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    Research Update 556


    Risk of intraocular inflammation after injection of antivascular endothelial growth factor agents: a meta-analysis.

    Retina (Philadelphia, Pa) 2022 Nov 1

    Patil NS, Dhoot AS, Popovic MM, Kertes PJ, Muni RH.

    Purpose: This meta-analysis investigates the incidence of intraocular inflammation (IOI) after intravitreal antivascular endothelial growth factor injections in neovascular age-related macular degeneration.

    Methods: A systematic search was performed on Ovid MEDLINE, Embase, and Cochrane Central from January 2005 to April 2021. Randomized controlled trials comparing IOI after intravitreal bevacizumab, ranibizumab, brolucizumab, or aflibercept in neovascular age-related macular degeneration were included. Primary outcomes were sight-threatening IOI, final best-corrected visual acuity, and change in best-corrected visual acuity from baseline. Secondary outcomes included the incidence of other IOI events. Meta-analysis was performed using a random-effects model.

    Results: Overall, 11,460 unique studies were screened, of which 14 randomized controlled trials and 6,759 eyes at baseline werAe included. There was no difference between agents for the risk of endophthalmitis and retinal vascular occlusion. Compared with aflibercept, brolucizumab had a higher incidence of generalized IOI (risk ratio = 6.24, 95% confidence interval = [1.40-27.90]) and vitreous haze/floaters (risk ratio = 1.64, 95% confidence interval = [1.00-2.67]). There were no significant differences between comparators for other secondary end points.

    Conclusion: There was no difference in the risk of severe sight-threatening IOI outcomes between intravitreal antivascular endothelial growth factor agents. There was a significantly higher risk of generalized IOI after brolucizumab relative to aflibercept. Our results alongside other recent safety findings suggest the need for further investigation in the risk-benefit profile of brolucizumab for the treatment of neovascular age-related macular degeneration.

    DOI: 10.1097/IAE.0000000000003582


    Reticular Pseudodrusen Are Associated With More Advanced Para-Central Photoreceptor Degeneration in Intermediate Age-Related Macular Degeneration.

    Investigative Ophthalmology & Visual Science. 2022 Oct 3

    Trinh M, Eshow N, Alonso-Caneiro D, Kalloniatis M, Nivison-Smith L.

    Purpose: The purpose of this study was to examine retinal topographical differences between intermediate age-related macular degeneration (iAMD) with reticular pseudodrusen (RPD) versus iAMD without RPD, using high-density optical coherence tomography (OCT) cluster analysis.

    Methods: Single eyes from 153 individuals (51 with iAMD+RPD, 51 with iAMD, and 51 healthy) were propensity-score matched by age, sex, and refraction. High-density OCT grid-wise (60 × 60 grids, each approximately 0.01 mm2 area) thicknesses were custom-extracted from macular cube scans, then compared between iAMD+RPD and iAMD eyes with correction for confounding factors. These “differences (µm)” were clustered and results de-convoluted to reveal mean difference (95% confidence interval [CI]) and topography of the inner retina (retinal nerve fiber, ganglion cell, inner plexiform, and inner nuclear layers) and outer retina (outer plexiform/Henle’s fiber/outer nuclear layers, inner and outer segments, and retinal pigment epithelium-to-Bruch’s membrane [RPE-BM]). Differences were also converted to Z-scores using normal data.

    Results: In iAMD+RPD compared to iAMD eyes, the inner retina was thicker (up to +5.89 [95% CI = +2.44 to +9.35] µm, P < 0.0001 to 0.05), the outer para-central retina was thinner (up to -3.21 [95% CI = -5.39 to -1.03] µm, P < 0.01 to 0.001), and the RPE-BM was thicker (+3.38 [95% CI = +1.05 to +5.71] µm, P < 0.05). The majority of effect sizes (Z-scores) were large (-3.13 to +1.91).

    Conclusions: OCT retinal topography differed across all retinal layers between iAMD eyes with versus without RPD. Greater para-central photoreceptor thinning in RPD eyes was suggestive of more advanced degeneration, whereas the significance of inner retinal thickening was unclear. In the future, quantitative evaluation of photoreceptor thicknesses may help clinicians monitor the potential deleterious effects of RPD on retinal integrity.

    DOI: 10.1167/iovs.63.11.12


    Incidence of New Diabetic Macular Edema in Fellow Eyes of Patients in the VISTA and VIVID Studies.

