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Research Update 574


Effect of statins on the age of onset of age-related macular degeneration.

Graefe’s Archive for Clinical and Experimental Ophthalmology. 2023 Mar 14.

Ganesh D, Chiang JN, Corradetti G, Zaitlen N, Halperin E, Sadda SR.

Background: This study evaluated the relationship between statin use and the age of onset of age-related macular degeneration (AMD).

Methods: Electronic Health Records from 52,840 patients evaluated at University of California Los Angeles (UCLA) Ophthalmology Clinics and 9,977 patients evaluated at University of California San Francisco (UCSF) Ophthalmology Clinics were screened. Survival analysis was performed using Cox proportional hazards regression models and visualized using Kaplan Meier survival curves, with the following covariates-sex, ethnicity, smoking history, fluoxetine use, obesity, diabetes mellitus, and hypertension.

Results: 5,498 of 52,840 patients at UCLA were diagnosed with AMD. Statin use was associated with a later AMD onset (HR = 0.8823, p < 0.0001), while female sex (HR = 1.0852, p= 00,035), obesity (HR = 1.4555, p < 0.0001), and fluoxetine (HR = 1.3797, p= 0.0003) were associated with an earlier AMD onset. Non-hispanic black (HR = 0.5687, p < 0.0001) and hispanic ethnicities (HR = 0.8269, p= 0.0028) were associated with a later AMD onset. When stratifying for ethnicity, statins, fluoxetine, sex, and obesity were significant only within non-hispanic white subjects. Statin use was significant among patients with dry AMD (HR = 0.8410, p= 0.0001) but not wet AMD (0.9188, p= 0.0351). In the replication cohort, 526 of 9,977 patients at UCSF had AMD. Associations between statins (HR = 0.7643, p= 0.0033), non-hispanic black ethnicity (HR = 0.5043, p= 0.0035), and obesity (HR = 1.9602, p < 0.0001) on AMD onset were confirmed.

Conclusions: In both cohorts, statin use and non-hispanic black ethnicity are associated with a later AMD onset, while obesity with an earlier AMD onset.

DOI: 10.1007/s00417-023-06017-0


Severe Visual Loss During Anti-Vegf Intravitreal Injections in Neovascular Age-Related Macular Degeneration Timing, Prognosis And Optical Coherence Tomography Findings.

Retina. 2023 Mar 9.

Grassi MO, Monteleone G, Pozharitskiy N, Molfetta T, Boscia G, Alessio G, Boscia F.

Purpose: Intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) is the standard of care for neovascular age-related macular degeneration (nAMD). However, a small subgroup of patients still experience severe visual impairment, which may be related to the number of IVI administered.

Methods: This retrospective observational study analyzed data from patients with sudden severe visual decline (≥15 Early Treatment Diabetic Retinopathy Study [ETDRS] letters loss between two consecutive IVIs) during anti-VEGF treatment for nAMD. Best correct visual acuity examination, optical coherence tomography (OCT) and OCT angiography (OCTA) were performed before every IVI and central macular thickness (CMT) and drug injected were collected.

Results: 1019 eyes received anti-VEGF IVI for nAMD from December 2017 to March 2021. Severe VA loss occurred in 15.1% after a median of 6 (range 1-38) IVI. Ranibizumab was injected in 52.8%, and aflibercept in 31.9% of cases. Functional recovery after 3 months was significant, without further improvement at 6 months. Visual prognosis relative to the percentage of CMT change showed better visual outcome in eyes with no substantial change in CMT compared to an increase of >20% or a decrease of >5%.

Conclusion: In this first real-life study exploring severe VA loss during anti-VEGF treatment in patients with nAMD, we found that it was not unusual for a ≥15 ETDRS letters loss to occur between two consecutive IVIs, often within 9 months of diagnosis and 2 months after the last IVI. Close follow-up and a proactive regimen should be preferred, at least in the first year.

DOI: 10.1097/IAE.0000000000003774

Benefit of intravitreal injections in patients with sub-threshold baseline visual acuity: a retrospective single-centre study.

Graefe’s Archive for Clinical and Experimental Ophthalmology. 2023 Mar 16.

Grimm NA, Fahimi S, Kück F, Take P, Lauermann P, Nguyen-Hoehl A, Hoerauf H, Feltgen N, Bemme S.

Purpose: To investigate the lower visual acuity threshold for recommending intravitreal injection therapy (IVI). The lower limit of 1.3 logMAR best-corrected visual acuity (BCVA) was adopted in 2006 and has been maintained since then.

