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    Research update: 503

    The latest research highlights for 21 July 2021.

    Research update 503


    Patient-reported outcome measures in ophthalmology: too difficult to read?

    BMJ Open Ophthalmol. 2021 Jun 15;6(1):e000693.

    Deanna J Taylor, Lee Jones, Laura Edwards, David P Crabb  

    PMID: 34212114 PMCID: PMC8208024 DOI: 10.1136/bmjophth-2020-000693

    Objective: Patient-reported outcome measures (PROMs) are commonly used in clinical trials and research. Yet, in order to be effective, a PROM needs to be understandable to respondents. The aim of this cross-sectional analysis was to assess reading level of PROMs validated for use in common eye conditions.

    Methods and analysis: Readability measures determine the level of education a person is expected to have attained to be able to read a passage of text; this was calculated using the Flesch-Kincaid Grade Level, FORCAST and Gunning-Fog tests within readability calculations software package Oleander Readability Studio 2012.1. Forty PROMs, previously validated for use in at least one of age-related macular degeneration, glaucoma and/or diabetic retinopathy, were identified for inclusion via a systematic literature search. The American Medical Association (AMA) and National Institutes of Health (NIH) recommend patient materials should not exceed a sixth-grade reading level. Number of PROMs exceeding this level was calculated.

    Results: Median (IQR) readability scores were 7.9 (5.4-10.5), 9.9 (8.9-10.7) and 8.4 (6.9-11.1) for Flesch-Kincaid Grade Level, FORCAST and Gunning-Fog test, respectively. Depending on metric used, this meant 61% (95% CI 45% to 76%), 100% (95% CI 91% to 100%) and 80% (95% CI 65% to 91%) exceeded the recommended threshold.

    Conclusion: Most PROMs commonly used in ophthalmology require a higher reading level than that recommended by the AMA and NIH and likely contain questions that are too difficult for many patients to read. Greater care is needed in designing PROMs appropriate for the literacy level of a population.


    Lean approach to the management of patients undergoing intravitreal injections during COVID-19 pandemic

    Ther Adv Ophthalmol. 2021 Jun 17;13:25158414211018893.

    Marco Verolino, Piergiacomo Grassi, Gennaro Sosto, Gaetano D’Onofrio, Stefania De Simone, Ciro Costagliola  

    PMID: 34212127 PMCID: PMC8216374 DOI: 10.1177/25158414211018893

    Background: To introduce Lean approach principles in the management of patients undergoing intravitreal injections (IVIs) for wet age-related macular degeneration.

    Methods: Retrospective single-centre cohort study. Services location, IVIs scheduling, utilization of staff, data recording methods, ophthalmic examination and surgical procedures were analysed; a new Intravitreal Injection Centre (IVIC) was developed according to Lean principles. Mean number of daily IVIs performed, mean time between registration and discharge, mean turnover time in between patients, percentages of performed IVIs on the monthly scheduled IVIs and of patients rating their experience ⩾8/10 via standardized feedback questionnaires were retrospectively analysed.

    Results: The mean IVIs number per day increased from 20 ± 4.08 to 50 ± 7.07, and the mean time between registration and discharge of a patient decreased from 240 ± 14.14 to 60 ± 8.16 min (p = 0.00057 and p < 0.00001, respectively). Mean turnover time in between patients decreased from 10 ± 1.41 to 8 ± 2 min (p = 0.055). The percentage of monthly IVIs performed on the total of scheduled IVIs increased from 60% to 100%, and the percentage of satisfied patients who rated IVIC ⩾8/10 increased from 45% to 95% (p = 0.0177 and p < 0.00105, respectively).

    Conclusion: The IVIC improved the quality, efficiency, speed of the overall procedures and clinical capacity of the IVI service through a fast one-way route for patients, limiting time wasted and total distance travelled. This model facilitates the creation of a one-stop clinic through the just-in-time management principle and may be relevant to other ophthalmology services.

    Remodelling intravitreal therapy pathways for macular disease during the COVID-19 pandemic and an Austrian national lockdown

    BMJ Open Ophthalmol. 2020 Sep 18;5(1):e000560.

    Josef Huemer, Julius Hienert, Cornelia Hirn, Christoph Hackl, Stephan M Radda, Oliver Findl  

    PMID: 34192151 PMCID: PMC7503197 DOI: 10.1136/bmjophth-2020-000560

    Objective: To analyse the remodelling and recovery of a relocated intravitreal injection (IVI) service with an adapted treatment regimen in a tertiary referral centre during a nationwide lockdown with initial cancellation of all non-emergency treatments caused by the COVID-19 pandemic.

    Methods and analysis: For this retrospective observational study at Hanusch Hospital, Vienna, between 16 March 2020 and 5 May 2020, we conducted an analysis of an appointment booking system based on prioritisation incorporating disease class, severity and fellow eye status by evidence-based impact on irreversible structural impairment and survey data from telephone interviews. Recapture time was defined as the time-to-discard the backlog of patients in need for treatment. Non-attendance was stratified as treatment refusal for personal reasons and non-attendance due to lockdown-related restrictions.

    Results: Of the 1109 patients, 241 (21.7%) were considered as highly urgent, 269 (24.3%) as urgent, 402 (36.2%) as semiurgent and 197 (17.8%) as non-urgent. Recapture time was 15 days for highly urgent patients, 22 days for urgent patients, 43 days for semiurgent patients and 46 days for non-urgent patients. The proportion of patients who refused treatment due to personal reasons was 5.2%, with a mean age of 82.4 years; 29 patients (2.6%) could not attend due to lockdown-related restrictions.

    Conclusion: By streamlining treatment based on urgency as well as increasing the number of bilateral IVI, recapture time was fast. We could provide a safe treatment environment for healthcare professionals and patients after resetting the injection service outside of the hospital with increased levels of protection.


    Real-World Anti-Vascular Endothelial Growth Factor Therapy Outcomes in Myopic Choroidal Neovascularization

    Clin Ophthalmol. 2021 Jun 25;15:2753-2758.

    Devangna Bhatia, Alexander Mehta, Joanna DaCosta, Oonagh Crothers, James Stephen Talks

    PMID: 34211264 PMCID: PMC8240844 DOI: 10.2147/OPTH.S311816

    Aim: Evaluation of real-world outcomes of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in the primary treatment of choroidal neovascularization (CNV) secondary to pathological myopia.

