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    Research update: 524

    The latest research highlights for 20 December 2021.


    Hyporeflective Cores within Drusen: Association with Progression of Age-Related Macular Degeneration and Impact on Visual Sensitivity 

    Ophthalmol Retina.2021 Dec 3;S2468-6530(21)00362-6. 

    Kai Lyn Goh, Carla J Abbott, Xavier Hadoux, Maxime Jannaud, Lauren A B Hodgson, Peter van Wijngaarden, Robyn H Guymer, Zhichao Wu

    Purpose: To examine the association between hyporeflective cores within drusen (HCD) and disease progression in age-related macular degeneration (AMD) and with visual function. 

    Design: Longitudinal observational study. 

    Participants: 280 eyes from 140 participants with bilateral large drusen, without late AMD. 

    Methods: Multimodal imaging (MMI) and microperimetry were performed at baseline, and then every 6 months for up to 3 years. Baseline optical coherence tomography (OCT) scans were graded for the presence of HCD and used to calculate drusen volume. The total area of the drusenoid lesions containing hyporeflective cores (HCD extent) on color fundus photographs (CFPs) was calculated. CFPs were also graded for the presence of pigmentary abnormalities. The association between HCD extent with progression to late AMD (including OCT signs of atrophy) and visual sensitivity measured by microperimetry at baseline and its rate of change over time was evaluated, with and without adjustment for confounders of drusen volume, pigmentary abnormalities, and age. 

    Main outcome measures: Time to develop late AMD and visual sensitivity. 

    Results: Twenty (7%) eyes from 12 (9%) individuals were found to have HCD at baseline, which was associated with a non-significantly increased rate of progression to late AMD (unadjusted P = 0.050). HCD extent was significantly associated with an increased rate of progression to late AMD (unadjusted P = 0.034) and lower visual sensitivity at baseline (unadjusted P < 0.001). However, these associations were no longer significant (P ≥ 0.264 for both) after adjusting for known risk factors for AMD progression. HCD extent was also not associated with a faster rate of visual sensitivity decline prior to the development of late AMD, with or without adjustment (P ≥ 0.674 for both). Increasing age and larger drusen volume was associated with HCD extent (P ≤ 0.041). 

    Conclusions: In a cohort with bilateral large drusen, HCD presence and extent was not independently associated with an increased rate of progression to late AMD over 3 years, nor with lower visual sensitivity or an increased rate of visual sensitivity decline prior to the development of late AMD, after adjusting for known risk factors of disease progression. 

    DOI: 10.1016/j.oret.2021.11.004 


    The 12- and 24-Month Effects of Intravitreal Ranibizumab, Aflibercept and Bevacizumab on Intraocular Pressure: A Network Meta-Analysis 

    Ophthalmology.2021 Dec 3;S0161-6420(21)00917-9. 

    Keean Nanji, Gurkaran S Sarohia, Kevin Kennedy, Tiandra Ceyhan, Tyler McKechknie, Mark Phillips, Tahira Devji , Lehana Thabane, Peter Kaiser, David Sarraf, Sunir J Garg, Sobha Sivaprasad, Charles C Wykoff, Sophie Bakri, Tom Sheidow, Mohit Bhandari, Varun Chaudhary

    Topic: To investigate the effect of anti-vascular endothelial growth factor (VEGF) intravitreal injections on intraocular pressure (IOP) 12- and 24-months after initiation. 

    Clinical relevance: It is unclear whether serial anti-VEGF injections result in sustained increases in IOP. 

    Methods: Randomized control trials (RCTs) comparing anti-VEGF agents to each other or to a control for the treatment of neovascular age-related macular degeneration, retinal vein occlusions or diabetic macular edema were included. Pairwise meta-analysis and Bayesian network meta-analysis were performed examining the proportion of patients at 12- and 24-months whose IOP: a) increased ≥5mmHg from baseline on consecutive visits, b) increased ≥10mmHg from baseline at any visit, c) was ≥21mmHg on consecutive visits, d) was ≥25mmHg at any visit, e) was ≥30mmHg at any visit, f) prompted initiation of IOP lowering medications and g) increased as per the clinicians’ discretion. Certainty of evidence was informed by Cochrane Collaboration’s Risk of Bias Tool and GRADE (Grading of Recommendations Assessments, Development and Evaluations) guidelines. 

