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    Research update: 525

    The latest research highlights for 31 January 2022.


    Central Retinal Vein Occlusion Following BNT162b2 (Pfizer-BioNTech) COVID-19 Messenger RNA Vaccine 

    Retin Cases Brief Rep.2021 Dec 1. 

    Paras P Shah, Samuel Gelnick, Jonathan Jonisch, Rashmi Verma 

    Purpose: Coronavirus disease 2019 (COVID-19) has had a wide-ranging public health impact, contributing to at least 5 million deaths globally at the time of this report. Although thromboembolic events following COVID-19 vaccination have been an ongoing concern, only a limited number of ophthalmic manifestations have been reported to date. 

    Methods: We obtained a detailed history, hypercoagulable workup, best-corrected visual acuity (BCVA), Humphrey visual field (HVF), dilated fundus exam (DFE), and multimodal imaging including optical coherence tomography (OCT), fundus fluorescein angiography (FFA), and fundus photography. 

    Results: A 27-year-old female was diagnosed with central retinal vein occlusion (CRVO) a few days after her first dose of the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine. Detailed elicitation of her history and a full hypercoagulable workup did not reveal any primary risk factors that could have explained her disease process. After the patient received the second dose, her symptoms deteriorated significantly and worsening peripapillary hemorrhage were seen on DFE. The patient was treated with intravitreal injections of ranibizumab and followed closely, which showed improvement of her CRVO. 

    Conclusion: Given the chronology of the patient’s condition, we believe that the CRVO which occurred due to the first dose was exacerbated by an intense immunological reaction after the second dose. The severity of this complication, despite its rarity, must be emphasized and weighed in but should not preclude the extensive benefits of vaccination. 

    DOI: 10.1097/ICB.0000000000001214 


    Effects of delay in anti-vascular endothelial growth factor intravitreal injections for neovascular age-related macular degeneration 

    Graefes Arch Clin Exp Ophthalmol.2022 Jan 11;1-8. 

    Joel Hanhart, Rony Wiener, Hashem Totah, Evgeny Gelman, Yishay Weill, Adi Abulafia, David Zadok

    Purpose: To assess the impact of COVID-19-related delay in intravitreal injection timing on macular structure and visual acuity (VA) among patients treated for neovascular age-related macular degeneration (nvAMD). 

    Methods: We reviewed demographic and clinical data and macular ocular computerized tomographic images of 34 patients (48 eyes, group A) who did not follow their injection schedule during the first wave of COVID-19 and compared them to 46 patients (71 eyes, group B) who did. Functional worsening was defined as a loss of at least 0.1 in decimal VA. Anatomic worsening was defined as new or increased subretinal/intraretinal fluids or new hemorrhage. 

    Results: The planned mean ± standard deviation intervals between the intravitreal injections were 5.7 ± 2.7 weeks for group A and 5.5 ± 2.4 weeks for group B (P = 0.60). The actual intervals were 13.6 ± 6.8 (7.9 ± 5.2 weeks’ delay) and 5.3 ± 2.4 weeks (no delay), respectively (P < 0.001). The best corrected visual acuity worsened in 23 group A eyes (47.9%) and in 6 group B eyes (8.5%) (odds ratio [OR] 9.97, P < 0.001). Anatomic features indicative of nvAMD worsening were detected in 31 group A eyes (64.6%) and in 16 group B eyes (22.5%) (OR 5.73, P < 0.001). A new macular hemorrhage was observed in 4 group A eyes (8.3%) and in no group B eyes (P = 0.09). 

    Conclusion: Delay in timely retinal care during the COVID-19 restrictions period resulted in short-term negative outcomes, including macular bleeding, in nvAMD patients. 

    DOI: 10.1007/s00417-021-05505-5 

    Hyperreflective Foci and Subretinal Fluid Are Potential Imaging Biomarkers to Evaluate Anti-VEGF Effect in Diabetic Macular Edema 

    Front Physiol.2021 Dec 23;12:791442. 

    Shiyue Qin, Chaoyang Zhang, Haifeng Qin, Hai Xie, Dawei Luo, Qinghua Qiu, Kun Liu, Jingting Zhang, Guoxu Xu, Jingfa Zhang

    Purpose: The aim was to investigate the effect and underlying mechanism of anti-vascular endothelial growth factor (anti-VEGF) in diabetic macular edema (DME) by optical coherence tomography angiography (OCTA).