    Patients and methods: A retrospective cohort analysis of treatment naive patients with myopic CNV who received treatment with either intravitreal ranibizumab or aflibercept over a 12-year period from September 2007 to May 2020 was performed. Baseline features, treatment factors and outcomes were compared between younger and older patients and final visual outcome was assessed for associated factors.

    Results: Thirty-seven eyes of 36 patients (24 females, 12 males) were included. Mean age was 58 years (range=26-89 years). Of these patients, 11/36 (31%) were ≤50 years of age and 25/36 (69%) were ≥51 years of age. Seventy-three percent (27/37) of eyes were phakic. One patient received bilateral treatment for myopic CNV. Median spherical equivalent was -8.50 diopters. Seventy percent (26/37) of eyes commenced primary treatment with ranibizumab, and 11/37 (30%) eyes commenced treatment with aflibercept. There were no significant differences between treatment factors and outcomes of younger and older patients. Median number of injections was 3 over a median follow-up period of 24.6 months. Mean CRT decreased by 126μm and median visual improvement was +6 letters. Analysis showed that younger age (p=0.022) and fewer injections (p=0.004) were associated with better visual outcomes.

    Conclusion: Myopic CNV requires less frequent anti-VEGF intravitreal therapy over a shorter follow-up period than both neovascular age-related macular degeneration and diabetic macular edema. Increased frequency of administration of intravitreal anti-VEGF treatment did not improve vision. Younger age is associated with a better final visual outcome. These findings may help to advise patients about the prognosis of treatment and help guide treatment decisions.

    Phase I Study of the Anti-HtrA1 Antibody-Binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-Related Macular Degeneration

    Am J Ophthalmol. 2021 Jun 29;S0002-9394(21)00342-1.

    Arshad M Khanani, Vrinda S Hershberger, Dante J Pieramici, Rahul N Khurana, Flavia Brunstein, Ling Ma, Katie F Maass, Lee A Honigberg, Irene Tom, Hao Chen, Erich C Strauss, Phillip Lai 

    PMID: 34214452 DOI: 10.1016/j.ajo.2021.06.017

    Purpose: FHTR2163 is a novel antigen-binding fragment (Fab) directed against high-temperature requirement protein A1 (HtrA1). HtrA1 inhibition may preserve retinal integrity and slow disease progression in geographic atrophy (GA) secondary to age-related macular degeneration (AMD). This study examined the safety, pharmacokinetics, immunogenicity, and changes in the HtrA1-specific substrate Dickkop-related protein 3 (DKK3) in patients with GA who received FHTR2163.

    Design: Phase I, open-label, single ascending dose escalation and multiple-dose expansion study Methods: Adults age ≥ 50 with GA secondary to AMD with best corrected visual acuity ranging between Snellen 20/125 and 20/400 were enrolled. In the first stage, a single intravitreal injection of FHTR2163 was given in 5 dose-escalation cohorts ranging from 1-20 mg (n=3 patients/cohort; n=15 total patients). The second stage evaluated the maximum tested dose of 20 mg administered every 4 weeks for 3 doses (n=13 patients).

    Results: No dose limiting toxicities or ocular serious AEs were reported; most frequently reported AEs in the study eye were conjunctival hemorrhage (n=7), conjunctival hyperemia (n=4), and eye pain (n=2). No non-ocular or ocular AEs were assessed as drug related. There were no clinically significant changes in ocular exams. A sustained pharmacodynamic effect of anti-HtrA1 was observed in the aqueous humor as measured by levels of cleaved DKK3.

    Conclusions: FHTR2163, a novel Fab directed against HtrA1, was well tolerated with no DLTs or significant ocular AEs. The molecule when injected intravitreally for 3 doses, showed a sustained pharmacodynamic effect at the maximum tested dose of 20 mg.

    Subfoveal Choroidal Thickness and Treatment Outcomes of Intravitreal Aflibercept for Branch Retinal Vein Occlusion

    Life (Basel). 2021 Jun 17;11(6):572.

    Yoshihito Sakanishi, Syu Morita, Keitaro Mashimo, Kazunori Tamaki, Nobuyuki Ebihara 

    PMID: 34204557 PMCID: PMC8235093 DOI: 10.3390/life11060572

    We aimed to investigate the relationship between subfoveal choroidal thickness (SCT) and treatment outcomes of intravitreal aflibercept (IVA) for macular edema (ME) due to branch retinal vein occlusion (BRVO). We retrospectively evaluated 46 patients with treatment-naive BRVO-ME who underwent IVA treatment between March 2016 and February 2017. There was no significant difference in visual acuity within 6 months (0.29 ± 0.20 vs. 0.27 ± 0.19, p = 0.338), the mean central foveal thickness improvement (332.0 ± 162.2 μm vs. 303.9 ± 166.6 μm, p = 0.492), and the mean number of IVA injections (1.7 ± 0.7 vs. 1.6 ± 0.7 times, p = 0.658) between the SCT thickened (n = 26 patients, 26 eyes) and SCT non-thickened groups (n = 20 patients, 20 eyes). The rate of ME recurrence was significantly lower in the SCT decreased group (6/17 eyes (35.2%) vs. 19/30 eyes (63.3%); p = 0.038). In conclusion, pretreatment choroidal thickening does not affect the therapeutic effect of IVA for BRVO, but ME recurrence was lower in cases of treatment-related choroidal thinning. Thus, changes in SCT may be a therapeutic indicator of IVA for acute BRVO.

    Switching to Brolucizumab in Neovascular Age-Related Macular Degeneration Incompletely Responsive to Ranibizumab or Aflibercept: Real-Life 6 Month Outcomes

    J Clin Med. 2021 Jun 17;10(12):2666.

