 69.23 and 108.3 ± 69.51 mm2, P < 0.001). No significant differences were found between mean extension of retinal and choroidal ischemic areas measured with EFI-OCTA and FA/ICGA 55° (69.64 ± 51.92 and 47.23 ± 33.59 mm2). The mean vessel density of EFI-OCTA (retina and choroid segmentation) was significantly different compared to OCTA without EFI (P < 0.05). Retinal vessel density was negatively correlated to retinal extension of nonperfused areas (r = -0.5, P = 0.02), and choroidal vessel density was negatively correlated to choroidal nonperfused areas (r = -0.6, P = 0.003) measured with EFI-OCTA. CONCLUSION In our series, EFI-OCTA captured larger areas than OCTA without EFI and FA/ICGA with 55° lens. EFI-OCTA images showed a good definition of retinal and choroidal vascular changes after radiotherapy, suggesting a possible role of this safe and noninvasive imaging technique in the follow-up of patients with radiation retinopathy.
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Dexamethasone implants in patients with diabetic macular edema undergoing cataract surgery: Italian expert panel consensus statements.
Alessio, G, Boscia, F, Caporossi, A, Panozzo, G, Reibaldi, M, Staurenghi, G, Varano, M, Bandello, F
European journal of ophthalmology. 2021;(3):1122-1127
Abstract
PURPOSE Intravitreal corticosteroid implants based on sustained-release dexamethasone provide effective retinal delivery of drug for around 6 months for the treatment of diabetic macular edema (DME). As current recommendations on the management of patients with DME undergoing cataract surgery are limited, this article aims to highlight issues and provide guidance on the use of dexamethasone intravitreal implants (DEX-DDS) in patients with DME undergoing cataract surgery, based on the consensus findings of a panel of Italian experts. METHODS The panel developed a survey regarding the use of DEX-DDS in patients with DME undergoing cataract surgery, following a comprehensive literature search. The results of the survey were discussed at an experts' meeting in September 2018, with a structured approach to determining consensus. The routine management of patients with DME undergoing cataract surgery was also developed for use as a basis of discussion to highlight current issues. RESULTS Eight consensus statements are presented, along with key issues that highlight controversial/outstanding issues in the use of DEX-DDS in DME patients with cataracts. CONCLUSION The consensus statements can help provide practical guidance for clinicians in daily practice on the rationale, patient diagnosis and selection, and optimal management of patients with DME undergoing cataract surgery.
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Outer Retinal Layer Thickening Predicts the Onset of Exudative Neovascular Age-Related Macular Degeneration.
Invernizzi, A, Parrulli, S, Monteduro, D, Cereda, MG, Nguyen, V, Staurenghi, G, Cheung, CMG, Gillies, M, Teo, KYC
American journal of ophthalmology. 2021;:19-27
Abstract
PURPOSE To assess changes in outer retinal layer (ORL) thickness before the development of exudative macular neovascularization (MNV) in eyes with age-related macular degeneration. DESIGN Retrospective observational case series. METHODS Eyes with age-related macular degeneration that eventually developed exudative MNV followed with sequential optical coherence tomography for ≥2 years before the exudation occurred were enrolled. The ORL thickness was automatically calculated by the optical coherence tomography software for each sector of the early treatment diabetic retinopathy study map at each follow-up visit. The ORL thickness change from baseline to the day when the exudative MNV developed was compared between sectors that eventually developed exudative MNV and those that did not. RESULTS Forty-seven eyes (47 patients) were included. At baseline (24 ± 3 months before exudative MNV), mean (standard deviation) ORL thickness of sectors that eventually developed exudative MNV was similar to that of sectors that did not (85.2 [8.2] µm vs 86.8 [5.7] µm, P = .08). ORL thickness significantly increased in sectors that developed exudative MNV compared with those that did not (+5.8 [10.4] µm vs -2.8 [3.6] µm, P < .01). The regression model based on these data predicted an increase in ORL thickness from baseline of +4.2% 55 days and +11.1% 30 days before exudative MNV was detected. The ORL thickness of areas that did not develop exudative MNV did not change. CONCLUSION Thickening of the ORL begins in the area where exudative MNV will develop long before the exudation, accelerating significantly in the last 2 months. The occurrence of exudative MNV could be predicted by 2 months using this simple analysis.
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The In Vivo Correlation between Retinal Pigment Epithelium Thickness and Quantitative Fundus Autofluorescence in a White Population.