    Retina (Philadelphia, Pa). 2022 Oct 17

    Dhoot DS, Moini H, Reed K, Silva FQ, Berliner A, Du W, Sharma S.

    Purpose: To characterize diabetic macular edema (DME) incidence in fellow eyes of patients treated for DME in the study eye.

    Methods: This post hoc analysis of VISTA/VIVID data evaluated fellow eyes without DME at baseline through Week 100. DME presence in the fellow eye was inferred by investigator-reported DME adverse events and use of DME treatments.

    Results: Over 100 weeks, 44.9%, 44.2%, and 42.9% of fellow eyes developed DME in the intravitreal aflibercept injection (IAI) 2 mg q4 weeks (n=245), IAI 2 mg q8 weeks (n=258), and laser control (n=252) groups, respectively. Mean time to DME development in combined treatment groups was ∼6 months. Multivariable regression analysis confirmed patients with shorter diabetes duration (hazard ratio [HR] per 10-year decrease, 1.16; 95% confidence interval [CI], 1.03, 1.30; P = 0.0160) and thicker baseline study eye central subfield thickness (CST) (HR per 10-µm increase, 1.01; 95% CI, 1.01, 1.02; P = 0.0002) were at higher risk of developing DME in the fellow eye.

    Conclusion: Among patients with DME in 1 eye at baseline, almost half developed DME in the fellow eye over 2 years. Shorter duration of diabetes and thicker study eye CST were predictors of DME development in the fellow eye.

    DOI: 10.1097/IAE.0000000000003658


    Risk factors and clinical significance of prechoroidal cleft in eyes with neovascular age-related macular degeneration in Caucasian patients.

    Acta Ophthalmologica. 2022 Oct 18.

    Kredi G, Iglicki M, Gomel N, Hilely A, Loewenstein A, Habot-Wilner Z, Zur D.

    Objective: The objective of the study was to investigate the prevalence, risk factors and clinical significance of prechoroidal cleft (PC) among neovascular age-related macular degeneration (nAMD) patients in a Caucasian population.

    Design: A retrospective observational cohort study.

    Methods: A total of 140 patients with naive nAMD were treated with anti-vascular endothelial growth factor (VEGF) injections and a follow-up of ≥24 months. Optical coherence tomography (OCT) scans were graded for the presence of PC, central subfield foveal thickness (CSFT), maximal retinal thickness (MRT), pigment epithelial detachment (PED), presence of intraretinal fluid (IRF), subretinal fluid (SRF) and subretinal hyper-reflective material (SHRM) at baseline, 3, 6, 12 and 24 months. Best corrected visual acuity (BCVA) and anti-VEGF treatments were recorded.

    Results: Out of 140, 21 eyes (15%) developed PC. BCVA improved significantly from 0.68 ± 0.56 to 0.62 ± 0.59 logMAR after 24 months (p = 0.008). The change in BCVA was not related to the presence of cleft (p = 0.208). Multivariate analysis confirmed that higher baseline CSFT (p = 0.011, OR = 1.004, 95%, CI 1.001-1.007) and the presence of multi-layered PED (p < 0.001, OR = 21.153, 95%, CI 5.591-80.026) were both predictive for development of PC. Eyes with PC received more injections than eyes without PC.

    Conclusion: Prechoroidal cleft was found in 15% of Caucasian nAMD patients treated with anti-VEGF injections and was related to greater retinal and PED height, as well as presence of multi-layered PED. Eyes with PC required more anti-VEGF injections. The presence of PC correlates with disease activity, and intensive anti-VEGF suppression can preserve vision.

    DOI: 10.1111/aos.15273

    Anatomical and functional correlates of cystic macular edema in retinitis pigmentosa.

    PLoS One. 2022 Oct 21

    Ruff A, Tezel A, Tezel TH.