    Christof Haensli, Isabel B Pfister, Justus G Garweg 

    PMID: 34204266 PMCID: PMC8235134 DOI: 10.3390/jcm10122666

    Purpose: The aim of this study was to evaluate the effect of switching treatment in eyes with neovascular age-related macular degeneration (nAMD) and treatment intervals of ≤6 weeks to brolucizumab. Methods: In this prospective series, eyes with persisting retinal fluid under aflibercept or ranibizumab every 4-6 weeks were switched to brolucizumab. Visual acuity (BCVA), reading acuity (RA), treatment intervals, central subfield thickness (CST), and the presence of intra- and subretinal fluid were recorded over 6 months. Results: Seven of 12 eyes completed the 6 month follow-up and received 4.4 ± 0.5 brolucizumab injections within 28.0 ± 2.8 weeks. Treatment intervals increased from 5.3 ± 0.9 weeks to 9.0 ± 2.8 weeks (95% confidence interval of extension (CI): 1.6 to 5.9). BCVA improved from 67.8 ± 7.2 to 72.2 ± 7.5 (95% CI: -0.3 to 9.1) ETDRS letters, RA improved from 0.48 ± 0.15 to 0.31 ± 0.17 LogRAD (95% CI: 0.03 to 0.25), and CST improved from 422.1 ± 97.3 to 353.6 ± 100.9 µm (95% CI: -19.9 to 157.1). Treatment was terminated early in five eyes (two intraocular inflammations with vascular occlusion without vision loss, one stroke, and two changes in the treatment plan). Conclusions: Improvement in visual performance and longer treatment intervals in our series over 6 months indicate the potential of brolucizumab to reduce the treatment burden in nAMD, while two instances of intraocular inflammation were encountered.

    Real-World Experience with Brolucizumab in Wet Age-Related Macular Degeneration: The REBA Study

    J Clin Med. 2021 Jun 23;10(13):2758.

    Alper Bilgic, Laurent Kodjikian, Francesc March de Ribot, Vaishali Vasavada, Jesus H Gonzalez-Cortes, Amro Abukashabah, Aditya Sudhalkar, Thibaud Mathis  

    PMID: 34201729 DOI: 10.3390/jcm10132758

    The aim of the present study was to determine the efficacy and safety of intravitreal brolucizumab therapy for neovascular age-related macular degeneration (AMD) in the real-world setting. The REBA study (real-world experience with brolucizumab in wet AMD) was a retrospective, observational, multicentric study that included 78 consecutive patients (105 eyes), with neovascular AMD, who received brolucizumab therapy. Both treatment-naive and switch-therapy patients were included. Switch therapy was based either on fluid recurrence, fluid recalcitrance, or inability to extend beyond q4/q6. All relevant data were collected. The primary outcome measure was change in best-corrected visual acuity (BCVA) over time. Secondary outcome measures included determination of change in central subfield thickness (CST) and complications. The mean baseline BCVA was 49.4 ± 5.4 letters and 40 ± 3.2 letters, and corresponding mean BCVA gain was +11.9 ± 3.9 letters (p = 0.011) and +10.4 ± 4.8 letters (p = 0.014) in the treatment-naive and switch-therapy groups, respectively. The change in CST was significantly decreased in the treatment-naive (p = 0.021) and the switch-therapy (p = 0.013) groups. The mean follow-up was 10.4 months in both groups. One patient in the switch-therapy group developed vascular occlusion and another a macular hole after the fifth brolucizumab injection. Both patients recovered uneventfully. In conclusion, patients showed a very good anatomical and functional response to brolucizumab therapy in the real world, regardless of prior treatment status, until the end of the follow-up period. Two significant untoward events were noted.

    Biomarkers in Early Response to Brolucizumab on Pigment Epithelium Detachment Associated with Exudative Age-Related Macular Degeneration

    Biomedicines. 2021 Jun 10;9(6):668.

    Marco Rispoli, Chiara M Eandi, Luca Di Antonio, Raphael Kilian, Andrea Montesel, Maria C Savastano 

    PMID: 34200829 PMCID: PMC8230427 DOI: 10.3390/biomedicines9060668

    Background: The purpose of this study was to describe early changes in the morphology of pigment epithelium detachments (PED) after an intravitreal injection of Brolucizumab into eyes with macular neovascularization secondary to exudative age-related macular degeneration (e-AMD).

    Method: We included twelve eyes of 12 patients with PED secondary to e-AMD which were not responding to prior anti-VEGF treatments. An ophthalmic examination and an assessment of PED-horizontal maximal diameter (PED-HMD), PED-maximum high (PED-MH) and macular neovascularization (MNV) flow area (MNV-FA) by the means of structural optical coherence tomography (OCT) and OCT Angiography (OCT-A) were performed at baseline, as well as 1, 7, 14 and 30 days after the injection.

    Results: The mean age of the population of study was 78.4 (SD ± 4.8). The mean number of previous Ranibizumab or Aflibercept injections was 13 (SD ± 8). At the last follow-up visit, the PED-HMD did not significantly change (p = 0.16; F(DF:1.94, 20,85) = 1.9), the PED-MH showed a significant reduction [p = 0.01; F(DF:1.31, 14.13) = 6.84.] and the MNV-FA did not significantly differ (p = 0.1; F(1.97, 21.67) = 2.54) from baseline. No signs of ocular inflammation were observed during follow-up.

    Conclusions: A single Brolucizumab injection was able to determine the short-term effects on PEDs’ anatomical features of eyes with an unresponsive e-AMD.

    Safety and Efficacy of Intravitreal Risuteganib for Non-Exudative AMD: A Multicenter, Phase 2a, Randomized, Clinical Trial

    Ophthalmic Surg Lasers Imaging Retina. 2021 Jun;52(6):327-335.

    David S Boyer, Victor H Gonzalez, Derek Y Kunimoto, Raj K Maturi, Richard H Roe, Michael A Singer, Samantha Xavier, Julie A Kornfield, Baruch D Kuppermann, Hugo Quiroz-Mercado, Janine Aubel, Hampar L Karageozian, John Y Park, Vicken H Karageozian, Lisa Karageozian, Melvin A Sarayba, Peter K Kaiser

    PMID: 34185587 DOI: 10.3928/23258160-20210528-05

    Background and objective: To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD).

    Patients and methods: This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks.

    Results: Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 (P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatment-related treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported.

    Conclusions: Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32-week observation period.

    Rates of Suspected Endophthalmitis Following Intravitreal Injections in Clinical Practices in the United States

    Ophthalmic Surg Lasers Imaging Retina. 2021 Jun;52(6):312-318.