Methods: In this retrospective study, data from patients with a logMAR BCVA ≤ 1.3 and 24 months follow-up were analysed. We included patients with neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME), or retinal vein occlusion (RVO).

Results: The data from 164 patients (nAMD: 107; DME: 15; RVO: 42) were analysed. We observed a significant improvement at all time intervals (0 to 6, 6 to 12, 12 to 18, and 18 to 24 months after initiating IVI) compared to baseline. Across all indications, median BCVA improved from 1.4 to 1.0 within the first 6 months and remained stable within 24 months. Patients received a median of 5 and 10 injections within 6 and 24 months, respectively. Median foveal retinal thickness was 594.5 μm at baseline and dropped to 244.5 μm, 235.5 µm, 183 µm, and 180 µm during the four consecutive time intervals.

Conclusion: Patients with nAMD, DME, and RVO with poor baseline BCVA may also benefit from intravitreal therapy with VEGF-inhibitors. In the present study, we observed functional and morphological improvement over 2 years irrespective of the underlying macular disease. Those patients should not be excluded from therapy.

DOI: 10.1007/s00417-023-05989-3

Randomized Phase 2b Study of Brimonidine Drug Delivery System Generation 2 for Geographic Atrophy in Age-related Macular Degeneration.

Ophthalmology Retina. 2023 Mar 9

Freeman WR, Bandello F, Souied E, Guymer RH, Garg SJ, Chen FK, Rich R, Holz FG, Patel SS, Kim K, López FJ; BEACON Study Group.

Purpose: To evaluate the safety and efficacy of repeat injections of Brimonidine Drug Delivery System (Brimo DDS) Generation 2 (Gen 2) containing 400 μg brimonidine in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

Design: Phase 2b, randomized, multicenter, double-masked, sham-controlled, 30-month study (BEACON).

Participants: Patients diagnosed with GA secondary to AMD and multifocal lesions with total area >1.25 mm2 and ≤18 mm2 in the study eye.

Methods: Enrolled patients were randomized to treatment with intravitreal injections of 400-μg Brimo DDS (n=154) or sham procedure (n=156) in the study eye every 3 months from day 1 through month 21.

Main Outcome Measures: The primary efficacy endpoint was change from baseline in the GA lesion area in the study eye, assessed with fundus autofluorescence imaging, at month 24. Safety measures included treatment-emergent adverse events (AEs).

Results: The study was terminated early, at the time of the planned interim analysis, because of a slow GA progression rate (∼1.6 mm2/year) in the enrolled population. Least-squares mean (standard error) GA area change from baseline at month 24 (primary endpoint) was 3.24 (0.13) mm2 with Brimo DDS (n=84) versus 3.48 (0.13) mm2 with sham (n=91); the reduction in GA area change from baseline in the Brimo DDS group compared with the sham group was 0.25 mm2 (7%) (P = 0.150). At month 30, the GA area change from baseline was 4.09 (0.15) mm2 with Brimo DDS (n=49) versus 4.52 (0.15) mm2 with sham (n=46), a reduction of 0.43 mm2 (10%) with Brimo DDS compared with sham (P=0.033). Exploratory analysis showed numerically smaller loss over time in retinal sensitivity assessed with scotopic microperimetry with Brimo DDS compared with sham (P=0.053 at month 24). Treatment-related AEs were usually related to the injection procedure. No implant accumulation was observed.

Conclusions: Multiple intravitreal administrations of Brimo DDS (Gen 2) were well tolerated. The primary efficacy endpoint at 24 months was not met, but there was a numerical trend for reduction in GA progression at 24 months compared with sham treatment. The study was terminated early because of the lower-than-expected GA progression rate in the sham/control group.

DOI: 10.1016/j.oret.2023.03.001


Henle’s Fiber Layer Thickness and Area Measurement in Type 2 Diabetes Mellitus with and without Retinopathy Using a Modified Directional Optical Coherence Tomography Strategy.

Retina. 2023 Mar 9.

Ersoz MG, Kırık F, Isik B, Ozdemir H.

Purpose: To investigate Henle’s fiber layer (HFL), outer nuclear layer (ONL), and outer plexiform layer (OPL) thicknesses and areas in the eyes of patients with diabetes with no diabetic retinopathy (NDR), in eyes with non-proliferative diabetic retinopathy without diabetic macular edema (NPDR), and in healthy eyes using a modified directional optical coherence tomography (OCT) strategy.

Methods: In this prospective study, the NDR group included 79 participants, the NPDR group comprised 68, and the control group had 58 participants. HFL, ONL, and OPL thicknesses and areas were measured on a horizontal single OCT scan centered on the fovea using directional OCT.