    Results: 26 RCTs of 12,522 eyes were included. Aflibercept (2.0mg), bevacizumab (1.25mg), ranibizumab (0.3mg and 0.5mg) and non-injection controls were analyzed. 83 of 84 network estimates for comparisons between anti-VEGF agents demonstrated no statistically significant difference between groups (low to moderate certainty of evidence). Ranibizumab 0.5mg had higher rates than bevacizumab of IOP measurements ≥30mmHg at 12-months (low certainty of evidence). 53 of 56 network estimates for comparisons between anti-VEGF agents and controls demonstrated no statistically significant difference between groups (low to moderate certainty of evidence). Ranibizumab 0.5mg had higher rates of consecutive IOP increases ≥ 5mmHg at 24-months (low certainty of evidence) and higher rates of IOP increases as per the clinicians’ discretion at 12 and 24 months (low and very low certainty of evidence respectively). The 95% credible intervals in all comparisons without statistically significant effects did not rule out important clinical effects. The certainty of evidence in these comparisons is limited by imprecision. 

    Conclusion: Evidence from our network meta-analysis does not show any clear difference between anti-VEGF agents and controls when examining IOP increases 12- and 24-months after treatment initiation. Imprecision precludes definitive conclusions with the available data. 

    DOI: 10.1016/j.ophtha.2021.11.024 

    Intravitreal aflibercept following treat and extend protocol versus fixed protocol for treatment of neovascular age-related macular degeneration 

    Int J Retina Vitreous.2021 Dec 7;7(1):74. 

    Alaa Din Abdin, Asem Mohamed, Cristian Munteanu, Isabel Weinstein, Achim Langenbucher, Berthold Seitz, Shady Suffo

    Background: To assess the morphological and functional outcome of intravitreal aflibercept following the treat and extend protocol compared to the fixed protocol for treatment of eyes with neovascular age-related macular degeneration. 

    Methods: This retrospective study included 126 eyes of 113 patients with primary onset neovascular age-related macular degeneration who were followed for 12 months. All eyes were treated with 2 mg/0.05 mL aflibercept. All eyes received an upload with three monthly aflibercept injections. We subsequently studied two groups of eyes. For group 1, 54 eyes were treated following the treat and extend protocol. For group 2, 72 eyes were treated following the fixed protocol (fixed 2-monthly interval). Main outcome measures included: best corrected visual acuity (BCVA), central macular thickness (CMT) and number of injections. 

    Results: BCVA (logMAR) in group 1 vs group 2 was (0.61 ± 0.3 vs 0.72 ± 0.3, p = 0.09) before treatment and (0.48 ± 0.3 vs 0.51 ± 0.3, p = 0.6) after one year of treatment. CMT in group 1 vs group 2 was (371 ± 101 μm vs 393 ± 116 μm, p = 0.5) before treatment and (284 ± 60 μm vs 290 ± 67 μm, p = 0.1) after one year of treatment. Number of injections/eye in group 1 vs group 2 was (8.5 ± 2.2 vs 7.0 ± 0, p < 0.001). 

    Conclusions: Significant differences regarding BCVA and central macular thickness were not found between both treatment protocols during the first year of treatment using aflibercept. However, a significantly higher number of injections was needed for eyes in the treat and extend group during the first year of treatment. This might suggest that aflibercept should better not be extended past an 8 weeks interval during the first year of treatment. 

    Study registration: This study was approved by the Ethics Committee of the Medical Association of Saarland, Germany (Nr. 123/20, Date: 16.06.2020). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. 

    DOI: 10.1186/s40942-021-00349-x 

    Aqueous proteins help predict the response of neovascular age-related macular degeneration patients to anti-VEGF therapy

    J Clin Invest.2021 Dec 7;e144469. 