Cozzi, M, Viola, F, Belotti, M, Cigada, M, Cherepanoff, S, Staurenghi, G, Invernizzi, A
Ophthalmology. Retina. 2021;(4):365-373
Abstract
PURPOSE To investigate the influence of age on the thickness of the retinal pigment epithelium (RPE)/Bruch's membrane (BM) complex and the quantitative autofluorescence (qAF) and to study the possible correlation existing between these 2 parameters in a healthy White population. DESIGN Cross-sectional, observational study. PARTICIPANTS Healthy White volunteers aged 18 to 65 years. METHODS All subjects underwent spectral domain OCT (SD-OCT) and qAF imaging with the Heidelberg HRA-Spectralis (Heidelberg Engineering, Heidelberg, Germany). Spectral domain OCT images were analyzed using the in-built graph-based automatic segmentation algorithm for single retinal layer identification to assess RPE/BM complex thickness in vivo. The thickness values of both inner and outer rings of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, generated by the software using the "RPE" segmentation, were averaged to obtain a single RPE/BM complex thickness value in each eye. Quantitative autofluorescence images were also evaluated using a dedicated software. The qAF values of 8 subfields forming a ring centered onto the fovea were collected and averaged to obtain a single qAF value (qAF8) in each eye. The correlation among the RPE/BM complex thickness, the qAF value, and the age of the subjects was investigated. MAIN OUTCOME MEASURES The in vivo correlation between RPE/BM complex thickness and qAF. RESULTS A total of 105 eyes from 105 subjects (mean age, 42.1 ± 13.9 years; range, 18-65) were included in the analysis. The mean RPE/BM complex thickness significantly increased with age (r = 0.33, P = 0.0006). The values of qAF also positively increased with age (P < 0.0001). A significant correlation was found between qAF and RPE/BM complex thickness (r = 0.27, P = 0.004). After adjusting for age, iris color, and gender, the correlation remained significant only for subjects aged less than 40 years (P = 0.009). CONCLUSIONS BM complex thickness was significantly co/BM complex thickness increased with age in a healthy White population. A similar increase was found for qAF values. After adjusting for age and iris color, qAF and RPE/BM complex thickness were still correlated in subjects aged less than 40 years. The RPE/BM complex thickness could reflect the lipofuscin/melanolipofuscin accumulation in normal subjects, adding great interest in RPE cell biology.
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Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration: Results from the Prospective Proxima A and B Clinical Trials.
Holekamp, N, Wykoff, CC, Schmitz-Valckenberg, S, Monés, J, Souied, EH, Lin, H, Rabena, MD, Cantrell, RA, Henry, EC, Tang, F, et al
Ophthalmology. 2020;(6):769-783
Abstract
PURPOSE To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD). DESIGN Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials. PARTICIPANTS Eligible patients were aged ≥50 years. Patients in Proxima A had bilateral GA without choroidal neovascularization (CNV) in either eye (N = 295). Patients in Proxima B had GA without CNV in the study eye and CNV±GA in the fellow eye (fellow eye CNV cohort, n = 168) or GA without CNV in the study eye, no CNV/GA in the fellow eye (fellow eye intermediate AMD cohort, n = 32). METHODS Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics. MAIN OUTCOME MEASURES Prespecified end points included change in GA area from baseline, best-corrected visual acuity (BCVA) score assessed by Early Treatment Diabetic Retinopathy Study (ETDRS), and visual acuity under low-luminance (LLVA). RESULTS At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mm2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm2 in the fellow eye intermediate AMD cohort (Proxima B). Progression of GA was greater in patients with baseline nonsubfoveal (vs. subfoveal) GA lesions and tended to increase as baseline low-luminance deficit increased (all patients). Conversion to GA or CNV in the fellow eye occurred in 30% and 6.7% of participants, respectively, in the Proxima B intermediate AMD cohort at month 12. Adjusted mean (standard error) changes in BCVA and LLVA (ETDRS letters) in the study eye from baseline to 24 months were -13.88 (1.40) and -7.64 (1.20) in Proxima A, -9.49 (1.29) and -7.57 (1.26) in Proxima B fellow eye CNV cohort, and -11.48 (3.39) and -8.37 (3.02) in Proxima B fellow eye intermediate AMD cohort, respectively. CONCLUSIONS The prospective Proxima A and B studies highlight the severe functional impact of GA and the rapid rate of GA lesion progression over a 2-year period, including in patients with unilateral GA at baseline.
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Effect of Baseline Subretinal Fluid on Treatment Outcomes in VIVID-DME and VISTA-DME Studies.