Results: The foveal, parafoveal, and total HFL were significantly thinner in the NPDR group than in the NDR group and the control group (all p<0.05). The NDR group had significantly thinner foveal HFL thickness and area compared with the control group (all p<0.05). The NPDR group had significantly thicker ONL thickness and area in all regions than the other groups (all p<0.05). The OPL measurements did not differ between the groups (all p>0.05).

Conclusion: Directional OCT provides isolated thickness and area measurement of HFL. In patients with diabetes, the HFL is thinner, and HFL thinning begins before the presence of DR.

DOI: 10.1097/IAE.0000000000003778


Impact of major age-related eye disorders on health-related quality of life assessed by EQ-5D: a systematic review and meta-analysis.

Graefe’s Archive for Clinical and Experimental Ophthalmology. 2023 Mar 14.

Kai JY, Xu Y, Li DL, Zhou M, Wang P, Pan CW.

Purpose: This study is to quantitatively estimate the health-related quality of life (HRQOL) impact of major age-related eye diseases (AREDs) including cataract, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR) assessed by the EuroQoL Five-Dimensional Questionnaire (EQ-5D).

Methods: PubMed, Embase, Cochrane Library, and CINAHL were searched until October 20, 2022. Studies were included if they reported the EQ-5D health utility score (HUS) or visual analogue scale (VAS) score of both AREDs patients and healthy controls. The mean difference (MD) in HUS or VAS score between cases and controls and its 95% confidence interval (95%CI) were pooled using the random-effects model. We also performed sensitivity analysis using the leaving-one-out method and subgroup analyses by sample size and race. The prevalence in reporting any problems in the five EQ-5D dimensions was summarized and compared between cases and controls using the Chi-square test.

Results: Fifteen articles involving 30,491 participants were included in this review. Pooled estimates indicated reduced HUS in AMD patients (MD = - 0.04, 95%CI – 0.07, – 0.01; P = 0.009), DR patients (MD = - 0.03, 95%CI – 0.05, – 0.01; P = 0.01), and glaucoma patients (MD = - 0.06, 95%CI – 0.10, – 0.01; P = 0.01), compared with the controls. Significantly lower EQ-5D VAS score was also observed in cataract patients (MD = - 11.33, 95%CI – 13.47, – 9.18; P < 0.001) and DR patients (MD = - 6.41, 95%CI – 10.64, – 2.18; P = 0.003). AREDs patients reported usual activities and anxiety/depression problems more frequently than the control group.

Conclusions: Our findings confirmed the HRQOL impairment caused by major AREDs including AMD, cataract, DR, and glaucoma. High-quality studies with large sample sizes are warranted to further verify our results.

DOI: 10.1007/s00417-023-06034-z

Frequency of coexistent eye diseases and cognitive impairment or dementia: a systematic review and meta-analysis.

Eye (London). 2023 Mar 15.

Xu Y, Phu J, Aung HL, Hesam-Shariati N, Keay L, Tully PJ, Booth A, Anderson CS, Anstey KJ, Peters R.

Objective: We aim to quantify the co-existence of age-related macular degeneration (AMD), glaucoma, or diabetic retinopathy (DR) and cognitive impairment or dementia.

Method: MEDLINE, EMBASE, PsycINFO and CINAHL were searched (to June 2020). Observational studies reporting incidence or prevalence of AMD, glaucoma, or DR in people with cognitive impairment or dementia, and of cognitive impairment or dementia among people with AMD, glaucoma, or DR were included.

Results: Fifty-six studies (57 reports) were included but marked by heterogeneities in the diagnostic criteria or definitions of the diseases, study design, and case mix. Few studies reported on the incidence. Evidence was sparse but consistent in individuals with mild cognitive impairment where 7.7% glaucoma prevalence was observed. Prevalence of AMD and DR among people with cognitive impairment ranged from 3.9% to 9.4% and from 11.4% to 70.1%, respectively. Prevalence of AMD and glaucoma among people with dementia ranged from 1.4 to 53% and from 0.2% to 25.9%, respectively. Prevalence of DR among people with dementia was 11%. Prevalence of cognitive impairment in people with AMD, glaucoma, and DR ranged from 8.4% to 52.4%, 12.3% to 90.2%, and 3.9% to 77.8%, respectively, and prevalence of dementia in people with AMD, glaucoma and DR ranged from 9.9% to 62.6%, 2.5% to 3.3% and was 12.5%, respectively.

Conclusions: Frequency of comorbid eye disease and cognitive impairment or dementia varied considerably. While more population-based estimations of the co-existence are needed, interdisciplinary collaboration might be helpful in the management of these conditions to meet healthcare needs of an ageing population.