    Dilsher S Dhoot, Nick Boucher, John D Pitcher 3rd, Namrata Saroj

    PMID: 34185585 DOI: 10.3928/23258160-20210528-03

    Background and objective: To evaluate rates of suspected endophthalmitis following intravitreal injections of aflibercept, bevacizumab, ranibizumab (vial and pre-filled), dexamethasone implant, and triamcinolone in clinical practice.

    Patients and methods: Retrospective study of aggregated electronic medical records from the Vestrum Health Database. Eyes with a diagnosis of suspected endophthalmitis based on billing codes between January 2013 and June 2019 were included.

    Results: Total number of injections, suspected endophthalmitis cases, and medication rate, respectively, were: aflibercept (1,412,699; 687; 0.049%); bevacizumab (1,467,722; 379; 0.026%); ranibizumab vial (884,061; 233; 0.026%), ranibizumab pre-filled (427,763; 96; 0.022%); dexamethasone implant (49,464; 53; 0.107%); and triamcinolone (75,038; 110; 0.147%). Rates were lower for bevacizumab and ranibizumab (vial and pre-filled) compared to aflibercept, dexamethasone implant, and triamcinolone (P < .05). Triamcinolone had a higher rate compared to all of the other medications (P < .05).

    Conclusions: Suspected endophthalmitis rates following anti-vascular endothelial growth factor injections in clinical practice were similar to reported rates in clinical trials. Rates of suspected endophthalmitis following steroid injections trended higher with significantly higher rates with triamcinolone. 


    Model Structure Uncertainty in the Characterization and Growth of Geographic Atrophy

    Transl Vis Sci Technol. 2021 May 3;10(6):2.

    Janan Arslan, Kurt K Benke, Gihan Samarasinghe, Arcot Sowmya, Robyn H Guymer, Paul N Baird

    PMID: 34111247 PMCID: PMC8107635 DOI: 10.1167/tvst.10.6.2

    Purpose: To identify the most suitable model for assessing the rate of growth of total geographic atrophy (GA) by analysis of model structure uncertainty.

    Methods: Model structure uncertainty refers to unexplained variability arising from the choice of mathematical model and represents an example of epistemic uncertainty. In this study, we quantified this uncertainty to help identify a model most representative of GA progression. Fundus autofluorescence (FAF) images and GA progression data (i.e., total GA area estimation at each presentation) were acquired using Spectralis HRA+OCT instrumentation and RegionFinder software. Six regression models were evaluated. Models were compared using various statistical tests, [i.e., coefficient of determination (r2), uncertainty metric (U), and test of significance for the correlation coefficient, r], as well as adherence to expected physical and clinical assumptions of GA growth.

    Results: Analysis was carried out for 81 GA-affected eyes, 531 FAF images (range: 3-17 images per eye), over median of 57 months (IQR: 42, 74), with a mean baseline lesion size of 2.62 ± 4.49 mm2 (range: 0.11-20.69 mm2). The linear model proved to be the most representative of total GA growth, with lowest average uncertainty (original scale: U = 0.025, square root scale: U = 0.014), high average r2 (original scale: 0.92, square root scale: 0.93), and applicability of the model was supported by a high correlation coefficient, r, with statistical significance (P = 0.01).

    Conclusions: Statistical analysis of uncertainty suggests that the linear model provides an effective and practical representation of the rate and progression of total GA growth based on data from patient presentations in clinical settings.

    Translational relevance: Identification of correct model structure to characterize rate of growth of total GA in the retina using FAF images provides an objective metric for comparing interventions and charting GA progression in clinical presentations.

    The Spectrum of Central Choriocapillaris Abnormalities on Swept-Source Optical Coherence Tomography Angiography in the Fellow Eye of Unilateral Exudative Age-Related Macular Degeneration Patients: From Flow Deficits to Subclinical Non-Exudative Neovascularization

    J Clin Med. 2021 Jun 16;10(12):2658.

    Alexis Khorrami Kashi, Eric Souied, Selim Fares, Enrico Borrelli, Vittorio Capuano, Camille Jung, Giuseppe Querques, Alexandra Mouallem, Alexandra Miere 

    PMID: 34208728 PMCID: PMC8234697 DOI: 10.3390/jcm10122658

    We evaluated the spectrum of choriocapillaris (CC) abnormalities in the fellow eyes of unilateral exudative age-related macular degeneration (AMD) patients using swept-source optical coherence tomography angiography (SS-OCTA). Fellow eyes of unilateral exudative AMD patients were prospectively included between May 2018 and October 2018. Patients underwent a multimodal imaging including a SS-OCTA. Demographics and clinical findings were analyzed. The estimated prevalence of macular neovascularization (MNV) was computed. Number and size of flow deficits (FDs) and percentage of flow deficits (FD%) were computed on the compensated CC flow images with the Fiji software. We included 97 eyes of 97 patients (mean age was 80 ± 7.66 years, 39 males, 58 females). The prevalence of MNV in the studied eyes was 8.25% (8/97 eyes). In the 89 non-neovascular eyes, FD% averaged 45.84% ± 11.63%, with a corresponding total area of FDs of 4.19 ± 1.12 mm2. There was a higher prevalence of drusenoid pigment epithelial detachment in eyes with subclinical neovascularization (p = 0.021). Fellow eyes with unilateral exudative AMD encompassed a series of CC abnormalities, from FDs of the aging CC to subclinical non-exudative MNV.

    Identification of Diagnostic Biomarkers and Their Correlation with Immune Infiltration in Age-Related Macular Degeneration

    Diagnostics (Basel). 2021 Jun 12;11(6):1079.

