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    Research Update 565


    A systematic evaluation of human expert agreement on optical coherence tomography biomarkers using multiple devices.

    Eye (London, England). 2022 Dec 28.

    Michl M, Neschi M, Kaider A, Hatz K, Deak G, Gerendas BS, Schmidt-Erfurth U.

    Objectives: To assess the agreement in evaluating optical coherence tomography (OCT) variables in the leading macular diseases such as neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) among OCT-certified graders.

    Methods: SD-OCT volume scans of 356 eyes were graded by seven graders. The grading included presence of intra- and subretinal fluid (IRF, SRF), pigment epithelial detachment (PED), epiretinal membrane (ERM), conditions of the vitreomacular interface (VMI), central retinal thickness (CRT) at the foveal centre-point (CP) and central millimetre (CMM), as well as height and location of IRF/SRF/PED. Kappa statistics (κ) and intraclass correlation coefficient (ICC) were used to report categorical grading and measurement agreement.

    Results: The overall agreement on the presence of IRF/SRF/PED was κ = 0.82/0.85/0.81; κ of VMI condition was 0.77, that of ERM presence 0.37. ICC for CRT measurements at CP and CMM was excellent with an ICC of 1.00. Height measurements of IRF/SRF/PED showed robust consistency with ICC = 0.85-0.93. There was substantial to almost perfect agreement in locating IRF/SRF/PED with κ = 0.67-0.86. Between diseases, κ of IRF/SRF presence was 0.69/0.80 for nAMD, 0.64/0.83 for DMO and 0.86/0.89 for RVO.

    Conclusion: Even in the optimized setting, featuring certified graders, standardized image acquisition and the use of a professional reading platform, there is a disease dependent variability in biomarker evaluation that is most pronounced for IRF in nAMD as well as DMO. Our findings highlight the variability in the performance of human expert OCT grading and the need for AI-based automated feature analyses.

    DOI: 10.1038/s41433-022-02376-w


    Treatment of neovascular age-related macular degeneration: insights into drug-switch real-world from the Berlin Macular Registry.

    Graefe’s archive for clinical and experimental Ophthalmology. 2023 Jan 12. 

    Riemer T, Berndt D, Böker A, Urban J, Schrifl U, Rau S, Lehmann A, Joussen AM, Zeitz O.

    Purpose: Bevacizumab, ranibizumab, and aflibercept are commonly used to treat neovascular age-related macular degeneration (nAMD). The results of various interventional, mostly randomized head-to-head studies, indicate statistical non-inferiority of these three drugs. The results of these studies are often interpreted as the three drugs being freely interchangeable, resulting in some health systems to pressure ophthalmologists to preferentially use the less expensive bevacizumab. This study analyzes switching from aflibercept or ranibizumab to bevacizumab and back under real-world conditions in order to investigate the assumption of interchangeability of the drugs.

    Methods: Treatment data of IVT patients with diagnosed nAMD were extracted from the clinical Berlin Macular Registry database. Patients who underwent a drug switch from aflibercept or ranibizumab to bevacizumab were subject of this study. Statistical comparisons were pre-planned for best corrected visual acuity, central retinal thickness, macular volume, and length of injection interval. Additional endpoints were analyzed descriptively.

    Results: Mean visual acuity decreased from 0.57 ± 0.05 under aflibercept/ranibizumab to 0.68 ± 0.06 logMAR after the switch (P = 0.001; N = 63). CRT increased from 308 ± 11 µm to 336 ± 16 µm (P = 0.011; N = 63). About half of the subjects were switched back: visual acuity increased from 0.69 ± 0.08 logMAR to 0.58 ± 0.09 logMAR (N = 26). CRT decreased from 396 ± 28 to 337 ± 20 µm (N = 28).

    Conclusion: The data provides real-world evidence that there is loss of visual acuity and an increase in retinal edema after switching to bevacizumab. Thus, the assumption of free interchangeability cannot be confirmed in this cohort.

    DOI: 10.1007/s00417-022-05952-8

    Clinical efficacy and safety of intravitreal fluocinolone acetonide implant for the treatment of chronic diabetic macular oedema: five-year real-world results.