DOI: 10.1038/s41433-023-02481-4


Association Between Glycemic Status and Age-Related Macular Degeneration: A Nationwide Population-Based Cohort Study.

Diabetes & Metabolism. 2023 Mar 15

Lee H, Han KD, Shin J.

Aim: – The risk of dry and wet age-related macular degeneration (AMD) based on fasting glucose levels and disease duration of type 2 diabetes was investigated.

Methods: – Using a health insurance claims database and the results of health examinations in South Korea, we conducted a retrospective, population-based cohort study of 2,103,604 adults ≥ 45 years of age who were AMD-free based on health checkups in 2009 and observed from January 1, 2011, to December 31, 2018. Glycemic status was classified into five groups: normal, impaired fasting glucose, new-onset diabetes (fasting glucose level ≥ 126 mg/dl but no diabetes diagnosis or diabetes medication), diabetes diagnosis < 5 years, and diabetes ≥ 5 years. According to the presence and absence of choroidal neovascularization, AMD was classified as wet AMD and dry AMD, respectively. Adjusted hazard ratios (HRs) of AMD occurrence were estimated in each category.

Results: – For dry AMD (n=36,271, 1.72%), the HR was 1.192 (1.141-1.245) among subjects with diabetes < 5 years and 1.294 (1.242-1.349) among subjects with diabetes ≥ 5 years compared with subjects with normal glycemic status after adjusting for age, sex, body mass index, lifestyle, and medical history. For wet AMD (n=12,912, 0.61%), the HR was 1.103 (1.011-1.203) among subjects with new-onset diabetes, 1.252 (1.167-1.344) among subjects with diabetes < 5 years, and 1.506 (1.413-1.605) among subjects with diabetes ≥ 5 years. The HR of AMD was significantly increased among participants ≤ 65 years old and those who did not have hypertension.

Conclusions: – The incidence of dry and wet AMD increased among diabetes patients compared to the normal glycemic status group. These risks increased when the duration of diabetes was 5 years or more. The risk of wet AMD was increased among new-onset diabetes patients. These results suggest that high blood glucose levels without treatment might induce the vision-threatening condition of wet AMD, emphasizing the importance of early blood glucose management.

DOI: 10.1016/j.diabet.2023.101442


Macular Atrophy and Phenotypic Variability in Autosomal Dominant Stargardt-like Macular Dystrophy due to PROM1 mutation.

Retina. 2023 Mar 15.

Ricca AM, Han IC, Hoffman J, Stone EM, Sohn EH.

Purpose: To describe the phenotypic variability and rates of progression of atrophy in patients with PROM1-associated macular dystrophy (PAMD).

Methods: Patients in this retrospective, longitudinal case series from a tertiary center had clinical exam and multi-modal imaging performed. Areas of retinal pigment epithelium and ellipsoid zone loss over time via OCT were calculated by two independent graders.

Results: Fifteen patients from five kindreds with an Arg373Cys mutation in PROM1 were studied. Average age was 39 years; 80% were female. Visual acuity was 20/40 at presentation and 20/57 at last follow up (average 4.8 years). Three distinct macular phenotypes were observed: 1) central geographic atrophy (GA;13%), 2) multifocal GA (20%), and 3) bull’s eye maculopathy (BEM;67%). Overall rate of atrophy progression was 0.36 mm2/year, but the average rate of atrophy progression varied by macular phenotype: 1.08 mm2/year for central GA; 0.53 mm2/year for multifocal GA; and, 0.23 mm2/year for BEM.

Conclusions: Patients with PAMD demonstrate distinct phenotypes, with BEM being the most common. Average rate of atrophy progression may be similar to reported rates for ABCA4-related Stargardt disease and less than age-related macular degeneration. These results provide important measures for following treatment response in future gene and stem-cell based therapies.

DOI: 10.1097/IAE.0000000000003784

Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration.

Ophthalmology Science. 2022 Dec 30.

Seddon JM, Rosner B, De D, Huan T, Java A, Atkinson J.

Purpose: To evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV).

Design: Prospective, longitudinal study.

Participants: Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms.

Methods: Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates.

Main Outcome Measures: Progression to AAMD, GA, or NV.

Results: In the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P < 0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV (P = 0.049). CFI carriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P < 0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.03, 3.52) but not NV (OR = 0.96). Higher body mass index was associated with progression among CFI carriers (body mass index ≥ 25 vs. < 25; OR = 5.8; 95% CI 1.5, 22.3) but not for noncarriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011.

Conclusions: Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA.

DOI: 10.1016/j.xops.2022.100265