Korobelnik, JF, Lu, C, Katz, TA, Dhoot, DS, Loewenstein, A, Arnold, J, Staurenghi, G
Ophthalmology. Retina. 2019;(8):663-669
Abstract
PURPOSE To evaluate the effect of baseline subretinal fluid (SRF) on treatment outcomes with intravitreal aflibercept injection (IAI) versus laser treatment in patients with diabetic macular edema (DME) in the VIVID and VISTA studies. DESIGN Post hoc analysis of 2 randomized controlled trials. PARTICIPANTS Eight hundred seventy-two patients with DME. METHODS We randomized patients to receive IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser. MAIN OUTCOME MEASURES Effect of presence or absence of baseline SRF on visual outcomes in the integrated dataset at weeks 52 and 100. RESULTS Mean best-corrected visual acuity (BCVA) gains in the 2q4, 2q8, and laser arms at week 52 were +14.5, +11.0, and -2.3 letters, respectively, (those with baseline SRF) and +10.3, +10.6, and +2.5 letters, respectively, (those without). At week 100, mean gains were +13.5, +10.9, and -2.3 letters (those with baseline SRF) and +10.6, +10.0, and +2.7 letters (those without). The treatment effect for IAI versus laser from baseline to week 52 of 100 was greater for patients with baseline SRF versus those without (nominal P < 0.001, for interaction). The proportions of patients who gained 15 letters or more in the 2q4, 2q8, and laser arms at week 52 were 52.3%, 40.2%, and 8.9%, respectively, (those with baseline SRF) and 30.9%, 29.1%, and 8.2%, respectively, (those without) and at week 100 were 50.0%, 35.4%, and 12.9%, respectively, (those with baseline SRF) and 33.3%, 30.5%, and 12.5%, respectively, (those without). Time to first sustained SRF clearance seemed to be shorter in the IAI arms versus laser. The overall safety profile was similar in the IAI arms. CONCLUSIONS This post hoc analysis demonstrated the visual outcome benefits of IAI over laser, regardless of baseline SRF status. A greater treatment effect of IAI was observed in patients with baseline SRF versus those without; however, no meaningful impact of baseline SRF status on treatment outcomes with IAI was demonstrated, indicating that the differential effects of laser might have been the driving force behind the different treatment outcomes in both groups.
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Evaluating the Impact of Intravitreal Aflibercept on Diabetic Retinopathy Progression in the VIVID-DME and VISTA-DME Studies.
Mitchell, P, McAllister, I, Larsen, M, Staurenghi, G, Korobelnik, JF, Boyer, DS, Do, DV, Brown, DM, Katz, TA, Berliner, A, et al
Ophthalmology. Retina. 2018;(10):988-996
Abstract
PURPOSE To evaluate the impact of intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Tarrytown, NY) versus laser on progression of diabetic retinopathy (DR) severity in Intravitreal Aflibercept Injection in Vision Impairment due to DME (VIVID-DME) and Study of Intravitreal Aflibercept Injection in Patients with Diabetic Macular Edema (VISTA-DME). DESIGN Secondary and exploratory analyses of 2 phase 3, randomized, controlled studies. PARTICIPANTS All patients with a baseline Diabetic Retinopathy Severity Scale (DRSS) score based on fundus photograph (full analysis), patients who progressed to proliferative DR (PDR) (safety analysis) in VIVID-DME (n = 403) and VISTA-DME (n = 459), or both. METHODS We randomized patients with diabetic macular edema (DME) to intravitreal aflibercept 2 mg every 4 weeks (2q4), intravitreal aflibercept 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation at baseline and sham injections at every visit. MAIN OUTCOME MEASURES Proportions of patients with 2-step or more and 3-step or more improvements from baseline in DRSS score, who progressed to PDR, and who underwent panretinal photocoagulation (PRP). RESULTS Among patients with an assessable baseline DRSS score, most showed moderately severe or severe nonproliferative DR. The proportions of patients treated with 2q4, 2q8, and laser with a 2-step or more improvement in DRSS score at week 100 were 29.3%, 32.6%, and 8.2%, respectively, in VIVID-DME and 37.0%, 37.1%, and 15.6%, respectively, in VISTA-DME; the proportions with a 3-step or more improvement in DRSS score were 7.3%, 2.3%, and 0%, respectively, and 22.7%, 19.9%, and 5.2%, respectively. Fewer patients in the 2q4 and 2q8 groups versus the laser group progressed to PDR at week 100 in VISTA-DME (1.5% and 2.2% vs. 5.3%) and VIVID-DME (3.2% and 2.0% vs. 12.3%). The proportions of patients who underwent PRP were 2.9%, 0.7%, and 4.5%, respectively, in VIVID-DME and 1.9%, 0.7%, and 5.2%, respectively, in VISTA-DME. The most frequent serious ocular adverse event at week 100 was cataract (pooled intravitreal aflibercept, 1.7% of patients; laser, 3.5% of patients). CONCLUSIONS These analyses demonstrate the benefit of intravitreal aflibercept over laser with respect to DR progression, suggesting a benefit on DME, and on underlying DR.