    Cystoid macular edema (CME) is a major cause of central visual deterioration in retinitis pigmentosa. The exact reason for CME and its prognostic significance in this patient population is unknown. We seek to find clues to answer these questions by examining the anatomical correlations between retinal cysts and retinal morphometric parameters in a cohort of patients with retinitis pigmentosa and CME. For this reason, 103 patients (196 eyes) with untreated cystoid macular edema (CME) were identified from a pool of 578 genotyped patients with retinitis pigmentosa. Image analyses were conducted using three central horizontal OCT scans of these patients to calculate cross-sectional areas of the retinal nerve fiber layer, outer retinal, inner retinal, cysts, and total retinal areas. Lengths of the ellipsoid zone and outer limiting membrane were also measured. Best-fit curves were derived for analyzing the factors playing a role in the size of the retinal cysts and the patients’ visual acuity. Generalized Estimating Equation and multivariate linear regression analyses were conducted to determine the correlations between visual acuity, morphometric and clinical data, and the significant cyst size and visual acuity determinants. Twenty-five percent of the screened patients (103/578) had CME. Patients with autosomal dominant retinitis pigmentosa had the highest incidence of CME (43.6%, p<0.001) but also had the best visual acuity (20/34±20/30, p = 0.02). The total cyst area was 0.14±0.18 mm2. Outer retinal area (B = 0.214; p = 0.008), age (B = -0.003; p<0.001) and retinal nerve fiber area (B = 0.411; p = 0.005) were main determinants of the (r = 0.44; p<0.001) cyst size. Cysts resolved with progressing retinal degeneration. Length of the intact ellipsoid zone (B = -5.16E-5; p<0.001), the inheritance pattern (B = 0.04; p = 0.028) and retinal nerve fiber area (B = 0.751; p<0.001) were the main determinants of visual acuity. In patients with retinitis pigmentosa and cystoid macular edema, retinal nerve fiber layer thickness is associated with decreasing visual acuity and cyst size. This finding suggests that intraretinal cysts may compress retinal axons and cause subsequent visual loss in retinitis pigmentosa.

    DOI: 10.1371/journal.pone.0276629


    The influence of the topographic location of geographic atrophy on vision-related quality of life in nonexudative age-related macular degeneration.

    Graefe’s Archive for Clinical & Experimental Ophthalmology. 2022 Oct 21.

    Ahluwalia A, Shen LL, Bao Y, Sun M, Young BK, Park MM, Del Priore LV.

    Purpose: To examine associations between the topographic distribution of geographic atrophy (GA) and vision-related quality of life (VRQoL).

    Methods: This study included 237 eyes from 161 participants in the Age-Related Eye Disease Study (AREDS). GA lesions were manually delineated with color fundus photographs obtained by the AREDS Research Group and atrophic area was measured in an Early Treatment Diabetic Retinopathy Study (ETDRS) grid. VRQoL was measured using the National Eye Institute Visual Function Questionnaire (NEI-VFQ). Area of atrophy in the ETDRS grid subfields was correlated with VRQoL by linear regression modeling.

    Results: The average area of atrophy in the better and worse eye was 3.43mm2 and 7.15mm2 respectively. In multivariable analysis, VRQoL was not associated with total area of atrophy in the better eye (β, - 0.53; 95% confidence interval [CI], - 1.11 to 0.05; P = 0.07) or worse eye (β, 0.12; 95% CI, - 0.32 to 0.55; P = 0.59). However, area of atrophy in the central 1-mm-diameter zone of the better eye was significantly associated with VRQoL when the ETDRS subfields were examined individually (β, - 14.57; 95% CI, - 27.12 to - 2.02; P = 0.023), grouped into quadrants (β, - 18.35; 95% CI, - 30.03 to - 6.67; P = 0.002), inner and outer zones (β, - 17.26; 95% CI, - 29.38 to - 5.14; P = 0.006), or vertical and horizontal zones (β, - 18.97; 95% CI, - 30.18 to - 7.77; P = 0.001).

    Conclusion: In patients with GA, greater area of atrophy in the central 1-mm-diameter zone of the better eye was independently associated with lower VRQoL, while total area of atrophy in the better or worse eye was not.

    DOI: 10.1007/s00417-022-05849-6

    Low Vision Referral Patterns in Intermediate Age-Related Macular Degeneration.

    Current Eye Research. 2022 Oct 19.

    Larochelle RD, Patnaik JL, Lynch AM, Mandava N, Hanson K; University of Colorado Retina Research Group; *University of Colorado Retina Research Group:.

    Purpose: Sparse data exist regarding low vision (LV) services referral patterns. We retrospectively examined our institution’s intermediate age-related macular degeneration (iAMD) patients to determine factors influencing referral.

    Methods: We compared visual acuity (VA) and Visual Function Questionnaire (VFQ-25) composite and subscale scores for referred and non-referred iAMD patients. VA was collected at time of referral or most recent visit, and VFQ-25 was taken upon enrollment into the registry.