    Yuyang Zeng, Xiujuan Yin, Changzheng Chen, Yiqiao Xing  

    PMID: 34204836 PMCID: PMC8231534 DOI: 10.3390/diagnostics11061079

    Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of the central retina, with no suitable biomarkers for early diagnosis and treatment. This study aimed to find potential diagnostic biomarker candidates for AMD and investigate their immune-related roles in this pathology. Weight gene correlation analysis was first performed based on data from the Gene Expression Omnibus database and 20 hub genes were identified. The functional enrichment analyses showed that the innate immune response, inflammatory response, and complement activation were key pathways associated with AMD. Complement C1s (C1S), adrenomedullin (ADM), and immediate early response 5 like (IER5L) were identified as the crucial genes with favorable diagnostic values for AMD by using LASSO analysis and multiple logistic regression. Furthermore, a 3-gene model was constructed and proved to be of good diagnostic and predictive performance for AMD (AUC = 0.785, 0.840, and 0.810 in training, test, and validation set, respectively). Finally, CIBERSORT was used to evaluate the infiltration of immune cells in AMD tissues. The results showed that the NK cells, CD4 memory T cell activation, and macrophage polarization may be involved in the AMD process. C1S, ADM, and IER5L were correlated with the infiltration of the above immune cells. In conclusion, our study suggests that C1S, ADM, and IER5L are promising diagnostic biomarker candidates for AMD and may regulate the infiltration of immune cells in the occurrence and progression of AMD.

    Measuring the Contrast Sensitivity Function in Non-Neovascular and Neovascular Age-Related Macular Degeneration: The Quantitative Contrast Sensitivity Function Test

    J Clin Med. 2021 Jun 24;10(13):2768.

    Filippos Vingopoulos, Karen M Wai, Raviv Katz, Demetrios G Vavvas, Leo A Kim, John B Miller

    PMID: 34202569 DOI: 10.3390/jcm10132768

    Age-related macular degeneration (AMD) affects various aspects of visual function compromising patients’ functional vision and quality of life. Compared to visual acuity, contrast sensitivity correlates better with vision-related quality of life and subjectively perceived visual impairment. It may also be affected earlier in the course of AMD than visual acuity. However, lengthy testing times, coarse sampling and resolution, and poor test-retest reliability of the existing contrast testing methods have limited its widespread adoption into routine clinical practice. Using active learning principles, the qCSF can efficiently measure contrast sensitivity across multiple spatial frequencies with both high sensitivity in detecting subtle changes in visual function and robust test-retest reliability, emerging as a promising visual function endpoint in AMD both in clinical practice and future clinical trials.

    Vanishing pachy-choroid in pachychoroid neovasculopathy under long-term anti-vascular endothelial growth factor therapy

    BMC Ophthalmol. 2021 Jun 30;21(1):269.

    Benedikt Schworm, Nikolaus Luft, Leonie F Keidel, Thomas C Kreutzer, Tina R Herold, Siegfried G Priglinger, Jakob Siedlecki  

    PMID: 34193089 PMCID: PMC8243878 DOI: 10.1186/s12886-021-02022-1

    Background: To investigate the diagnostic value of choroidal thickness in the definition of pachychoroid neovasculopathy (PNV), especially in eyes treated with anti-vascular endothelial growth factor (VEGF) therapy.

    Methods: Twenty-two consecutive eyes of 11 patients with uni- or bilateral PNV were analyzed. Anti-VEGF treatment was correlated with changes in choroidal thickness on enhanced depth imaging optical coherence tomography.

    Results: There were 14 eyes with PNV and 8 non-neovascular partner eyes. Mean age was 64.2 ± 4.0 (range: 60-72), total follow-up was 1.8 ± 0.4 (1-2) years. In PNV eyes, choroidal thickness at baseline was 400 ± 58 (269-485) μm. After two years and 13 anti-VEGF injections on average, a mean reduction of – 39 ± 10 (- 26 to – 56) % to final 241 ± 52 (162-327) μm was observed (p < 0.0001). Meanwhile, choroidal thickness in the partner eyes remained stable (p > 0.13 for all comparisons). A significant correlation of choroidal thinning and anti-VEGF injection rate was observed at year one (r = – 0.79; R2 = 0.63; p = 0.00073) and two (r = – 0.69; R2 = 0.48; p = 0.019). While 85.7% of PNV eyes exceeded a pachychoroid threshold of ≥350 μm at baseline, this figure dropped to 21.4% at year one and 0% at year two.

    Conclusion: In PNV, choroidal thickness significantly decreases with anti-VEGF therapy, resembling a “vanishing pachy-choroid”, and thus does not represent a valid long-term diagnostic criterium, especially when differentiating PNV from nAMD.

    Focal electroretinogram and microperimetry testing of photoreceptor-retinal pigment epithelium function in intermediate age-related macular degeneration

    Acta Ophthalmol. 2021 Jun 29.

    Dario Messenio, Alessandro Babbi, Alessandra Guglielmi, Matteo Airaldi 

    PMID: 34189851 DOI: 10.1111/aos.14934

    Purpose: To compare the performance of focal electroretinogram (FERG) and fast mesopic microperimetry in evaluating macular function of intermediate age-related macular degeneration (iAMD) subjects with preserved visual acuity.

    Methods: Cross-sectional, observational study. Participants with drusen >125 µm and VA ≥80 ETDRS letters and age- and sex-comparable healthy subjects were consecutively enrolled in the study. Three photopic FERG recordings of the central 9° of the macula with luminance modulated stimuli flickering at 42.5 Hz and a fast mesopic microperimetry with a custom pattern of 3 central (CS) and 3 paracentral (pCS) stimuli at 1.2° and 6° from fixation were acquired.

    Results: Overall, 112 eyes of 77 participants (age 73.0 ± 7.1 years, 47 iAMD eyes) were analysed. Mean FERG amplitude, CS and pCS (all p < 0.05) were lower in the iAMD group. A significant association was observed between FERG amplitude and iAMD (OR 9.58, p < 0.001) in multiple logistic regression analysis. Z-scores of FERG were lower than microperimetry in iAMD (p = 0.002) but not for healthy participants. AUC of the ROC curve was greater for FERG than microperimetry (0.895 versus 0.644 and 0.675, both p < 0.05).

    Conclusion: Focal ERG objectively measures a cumulative response originating from the photoreceptor-RPE complex of the central 9° of the macula and demonstrated high accuracy in identifying decreased central macular function in iAMD patients with preserved visual acuity, performing better than fast mesopic microperimetry. Focal ERG should be considered a reliable technique for measuring retinal sensitivity of iAMD patients.