    Methods: Twenty-five eyes in 18 treatment-naïve patients with DME were included. All eyes were imaged by OCTA at baseline and 1 week after monthly intravitreal aflibercept injection (IAI). Visual acuity was measured as best corrected visual acuity (BCVA). Additional parameters were evaluated by OCTA, including central macular thickness (CMT), the number of hyperreflective foci (HRF), foveal avascular zone (FAZ), vessel density (VD) in the deep capillary plexus (DCP), the en-face area of cystoid edema in DCP segmentation, and subretinal fluid (SRF) height.

    Results: The mean time between baseline and final follow-up by OCTA was 79.24 ± 38.15 (range, 28-163) days. Compared with baseline, BCVA was increased significantly after the 3rd IAI, while CMT was decreased significantly from the 1st IAI. SRF height and the area of cystoid edema in DCP segmentation were decreased significantly after the 2nd IAI compared with baseline. The number of HRF was decreased significantly after the 1st IAI (8.87 ± 9.38) compared with baseline (11.22 ± 10.63). However, FAZ’s area and perimeter as well as VD in DCP showed no significant changes post-treatment.

    Conclusion: Anti-VEGF is effective in treating DME, improving visual acuity and decreasing macular edema. The decreased HRF indicates anti-inflammatory effects of aflibercept to deactivate retinal microglia/macrophages. The decreased cystoid edema and SRF height indicated improved drainage function of Müller glial cells and retinal pigment epithelium after IAI. 

    DOI: 10.3389/fphys.2021.791442 


    Geographic Atrophy Progression Is Associated with Choriocapillaris Flow Deficits Measured With Optical Coherence Tomographic Angiography 

    Invest Ophthalmol Vis Sci.2021 Dec 1;62(15):28. 

    Qi Sheng You, Acner Camino, Jie Wang, Yukun Guo, Christina J Flaxel, Thomas S Hwang, David Huang, Yali Jia, Steven T Bailey

    Purpose: The purpose of this study was to assess the associations between baseline choriocapillaris (CC) flow deficits and geographic atrophy (GA) progression. 

    Methods: In this prospective cohort study, patients with GA underwent 3 × 3-mm macular spectral-domain optical coherence tomographic angiography (OCTA) at baseline and follow-up visits. Annual GA enlargement rate was defined as change of square root of GA area in 12 months. Shadow areas due to iris, media opacity, retinal vessels, and drusen were excluded. CC vessel density (CC-VD) in non-GA areas was measured using a validated machine-learning-based algorithm. Low perfusion area (LPA) was defined as capillary density below the 0.1 percentile threshold of the same location of 40 normal healthy control eye. Focal perfusion loss (FPL) was defined as percentage of CC loss within LPA compared with normal controls. 

    Results: Ten patients with GA were enrolled and followed for 26 months on average. At baseline, the mean GA area was 0.84 ± 0.70 mm2. The mean CC-VD was 44.5 ± 15.2%, the mean LPA was 4.29 ± 2.6 mm2, and the mean FPL was 50.4 ± 28.2%. The annual GA enlargement rate was significantly associated with baseline CC-VD (r = -0.816, P = 0.004), LPA (r = 0.809, P = 0.005), and FPL (r = 0.800, P = 0.005), but not with age (r = 0.008, P = 0.98) and GA area (r = -0.362, P = 0.30). 

    Conclusions: Baseline CC flow deficits were significantly associated with a faster GA enlargement over the course of 1 year, suggesting the choriocapillaris perfusion outside of a GA area may play a role in GA progression. 

    DOI: 10.1167/iovs.62.15.28

    Baseline predictors for subretinal fibrosis in neovascular age-related macular degeneration 

    Sci Rep.2022 Jan 7;12(1):88. 

    Philipp K Roberts, Markus Schranz, Alice Motschi, Sylvia Desissaire, Valentin Hacker, Michael Pircher, Stefan Sacu, Wolf Buehl, Christoph K Hitzenberger, Ursula M Schmidt-Erfurth


    To find baseline predictors for subretinal fibrosis (SF) in neovascular age-related macular degeneration (nAMD). Forty-five eyes of 45 participants with treatment-naïve nAMD were consecutively enrolled and treated according to a standardized treat-and-extend protocol. Spectral-domain optical coherence tomography (OCT), color fundus photography and fluorescein angiography as well as novel imaging modalities polarization-sensitive OCT and OCT angiography (OCTA) were performed to detect SF after 1 year and find baseline predictors for SF development. Baseline OCTA scans were evaluated for quantitative features such as lesion area, vessel area, vessel junctions, vessel length, vessel endpoints and mean lacunarity. Additionally, the type of macular neovascularization, the presence of subretinal fluid, intraretinal fluid (IRF), subretinal hyperreflective material (SHRM), retinal hemorrhage as well as best-corrected visual acuity (BCVA) were evaluated. After 12 months 8 eyes (18%) developed SF. Eyes with SF had worse baseline BCVA (p = .001) and a higher prevalence of IRF (p = .014) and SHRM at baseline (p = .017). There was no significant difference in any of the evaluated quantitative OCTA parameters (p > .05) between eyes with and without SF. There were no quantitative baseline microvascular predictors for SF in our study. Low baseline BCVA, the presence of IRF and SHRM, however, are easily identifiable baseline parameters indicating increased risk. 