    Xuan Cao, Jaron Castillo Sanchez, Aumreetam Dinabandhu , Chuanyu Guo, Tapan P Patel, Zhiyong Yang, Ming-Wen Hu, Lijun Chen, Yuefan Wang, Danyal Malik, Kathleen Jee, Yassine J Daoud, James T Handa, Hui Zhang, Jiang Qian, Silvia Montaner, Akrit Sodhi

    Background: To reduce the treatment burden for patients with neovascular age-related macular degeneration (nvAMD), emerging therapies targeting vascular endothelial growth factor (VEGF) are being designed to extend the interval between treatments, thereby minimizing the number of intraocular injections. However, which patients will benefit from longer-acting agents is not clear. 

    Methods: Eyes with nvAMD (n=122) underwent 3 consecutive monthly injections with currently available anti-VEGF therapies, followed by a treat-and-extend protocol. Patients who remained quiescent 12 weeks from their prior treatment entered a “treatment pause” and were switched to pro re nata (PRN) treatment (based on vision, clinical exam, and/or imaging studies). Proteomic analysis was performed on aqueous fluid to identify proteins that correlate with patients’ response to treatment. 

    Results: At the end of 1 year, 38/122 eyes (31%) entered a treatment pause (≥30 weeks). Conversely, 21/122 eyes (17%) failed extension and required monthly treatment at the end of year 1. Proteomic analysis of aqueous fluid identified proteins that correlated with patients’ response to treatment including proteins previously implicated in AMD pathogenesis. Interestingly, apolipoprotein-B100 (ApoB100), a principal component of drusen implicated in the progression of non-neovascular AMD, was increased in treated patients who required less frequent injections. ApoB100 expression was higher in AMD eyes compared to controls but was lower in eyes that develop choroidal neovascularization (CNV), consistent with a protective role. Accordingly, mice over-expressing ApoB100 were partially protected from laser-induced CNV. 

    Conclusions: Aqueous biomarkers could help identify nvAMD patients who may not require – nor benefit from – long-term treatment with anti-VEGF therapy. 

    DOI: 10.1172/JCI144469 

    Risk factors for emerging intraocular inflammation after intravitreal brolucizumab injection for age-related macular degeneration 

    PLoS One.2021 Dec 6;16(12):e0259879

    Ryo Mukai, Hidetaka Matsumoto, Hideo Akiyama

    Purpose: To analyze the risk factors associated with emerging intraocular inflammation (IOI) after intravitreal brolucizumab injection (IVBr) to treat age-related macular degeneration (AMD). 

    Methods: This study included 93 eyes of 90 patients. The incidence of emerging IOI was analyzed. The patients were classified into IOI or non-IOI groups, and background clinical characteristics in each group were compared. 

    Results: IOI occurred in 14 eyes of 14 cases (16%; five women, nine men [5:9]; IOI group) after IVBr; contrastingly, no IOI occurred in 76 patients (10 women, 66 men [10:66]; non-IOI group). The mean ages in IOI and non-IOI groups were 79.4 ± 8.1 and 73.8 ± 8.9 years old, respectively, and the average age in the IOI group was significantly higher than that in the non-IOI group (P = 0.0425). In addition, the percentages of females in the IOI and non-IOI groups were 43% and 13%, respectively, and IOI occurred predominantly in females (odds ratio: 4.95, P = 0.0076). Moreover, the prevalence of diabetes in the IOI and non-IOI groups was 64% and 32%, respectively, with a significant difference (odds ratio: 3.90, P = 0.0196). In contrast, the prevalence of hypertension in the IOI and non-IOI groups was 36% and 57%, respectively, with no significant difference (P = 0.15). 

    Conclusion: The comparison of clinical profiles of IOI or non-IOI cases in IVBr treatment for AMD suggests that the risk factors for IOI are old age, female sex, and history of diabetes; however, IOI with vasculitis or vascular occlusion in this cohort does not seem to cause severe visual impairment. Further studies are required to investigate potential risk factors for IOI. 