    Results: Thirty-six (15.5%) of the 232 iAMD patients were referred to LV. Referred patients were more likely to have older age, worse VA in both eyes, and lower VFQ-25 scores. Univariate analysis of VFQ-25 subscales demonstrated worse scores in general vision, near, distance, mental health, role limitations, dependency, and driving. Multivariable analysis revealed lower scores in general health, general vision, and driving. Forty-eight percent of non-referred patients had VA or VFQ-25 composite scores at least as poor as the median for referred patients. Two-thirds of patients who were not referred had no discernable obstacle to referral.

    Conclusions: Our institution refers patients with worse objective and functioning vision, but more patients may benefit from referral. Future studies should identify metrics to prompt referral and evaluate this approach.

    DOI: 10.1080/02713683.2022.2135104


    Refractive error change during treatment of diabetic macular edema: A Post Hoc Analysis of the Diabetic Retinopathy Clinical Research Protocol T Trial.

    Retina (Philadelphia, Pa) 2022 Nov 1

    Salabati M, Mahmoudzadeh R, Starr MR, Zhang Q, Sharpe J, Hsu J, Ho AC, Regillo C, Kuriyan AE.

    Purpose: To evaluate the impact of anti-vascular endothelial growth factor therapy on the refractive error in eyes with diabetic macular edema.

    Methods: Post hoc analysis of Diabetic Retinopathy Clinical Research protocol T. Spherical equivalent (SE) was calculated for study and fellow eyes at baseline, 1-year, and 2-year visits. The SE change of the eyes with edema was compared with those with resolved edema. The correlation between refractive error changes and central subfield thickness was evaluated.

    Results: Among 543 study eyes, SE changed from -0.17 (2.04) D at baseline visit to -0.16 (2.14) D at 2 years giving a hyperopic shift of 0.04 (0.82) D (P = 0.022). Among fellow eyes, mean (SD) SE changed from -0.19 (2.1) D at baseline to -0.11 (2.1) D at 2 years, giving a hyperopic shift of 0.12 (0.84) D (P = 0.001). No significant difference in SE shift was found between eyes with and without edema at 2 years in phakic (0.12D and 0.08 D, P = 0.87) and pseudophakic eyes (-0.24D and -0.08D, P = 0.30). The SE shift was not correlated with central subfield thickness change at the end of the second year (r = 0.02, P = 0.62).

    Conclusion: Diabetic macular edema patients have minimal changes in refractive error. The correction of refractive error may be considered during treatment, regardless of the presence of edema.

    DOI: 10.1097/IAE.0000000000003583


    Outcomes of Over 40,000 Eyes Treated for Diabetic Macula Edema in Routine Clinical Practice: A Systematic Review and Meta-analysis.

    Advances in Therapy. 2022 Oct 15

    Mehta H, Nguyen V, Barthelmes D, Pershing S, Chi GC, Dopart P, Gillies MC.

    Introduction: We investigated effectiveness and safety outcomes of diabetic macula edema (DME) treatment in routine clinical practice.

    Methods: A literature search was conducted of peer-reviewed articles published from January 2011 to September 2021. Studies of DME treatment in real-world practice of at least 6 months with at least 50 eyes at baseline were included. Randomized controlled trials (RCTs) were excluded. The primary outcome for this meta-analysis was change in visual acuity (VA) 12 months after starting treatment.

    Results: Of 3034 initially identified studies, 138 met selection criteria, representing more than 40,000 eyes. The mean 12-month VA gain was 4.6 letters (95% CI 3.7, 5.4; baseline 58.6) for vascular endothelial growth factor inhibitors (anti-VEGF), 4.4 (2.5, 6.3; baseline 54.2) for steroids, and 2.1 (- 1.2, 5.3; baseline 63.6) for macular laser. Australian and New Zealand studies had better baseline VA when initiating treatment compared with Asia, Europe, and North America, translating to better VA at 12 months. Fewer anti-VEGF injections were delivered in real-world practice than registrational RCTs. Neither systemic nor ocular safety was consistently reported.

    Conclusions: Intravitreal anti-VEGF or steroids for DME generally led to visual gains in real-world practice but these were less impressive than RCTs, with undertreatment and differences in baseline characteristics likely contributing factors.

    DOI: 10.1007/s12325-022-02326-8