    Classification of Pachychoroid on Optical Coherence Tomographic En Face Images Using Deep Convolutional Neural Networks

    Transl Vis Sci Technol. 2021 Jun 1;10(7):28.

    Kook Lee, Ho Ra, Jun Hyuk Lee, Jiwon Baek, Won Ki Lee  

    PMID: 34185057 DOI: 10.1167/tvst.10.7.28

    Purpose: To study the efficacy of deep convolutional neural networks (DCNNs) to differentiate pachychoroid from nonpachychoroid on en face optical coherence tomography (OCT) images at the large choroidal vessel.

    Methods: En face OCT images were collected from eyes with neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, and central serous chorioretinopathy. All images were prelabeled pachychoroid or nonpachychoroid based on quantitative and qualitative criteria for choroidal morphology on multimodal imaging by two retina specialists. In total, 1188 nonpachychoroid and 884 pachychoroid images were used for training (80%) and validation (20%). Accuracy for identification of pachychoroid by DCNN models was analyzed. Trained models were tested on a test set containing 79 nonpachychoroid and 93 pachychoroid images.

    Results: The accuracy on the validation set was 94.1%, 93.2%, 94.7%, and 94.4% in DenseNet, GoogLeNet, ResNet50, and Inception-v3, respectively. On a test set, each model demonstrated accuracy of 80.2%, 83.1%, 89.5%, and 90.1% and an F1 score of 0.782, 0.824, 0.904, and 0.901, respectively.

    Conclusions: DCNN models could classify pachychoroid and nonpachychoroid with good performance on OCT en face images. Automated classification of pachychoroid will be useful for tailored treatment of individual patients with exudative maculopathy.

    Translational relevance: En face OCT images can be used by DCNN for classification of pachychoroid.


    Long-term course and visual outcomes of prechoroidal cleft in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy

    Retina. 2021 Jun 21.

    Jae Hui Kim, Jong Woo Kim, Chul Gu Kim, Dong Won Lee

    PMID: 34173365 DOI: 10.1097/IAE.0000000000003242

    Purpose: To evaluate the regression of prechoroidal cleft, its influence on visual outcomes, and differences in visual outcomes between neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).

    Methods: This retrospective study included 61 patients exhibiting prechoroidal cleft who were treated with anti-vascular endothelial growth factor. The patients were divided into two groups according to the following categories: 1) regression of prechoroidal cleft: regression group vs. non-regression group and 2) type of neovascularization: neovascular AMD group vs. PCV group. Changes in visual acuity during the follow-up period were also compared between the two groups.

    Results: During the 52.4±17.4-month follow-up period, regression of prechoroidal cleft was noted in 17 patients (27.9%) at a mean of 25.7±18.3 months after the first identification. The degree of the logarithm of the minimum angle of resolution of visual deterioration was greater in the non-regression group (0.59±0.56, n=17) than in the regression group (0.25±0.61, n=44)(P=0.007) and in the neovascular AMD group (0.56±0.61, n=51) than in the PCV group (0.18±0.33, n=10)(P=0.034).

    Conclusions: Approximately 27.9% of prechoroidal cleft cases eventually regressed, in conjunction with relatively favorable visual outcomes. Considering the poor visual prognosis in neovascular AMD accompanied by prechoroidal cleft, more caution is required for this condition.

    Systemic complement activation levels in Stargardt disease

    PLoS One. 2021 Jun 25;16(6):e0253716.

    Patty P A Dhooge, Esmee H Runhart, Catherina H Z Li, Corrie M de Kat Angelino, Carel B Hoyng, Renate G van der Molen, Anneke I den Hollander 

    PMID: 34170959 DOI: 10.1371/journal.pone.0253716

    Purpose: Preclinical research provides evidence for the complement system as a potential common pathway in Stargardt disease (STGD1) and age-related macular degeneration (AMD) leading to retinal pigment epithelium (RPE) loss. However, systemic complement activation has not yet been assessed in STGD1 patients. We conducted a cross-sectional case-control study to assess systemic complement activation in STGD1 patients and its association with disease severity.

    Methods: Systemic concentrations of complement component C3 and its degradation product C3d were compared between 80 STGD1 patients and 80 controls that were frequency matched for age and sex. The C3d/C3 ratio was used as parameter of systemic complement activation. Within the STGD1 cohort, we additionally examined the association between the C3d/C3 ratio, demographic and behavioural factors (age, sex, smoking and BMI), and measures of disease severity (age at onset, visual acuity, and area of atrophy).

    Results: The C3d/C3 ratio did not significantly differ between patients (mean C3d/C3 ratio 3.5±1.4) and controls (mean C3d/C3 ratio 3.6±1.0), mean difference -0.156 (p = 0.804, independent samples t-test). The overall effect size was 8% (95% confidence interval, 3-15%). Elevated C3d/C3 ratios (>8.1) were found in three patients who all had a concomitant inflammatory condition at the time of blood draw. Within the patient cohort, C3 levels were associated with sex (mean difference -134, p = 0.001, independent samples t-test) and BMI (correlation coefficient 0.463, p<0.001, Spearman’s Correlation).

    Conclusions: Systemic complement levels were not elevated in STGD1 patients compared to age and sex matched controls and was not associated with STGD1 severity. Considering the continued absent proof of a systemic contribution of the complement system to RPE loss in STGD1 patients, we hypothesize that complement activation in STGD1 is more likely a local process. In light of upcoming complement-targeted therapies, further studies are needed that measure complement levels in the eye of STGD1 patients.

    Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration

    Life (Basel). 2021 Jun 29;11(7):635.

    Monica L Hu, Joel Quinn, Kanmin Xue 

    PMID: 34210002 DOI: 10.3390/life11070635

    Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer’s disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.

    Altered Blood Flow in the Ophthalmic and Internal Carotid Arteries in Patients with Age-Related Macular Degeneration Measured Using Noncontrast MR Angiography at 7T

    AJNR Am J Neuroradiol. 2021 Jul 1.