    Eye (London, England). 2022 Dec 13

    Dobler E, Mohammed BR, Chavan R, Lip PL, Mitra A, Mushtaq B.

    Background/Aim: To report 5-year real-world efficacy and safety data following the treatment of chronic diabetic macular oedema (DMO) with the intravitreal 0.19 mg fluocinolone acetonide implant(ILUVIEN).

    Methods: Retrospective cohort study of 31 eyes treated with ILUVIEN for chronic DMO at a tertiary centre in Birmingham (UK). Best corrected visual acuity (BCVA) and central retinal thickness (CRT) were recorded at baseline, and then at 1-,2-,3-, and 5-years. Safety was assessed based on intraocular pressure (IOP) -lowering medication, surgery, and other complications.

    Results: BCVA significantly improved 1-year post-ILUVIEN (+4.2 letters, p < 0.05) and gradually reverted to baseline levels over the 5-year period of follow-up (+0.2 letters at year-5). A significant and sustained CRT reduction was observed throughout the 5-years. The proportion of eyes on IOP-lowering medication increased from 16% at baseline, to 70% at 5-years (p < 0.001) with eyes on a mean of 1.3 medications. Laser trabeculoplasty (n = 2), cyclodiode laser (n = 1), and trabeculoplasty and trabeculotomy (n = 1, in the same eye; 3.2%) were required for uncontrolled IOP. Other complications included endophthalmitis (n = 1) and vitreous haemorrhage (n = 1). 58% of eyes required additional intravitreal injections, with a mean 29.2 months to first injection. We observed a 69% reduction in treatment burden following treatment with ILUVIEN implant.

    Conclusions: Our real-world results confirm the efficacy of the ILUVIEN implant over 5 years, with two-thirds of eyes having improved or stable visual acuity 5 years after ILUVIEN, and an overall sustained improvement in anatomical outcome. Although the rate of IOP-lowering medications use was higher than previously reported, the rate of incisional IOP-lowering surgery and other complications remained low and in keeping with rates reported in larger studies.

    DOI: 10.1038/s41433-022-02338-2


    Choroidal vascular alterations in age-related macular degeneration and polypoidal choroidal vasculopathy.

    Retina (Philadelphia, PA.) 2023 Jan 1;

    Cheung CMG, Wong MYZ, Teo KYC.

    Purpose: To evaluate morphologic alterations in choroidal veins in eyes with typical neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV).

    Methods: A retrospective review of baseline indocyanine green angiography in eyes with typical nAMD and PCV. We evaluated Haller layer veins in the early-phase indocyanine green angiography (before 2 minutes) for 1) macular anastomosis, 2) dilated Haller veins, and 3) focal variation in vessel caliber by at least 50% from the narrowest to largest diameters.

    Results: We included 70 patients with gradable indocyanine green angiography for the prespecified features in the study eye (36 typical nAMD and 34 PCV) and 59 fellow eyes. The median subfoveal choroidal thickness was 167 µm versus 219 µm, P = 0.08, in the presenting eyes in typical nAMD and PCV, respectively. Macular anastomosis was common in both typical nAMD and PCV (presenting eyes 58.3% vs. 58.8%. P = 0.97; fellow eyes 65.5% vs. 63.3%, P = 0.86). Dilated Haller veins were numerically less common in typical nAMD than PCV (presenting eyes 52.8% vs. 67.6%, P = 0.21; fellow eyes 65.5% vs. 70.0%, P = 0.71), while vascular caliber variation was numerically more common in typical nAMD than PCV (presenting eyes 72.2% vs. 63.8%, P = 0.45; fellow eyes 69.0% vs. 56.7%, P = 0.33). The presence of all three features was more common in the presenting eyes with PCV compared with typical nAMD (35.3% vs. 13.9%, P = 0.03). In a multivariable analysis, every increase of 100 µm of CT conferred a 2.75 risk of having all three features present.