    DOI: 10.1371/journal.pone.0259879 

    Treatment patterns and outcomes with antivascular endothelial growth factor agents for wet age-related macular degeneration in clinical practice: an analysis of the IRIS Registry 

    Can J Ophthalmol.2021 Dec 1;S0008-4182(21)00395-1. 

    Mathew W MacCumber, Justin S Yu, Alexandros Sagkriotis, Guruprasad B, Bhavya Burugapalli, Xiaoyu Bi, Neetu Agashivala, Charles C Wykoff

    Objective: To evaluate treatment patterns and outcomes of patients in the United States who received antivascular endothelial growth factor (anti-VEGF) agents for wet age-related macular degeneration (AMD). 

    Design: Retrospective study PARTICIPANTS: Patients with wet AMD. 

    Methods: Using the Intelligent Research in Sight Registry, we studied patients with wet AMD who received ≥1 anti-VEGF injection, who were ≥50 years old, and with ≥1.5 years of follow-up. Patients were grouped based on follow-up duration (in years): ≥1.5 (cohort 1), ≥2.5 (cohort 2), and ≥3.5 (cohort 3). 

    Results: Patient characteristics were similar between treatment groups. 36.8%, 34.5%, and 39.2% of ranibizumab, aflibercept, and all anti-VEGF eyes, respectively, had an injection interval <8 weeks in length at the end of year 1. Results were similar at year 2 and 3. In cohorts 1-3, visual acuity (VA) changes from baseline ranged from 0.3 to 0.7 (year 1), -1.3 to -1.7 (year 2), and -2.8 to -3.1 (year 3) Early Treatment Diabetic Retinopathy Study letters. By the end of year 3, 41%, 39%, and 42% of ranibizumab, aflibercept, and all anti-VEGF eyes, respectively, had discontinued treatment (no injection for >6 months). 

    Conclusion: Approximately one-third of eyes had injection intervals <8 weeks in length at the end of year 1. VA was slightly better at the end of year 1 and declined after the first year despite treatment. By the end of year 3, more than one-third of eyes had discontinued treatment. Given the high treatment burden, wet AMD patients may benefit from more durable approaches that require less frequent dosing. 

    DOI: 10.1016/j.jcjo.2021.10.008 


    Retinal Vein Occlusion Following Two Doses of mRNA-1237 (Moderna) Immunization for SARS-Cov-2: A Case Report 

    Ophthalmol Ther.2021 Dec 9;1-6. 

    Riccardo Sacconi, Filippo Simona, Paolo Forte, Giuseppe Querques 

    Introduction: Published data on possible ocular adverse events potentially associated with vaccination with the SARS-Cov-2 mRNA-1237 vaccine are scarce. In this report, we describe the case of a patient who had a hemispheric retinal vein occlusion potentially associated with being vaccinated with the second dose of the SARS-Cov-2 mRNA-1237 vaccine. 

    Methods: Case report including a discussion on multimodal imaging. 

    Results: A 74-year-old woman presented with painless vision loss in the right eye experienced 48 hours after receiving a second dose of the mRNA-1237 vaccine. The patient was receiving oral anticoagulant therapy for atrial fibrillation. Her best-corrected visual acuity (VA) was 20/32, and fundus examination showed venous congestion and widespread blot haemorrhages in the inferior quadrants. Based on multimodal imaging evaluation, the diagnosis of hemispheric retinal vein occlusion was made. Due to the development of cystoid macular oedema with intraretinal fluid and the decline in VA, the patient was treated with two injections of intravitreal ranibizumab, leading to functional improvement and regression of oedema. 

    Conclusions: We report a case with retinal vein occlusion 48 hours after vaccination with the SARS-Cov-2 mRNA-1237 vaccine; however, the relationship between these two events remains unclear. Further research is warranted to better understand the potential link between retinal thrombotic events and vaccination. 

    DOI: 10.1007/s40123-021-00441-3