    M L Hibert, Y I Chen, N Ohringer, W J Feuer, N K Waheed, J S Heier, M W Calhoun, P J Rosenfeld, J R Polimeni  

    PMID: 34210664 DOI: 10.3174/ajnr.A7187

    Background and purpose: Age-related macular degeneration is associated with reduced perfusion of the eye; however, the role of altered blood flow in the upstream ophthalmic or internal carotid arteries is unclear. We used ultra-high-field MR imaging to investigate whether the diameter of and blood flow in the ophthalmic artery and/or the ICA are altered in age-related macular degeneration and whether any blood flow changes are associated with disease progression.

    Materials and methods: Twenty-four patients with age-related macular degeneration and 13 similarly-aged healthy controls participated. TOF and high-resolution dynamic 2D phase-contrast MRA (0.26 × 0.26 × 2mm3, 100-ms effective sampling rate) was acquired at 7T. Vessel diameters were calculated from cross-sectional areas in phase-contrast acquisitions. Blood flow time-series were measured across the cardiac cycle.

    Results: The ophthalmic artery vessel diameter was found to be significantly smaller in patients with age-related macular degeneration than in controls. Volumetric flow through the ophthalmic artery was significantly lower in patients with late age-related macular degeneration, with a significant trend of decreasing volumetric ophthalmic artery flow rates with increasing disease severity. The resistance index was significantly greater in patients with age-related macular degeneration than in controls in the ophthalmic artery. Flow velocity through the ophthalmic artery and ICA was significantly higher in patients with age-related macular degeneration. Ophthalmic artery blood flow as a percentage of ipsilateral ICA blood flow was nearly double in controls than in patients with age-related macular degeneration.

    Conclusions: These findings support the hypothesis that vascular changes upstream to the eye are associated with the severity of age-related macular degeneration. Additional investigation into the potential causality of this relationship and whether treatments that improve ocular circulation slow disease progression is warranted.

    Hydroquinone Induces NLRP3-Independent IL-18 Release from ARPE-19 Cells

    Cells. 2021 Jun 6;10(6):1405.

    Niina Bhattarai, Eveliina Korhonen, Yashavanthi Mysore, Kai Kaarniranta, Anu Kauppinen

    PMID: 34204067 PMCID: PMC8229790 DOI: 10.3390/cells10061405

    Age-related macular degeneration (AMD) is a retinal disease leading to impaired vision. Cigarette smoke increases the risk for developing AMD by causing increased reactive oxygen species (ROS) production and damage in the retinal pigment epithelium (RPE). We have previously shown that the cigarette tar component hydroquinone causes oxidative stress in human RPE cells. In the present study, we investigated the propensity of hydroquinone to induce the secretion of interleukin (IL)-1β and IL-18. The activation of these cytokines is usually regulated by the Nucleotide-binding domain, Leucine-rich repeat, and Pyrin domain 3 (NLRP3) inflammasome. ARPE-19 cells were exposed to hydroquinone, and cell viability was monitored using the lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide salt (MTT) assays. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the levels of proinflammatory cytokines IL-1β and IL-18 as well as NLRP3, caspase-1, and poly (ADP-ribose) polymerase (PARP). Hydroquinone did not change IL-1β release but significantly increased the secretion of IL-18. Cytoplasmic NLRP3 levels increased after the hydroquinone treatment of IL-1α-primed RPE cells, but IL-18 was equally released from primed and nonprimed cells. Hydroquinone reduced the intracellular levels of PARP, which were restored by treatment with the ROS scavenger N-acetyl-cysteine (NAC). NAC concurrently reduced the NLRP3 levels but had no effect on IL-18 release. In contrast, the NADPH oxidase inhibitor ammonium pyrrolidinedithiocarbamate (APDC) reduced the release of IL-18 but had no effect on the NLRP3 levels. Collectively, hydroquinone caused DNA damage seen as reduced intracellular PARP levels and induced NLRP3-independent IL-18 secretion in human RPE cells.

    Plasma Rich in Growth Factors Promotes Autophagy in ARPE19 Cells in Response to Oxidative Stress Induced by Blue Light

    Biomolecules. 2021 Jun 28;11(7):954.

    Carlota Suárez-Barrio, Susana Del Olmo-Aguado, Eva García-Pérez, Luis Fernández-Vega-Cueto, Andrés Fernández-Vega Cueto, Begoña Baamonde-Arbaiza, Luis Fernández-Vega, Jesús Merayo-Lloves  

    PMID: 34203504 DOI: 10.3390/biom11070954

    Age-related macular degeneration (AMD) causes the degeneration of photoreceptors and retinal cells leading to vision loss in older subjects. Among possible exogenous risk factors, it has been recently proposed that long-term exposure to blue light could aggravate the course of AMD. In the search for therapeutic options, plasma rich in growth factors (PRGF) has been shown to enhance cell antioxidant pathways and protect photoreceptors against the harm produced by blue light, although its mechanism of action remains unknown. One possible mechanism, autophagy, is one of the most conservative cell renewal systems used in eukaryotes to destroy cellular components that have been damaged by some kind of insult. The oxidative stress of exposure to blue light is known to induce cell autophagy. In this study, we examined the combined effects on autophagy of blue light and PRGF in a retinal cell line, ARPE19. In response to treatment with both PRGF and blue light, we detected the modulated expression of autophagy markers such as NF-kB, p62/sqstm1, Atg5, LC3 and Beclin1, and inflammatory markers such as IL1B and IL18. Our findings suggest that PRGF promotes cell autophagy in response to exposure to blue light.

    Low-dose rAAV-mediated inhibition of VEGF can treat neovascular pathologies without inducing retinal vasculitis

    Hum Gene Ther. 2021 Jun 29.