    DOI: 10.1038/s41598-021-03716-8 


    Complement cascade inhibition in geographic atrophy: a review 

    Eye (Lond).2022 Jan 9. 

    Dhaval Desai, Pravin U Dugel


    The pathophysiology of dry age-related macular degeneration (AMD) and specifically geographic atrophy (GA) has been linked to the complement cascade. This cascade is part of the innate immune system and is made up of the classical, alternative, and lectin pathways. The pathways comprise a system of plasma and membrane-associated serum proteins that are activated with identification of a nonself entity. A number of these proteins have been implicated in the development and progression of dry AMD. The three pathways converge at C3 and cascade down through C5, making both of these proteins viable targets for the treatment of dry AMD. In addition, there are a number of complement factors, CFB, CFD, CFH, and CFI, which are potential therapeutic targets as well. Several different complement-directed therapeutics are being studied for the treatment of dry AMD with the hope that one of these approaches will emerge as the first approved treatment for GA. 

    DOI: 10.1038/s41433-021-01765-x 


    Dyslipidemia in age-related macular degeneration 

    Eye (Lond).2022 Jan 11. 

    Jonathan B Lin, Omar A Halawa, Deeba Husain, Joan W Miller, Demetrios G Vavvas


    Lipid-rich drusen are the sine qua non of age-related macular degeneration (AMD), the leading cause of blindness in older adults in the developed world. Efforts directed at uncovering effective therapeutic strategies have led to the hypothesis that altered lipid metabolism may play a pathogenic role in AMD. This hypothesis is supported by the fact that: (1) drusen, the hallmark histopathologic feature of AMD, are composed of lipids, (2) polymorphisms of genes involved in lipid homeostasis are associated with increased odds of AMD, (3) metabolomics studies show that patients with AMD have alterations in metabolites from lipid pathways, and (4) alterations in serum lipid profiles as a reflection of systemic dyslipidemia are associated with AMD. There is strong evidence that statins, which are well described for treating dyslipidemia and reducing risk associated with cardiovascular disease, may have a role for treating certain cohorts of AMD patients, but this has yet to be conclusively proven. Of interest, the specific changes in serum lipoprotein profiles associated with decreased cardiovascular risk (i.e., high HDL levels) have been shown in some studies to be associated with increased risk of AMD. In this review, we highlight the evidence that supports a role for altered lipid metabolism in AMD and provide our perspective regarding the remaining questions that need to be addressed before lipid-based therapies can emerge for specific cohorts of AMD patients. 

    DOI: 10.1038/s41433-021-01780-y 

    Review of gene therapies for age-related macular degeneration 

    Eye (Lond).2022 Jan 11. 

    Arshad M Khanani, Mathew J Thomas, Aamir A Aziz, Christina Y Weng, Carl J Danzig, Glenn Yiu, Szilárd Kiss, Nadia K Waheed, Peter K Kaiser


    Gene therapies aim to deliver a therapeutic payload to specified tissues with underlying protein deficiency. Since the 1990s, gene therapies have been explored as potential treatments for chronic conditions requiring lifetime care and medical management. Ocular gene therapies target a range of ocular disorders, but retinal diseases are of particular importance due to the prevalence of retinal disease and the current treatment burden of such diseases on affected patients, as well as the challenge of properly delivering these therapies to the target tissue. The purpose of this review is to provide an update on the most current data available for five different retinal gene therapies currently undergoing clinical trials for use against age-related macular degeneration (AMD) and the development of novel delivery routes for the administration of such therapies. Research has been performed and compiled from PubMed and the select authors of this manuscript on the treatment and effectiveness of five current retinal gene therapies: Luxturna, ADVM-022, RGX-314, GT-005, and HMR59. We present the available data of current clinical trials for the treatment of neovascular and dry age-related macular degeneration with different AAV-based gene therapies. We also present current research on the progress of developing novel routes of administration for ocular gene therapies. Retinal gene therapies offer the potential for life-changing treatment for chronic conditions like age-related macular degeneration with a single administration. In doing so, gene therapies change the landscape of treatment options for these chronic conditions for both patient and provider. 

    DOI: 10.1038/s41433-021-01842-1