    Conclusion: Choroidal vascular remodeling is common in both tAMD and PCV but may be driven by different stimuli.

    DOI: 10.1097/IAE.0000000000003629


    Relationships Between the Cumulative Incidences of Long-term Complications in Type 1 Diabetes: the DCCT/EDIC Study.

    Diabetes Care. 2022 Dec 15:

    Bebu I, Braffett BH, de Boer IH, Aiello LP, Bantle JP, Lorenzi GM, Herman WH, Gubitosi-Klug RA, Perkins BA, Lachin JM, Molitch ME; DCCT/EDIC Research Group

    Objective: To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels.

    Methods: Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years.

    Research Design And Results: The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90).

    Conclusions: Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.

    DOI: 10.2337/dc22-1744

    Impact of high myopia on inner retinal layer thickness in type 2 diabetes patients.

    Scientific Reports. 2023 Jan 6.

    Kim JT, Na YJ, Lee SC, Lee MW.

    To investigate the impact of the combination of type 2 diabetes (DM) and high myopia on inner retinal layer thickness of the macular area. The patients were divided into four groups: control (group 1), patients with DM without high myopia (group 2), patients with high myopia without DM (group 3), and patients with DM and high myopia (group 4). Ganglion cell complex (GCC) thickness was compared among the groups. Linear regression analysis was performed to identify factors associated with GCC thickness. A total of 194 eyes were enrolled: 59 in group 1, 52 in group 2, 49 in group 3, and 34 in group 4. The average parafovea GCC thicknesses were 113.9 ± 10.4, 112.4 ± 11.2, 112.2 ± 7.8, and 102.6 ± 15.1 μm (P < 0.001), and the average perifovea GCC thicknesses were 104.8 ± 13.2, 103.5 ± 10.8, 103.6 ± 8.8, and 93.9 ± 15.5 μm in groups 1, 2, 3 and 4, respectively (P = 0.001). In multivariate analyses, age (β = - 0.20, P = 0.007), DM duration (β = - 0.34, P = 0.023), and axial length (β = - 1.64, P < 0.001) were significantly associated with parafoveal GCC thickness. The GCC was significantly thinner when high myopia and DM were combined, compared to either condition alone. Additionally, age, DM duration, and axial length were significant factors associated with GCC thickness. The combination of mechanical stretching and neurodegeneration would accelerate neural damage to the retina, resulting in greater inner retinal layer thinning.

    DOI: 10.1038/s41598-023-27529-z


    Artificial intelligence-based fluid quantification and associated visual outcomes in a real-world, multicentre neovascular age-related macular degeneration national database.

    British Journal of Ophthalmology. 2023 Jan 10:

    Martin-Pinardel R, Izquierdo-Serra J, De Zanet S, Parrado-Carrillo A, Garay-Aramburu G, Puzo M, Arruabarrena C, Sararols L, Abraldes M, Broc L, Escobar-Barranco JJ, Figueroa M, Zapata MA, Ruiz-Moreno JM, Moll-Udina A, Bernal-Morales C, Alforja S, Figueras-Roca M, Gómez-Baldó L, Ciller C, Apostolopoulos S, Mosinska A, Casaroli Marano RP, Zarranz-Ventura J; from the FRB SPAIN-IMAGE Project Investigators.

    Aim: To explore associations between artificial intelligence (AI)-based fluid compartment quantifications and 12 months visual outcomes in OCT images from a real-world, multicentre, national cohort of naïve neovascular age-related macular degeneration (nAMD) treated eyes.

    Methods: Demographics, visual acuity (VA), drug and number of injections data were collected using a validated web-based tool. Fluid compartment quantifications including intraretinal fluid (IRF), subretinal fluid (SRF) and pigment epithelial detachment (PED) in the fovea (1 mm), parafovea (3 mm) and perifovea (6 mm) were measured in nanoliters (nL) using a validated AI-tool.

    Results: 452 naïve nAMD eyes presented a mean VA gain of +5.5 letters with a median of 7 injections over 12 months. Baseline foveal IRF associated poorer baseline (44.7 vs 63.4 letters) and final VA (52.1 vs 69.1), SRF better final VA (67.1 vs 59.0) and greater VA gains (+7.1 vs +1.9), and PED poorer baseline (48.8 vs 57.3) and final VA (55.1 vs 64.1). Predicted VA gains were greater for foveal SRF (+6.2 vs +0.6), parafoveal SRF (+6.9 vs +1.3), perifoveal SRF (+6.2 vs -0.1) and parafoveal IRF (+7.4 vs +3.6, all p<0.05). Fluid dynamics analysis revealed the greatest relative volume reduction for foveal SRF (-16.4 nL, -86.8%), followed by IRF (-17.2 nL, -84.7%) and PED (-19.1 nL, -28.6%). Subgroup analysis showed greater reductions in eyes with higher number of injections.

    Conclusion: This real-world study describes an AI-based analysis of fluid dynamics and defines baseline OCT-based patient profiles that associate 12-month visual outcomes in a large cohort of treated naïve nAMD eyes nationwide.

    DOI: 10.1136/bjo-2022-322297


    Incidence and multimodal imaging characteristics of macular neovascularisation subtypes in Chinese neovascular age-related macular degeneration patients.

    British Journal of Ophthalmology. 2023 Jan 13

    Zhang Y, Gan Y, Zeng Y, Zhuang X, Zhang X, Ji Y, Su Y, Wen F.

    Aims: To investigate the incidence of macular neovascularisation (MNV) subtypes of neovascular age-related macular degeneration (nAMD) and summarise these subtypes’ clinical features in the Chinese population using multimodal imaging.

    Methods: We retrospectively analysed 506 consecutive treatment-naïve nAMD patients (582 eyes). Incidence of MNV subtypes and clinical features were recorded based on their multimodal images. The classification of MNV subtypes in nAMD patients were referred to Consensus on Neovascular Age-related Macular Degeneration Nonmenclature (CONAN) study group classifications.

    Results: 460 eyes of 389 nAMD patients were included in our study. 68.5% (315/460) of nAMD eyes were from male. According to CONAN, we identified type 1 macular neovascularisation (MNV) in 61.1% of eyes (281/460), type 2 MNV in 16.3% of eyes (75/460), type 3 MNV in 2.0% of eyes (9/460), mixed type 1 and type 2 MNV in 20.6% of eyes (95/460). 58% of eyes (267/460) were diagnosed as polypoidal choroidal vasculopathy lesions (PCV). 45.2% of eyes (208/460) with PCV lesions were type 1 MNV and 12.8% of eyes (59/460) with PCV lesions were co-occurred with type 2 MNV.

    Conclusion: Based on the consensus anatomical classification system developed by the CONAN Study Group, we updated the incidence of MNV subtypes and found that PCV was the most common subtype and type 3 MNV was the least common subtype among Chinese nAMD patients. In addition, the co-occurrence of PCV and type 2 MNV was typically observed, and its frequency was reported in our study.

    DOI: 10.1136/bjo-2022-322392


    Smoking, dietary factors and major age-related eye disorders: an umbrella review of systematic reviews and meta-analyses.

    British Journal of Ophthalmology 2022 Dec 8:

    Kai JY, Zhou M, Li DL, Zhu KY, Wu Q, Zhang XF, Pan CW.

    Background: There is accumulating evidence of the associations between age-related eye diseases (AREDs) and smoking or dietary factors. We aimed to provide an umbrella review of the published literature pertaining to smoking or dietary intake as risk factors for major AREDs including cataract, glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy.

    Methods: We searched for pertinent systematic reviews or meta-analyses in PubMed and Web of Science until 16 April 2022. We reperformed the meta-analysis of each association using random effects models. The heterogeneity and 95% prediction interval were calculated. The presence of small-study effect or excess significance bias was also assessed.

    Results: In total, 64 associations from 25 meta-analyses and 41 associations from 10 qualitative systematic reviews were evaluated. There was convincing (class I) evidence for only one association, namely current smoking and cataract. Two factors had highly suggestive (class II) evidence, namely ever smoking associated with cataract and fish consumption associated with AMD. We also found suggestive (class III) evidence for associations between the dietary intake of omega-3 polyunsaturated fatty acid, lutein, zeaxanthin, vitamin C and the risk of cataract.

    Conclusions: Smoking as a risk factor for cataract was the most robust association we identified. We also identified several dietary elements associated with AREDs. Large prospective studies are warranted to further examine the associations discussed in this review.

    DOI: 10.1136/bjo-2022-322325

    The function of p53 and its role in Alzheimer’s and Parkinson’s disease compared to age-related macular degeneration.

    Frontiers in Neuroscience. 2022 Dec 21

    Wolfrum P, Fietz A, Schnichels S, Hurst J.

    The protein p53 is the main human tumor suppressor. Since its discovery, extensive research has been conducted, which led to the general assumption that the purview of p53 is also essential for additional functions, apart from the prevention of carcinogenesis. In response to cellular stress and DNA damages, p53 constitutes the key point for the induction of various regulatory processes, determining whether the cell induces cell cycle arrest and DNA repair mechanisms or otherwise cell death. As an implication, aberrations from its normal functioning can lead to pathogeneses. To this day, neurodegenerative diseases are considered difficult to treat, which arises from the fact that in general the underlying pathological mechanisms are not well understood. Current research on brain and retina-related neurodegenerative disorders suggests that p53 plays an essential role in the progression of these conditions as well. In this review, we therefore compare the role and similarities of the tumor suppressor protein p53 in the pathogenesis of Alzheimer’s (AD) and Parkinson’s disease (PD), two of the most prevalent neurological diseases, to the age-related macular degeneration (AMD) which is among the most common forms of retinal degeneration.

    DOI: 10.3389/fnins.2022.1029473


    Intravitreal aflibercept for idiopathic choroidal neovascularisation in paediatric age.

     BMJ Case Reports. 2023 Jan 12

    Viana AR, Lemos J, Oliveira MA, Teixeira C.

    A boy in early adolescence presented with a 1-week history of visual acuity impairment in his right eye (RE). Fundus examination of the RE revealed an elevated yellow-greyish lesion in the inferior temporal juxtafoveolar area. Findings on optical coherence tomography, fluorescein angiography and optical coherence tomography angiography were compatible with active choroidal neovascularisation (CNV). In the absence of a primary ocular pathology and a potential systemic secondary cause, it was assumed an idiopathic aetiology of CNV. The child was treated with intravitreal injections of aflibercept, showing good anatomical and functional responses. No complications were recorded after the injections. CNV in children is a rare ocular condition that can lead to permanent visual acuity impairment. Although the therapeutic approach remains controversial, anti-vascular endothelial growth factor intravitreal injections represent a safe and effective therapeutic option for CNV in children.

    DOI: 10.1136/bcr-2022-252270

    Type 3 macular neovascularization in a patient with pentosan polysulfate maculopathy.

    American Journal of ophthalmology case reports. 2022 Dec 5;

    Bousquet E, Lee BA, Santina A, Sadda S, Sarraf D.

    Purpose: To report the development of type 3 macular neovascularization (MNV) in a patient with pentosan polysulfate sodium (PPS) maculopathy one year after PPS cessation.

    Observation: A 72-year-old woman presented for decreased visual acuity in the left eye. Medical history was significant for interstitial cystitis treated with PPS for 11 years (cumulative dose of 1205 g) and PPS maculopathy. PPS was discontinued 1 year prior to presentation. Blue-light fundus autofluorescence and spectral domain optical coherence tomography confirmed the diagnosis of bilateral PPS maculopathy. OCT-angiography illustrated the development of type 3 MNV with intraretinal fluid in the left eye. Intravitreal injections of aflibercept were initiated with a good visual and anatomical response.

    Conclusion And Importance: This report describes the development of type 3 MNV in a patient with PPS macular toxicity one year after PPS cessation. This complication emphasizes the need for regular retinal surveillance even after discontinuation of the inciting drug.

    DOI: 10.1016/j.ajoc.2022.101771