    Shun-Yun Cheng, Yongwen Luo, Anneliese Malachi, Jihye Ko, Qin Su, Jun Xie, Bo Tian, Haijiang Lin, Xiao Ke, Qiang Zheng, Phillip W L Tai, Guangping Gao, Claudio Punzo  

    PMID: 34182803 DOI: 10.1089/hum.2021.132

    The wet form of age-related macular degeneration (AMD) is characterized by neovascular pathologies that if untreated can result in edemas followed by rapid vision loss. Inhibition of vascular endothelial growth factor (VEGF) has been used to successfully treat neovascular pathologies of the eye. Nonetheless, some patients require frequent intravitreal injections of anti-VEGF drugs, increasing the burden and risk of complications from the procedure to affected individuals. rAAV-mediated expression of anti-VEGF proteins is an attractive alternative to reduce risk and burden to patients. However, controversy remains as to the safety of prolonged VEGF inhibition in the eye. Here, we show that two out of 4 rAAV serotypes tested by intravitreal delivery to express the anti-VEGF drug conbercept lead to a dose-dependent vascular sheathing pathology that is characterized by immune cell infiltrates, reminiscent of vasculitis in humans. We show that this pathology is accompanied by increased expression in vascular cells adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), both of which promote extravasation of immune cells from the vasculature. While formation of the vascular sheathing pathology is prevented in immunodeficient Rag mice that lack B-and T-cells, increased expression of VACM1 and ICAM1 on still occurs, indicating that inhibition of VEGF function leads to expression changes in cell adhesion molecules that promote extravasation of immune cells. Importantly, a ten-fold lower dose of one of the vectors that causes a vascular sheathing pathology is still able to reduce edemas resulting from choroidal neovascularization without causing any vascular sheathing pathology and only minimal increase in VCAM1 expression. The data suggest that treatments of neovascular eye pathologies with rAAV-mediated expression of anti VEGF drugs can be developed safely. However, viral load needs to be adjusted to the tropisms of the serotype and the expression pattern of the promoter.

    TPC2 promotes choroidal angiogenesis and inflammation in a mouse model of neovascular age-related macular degeneration

    Life Sci Alliance. 2021 Jun 28;4(8):e202101047.

    Yanfen Li, Christian Schön, Cheng-Chang Chen, Zhuo Yang, Raffael Liegl, Elisa Murenu, Benedikt Schworm, Norbert Klugbauer, Christian Grimm, Christian Wahl-Schott, Stylianos Michalakis, Martin Biel

    PMID: 34183443 DOI: 10.26508/lsa.202101047

    Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly and can be classified either as dry or as neovascular (or wet). Neovascular AMD is characterized by a strong immune response and the inadequate release of cytokines triggering angiogenesis and induction of photoreceptor death. The pathomechanisms of AMD are only partly understood. Here, we identify the endolysosomal two-pore cation channel TPC2 as a key factor of neovascularization and immune activation in the laser-induced choroidal neovascularization (CNV) mouse model of AMD. Block of TPC2 reduced retinal VEGFA and IL-1β levels and diminished neovascularization and immune activation. Mechanistically, TPC2 mediates cationic currents in endolysosomal organelles of immune cells and lack of TPC2 leads to reduced IL-1β levels in areas of choroidal neovascularization due to endolysosomal trapping. Taken together, our study identifies TPC2 as a promising novel therapeutic target for the treatment of AMD.

    Retinal Pigment Epithelium Transplantation in a Non-human Primate Model for Degenerative Retinal Diseases

    J Vis Exp. 2021 Jun 14;(172).

    Ivan Seah, Zengping Liu, Daniel Soo Lin Wong, Wendy Wong, Graham E Holder, Veluchamy Amutha Barathi, Gopal Lingam, Xinyi Su, Boris V Stanzel  

    PMID: 34180899 DOI: 10.3791/62638

    Retinal pigment epithelial (RPE) transplantation holds great promise for the treatment of inherited and acquired retinal degenerative diseases. These conditions include retinitis pigmentosa (RP) and advanced forms of age-related macular degeneration (AMD), such as geographic atrophy (GA). Together, these disorders represent a significant proportion of currently untreatable blindness globally. These unmet medical needs have generated heightened academic interest in developing methods of RPE replacement. Among the animal models commonly utilized for preclinical testing of therapeutics, the non-human primate (NHP) is the only animal model that has a macula. As it shares this anatomical similarity with the human eye, the NHP eye is an important and appropriate preclinical animal model for the development of advanced therapy medicinal products (ATMPs) such as RPE cell therapy. This manuscript describes a method for the submacular transplantation of an RPE monolayer, cultured on a polyethylene terephthalate (PET) cell carrier, underneath the macula onto a surgically created RPE wound in immunosuppressed NHPs. The fovea-the central avascular portion of the macula-is the site of the greatest mechanical weakness during the transplantation. Foveal trauma will occur if the initial subretinal fluid injection generates an excessive force on the retina. Hence, slow injection under perfluorocarbon liquid (PFCL) vitreous tamponade is recommended with a dual-bore subretinal injection cannula at low intraocular pressure (IOP) settings to create a retinal bleb. Pretreatment with an intravitreal plasminogen injection to release parafoveal RPE-photoreceptor adhesions is also advised. These combined strategies can reduce the likelihood of foveal tears when compared to conventional techniques. The NHP is a key animal model in the preclinical phase of RPE cell therapy development. This protocol addresses the technical challenges associated with the delivery of RPE cellular therapy in the NHP eye.

    Long-term progression of geographic atrophy in age-related macular degeneration does the phakic status matter?

    Graefes Arch Clin Exp Ophthalmol. 2021 Jun 25.

    Carolina Madeira, Gonçalo Godinho, Rodrigo Vilares-Morgado, João Beato, João Pinheiro-Costa, Ângela Carneiro, Fernando Falcão-Reis, Manuel Falcão 

    PMID: 34169351 DOI: 10.1007/s00417-021-05255-4

    Purpose: To assess the long-term risk of geographic atrophy (GA) progression after cataract surgery.

    Methods: Subjects with GA secondary to AMD followed for at least 1 year with fundus autofluorescence imaging and with at least two visits at our centre were included. Patients with wet AMD, disciform scar, past history of intravitreal injections or laser treatment, other maculopathies and with poor quality images were excluded. GA area at baseline and at follow-up visit was measured. Three study groups were defined according to their phakic status: (A) pseudophakia, (B) phakic and (C) phacoemulsification surgery performed during the study. Differences of GA area progression were compared between these study groups. In addition, comparison between GA progression rate in group (C) before and after the surgery was performed. The enlargement rate (ER) was calculated for lesion size after transforming the measurements to the square-root scale.

    Results: A total of 92 eyes of 92 patients were enrolled. Median follow-up time was 4 [1-10] years. Regarding the eye’s phakic status, 29 (31.5%) were pseudophakic and 63 (68.5%) were phakic; of these, 22 underwent phacoemulsification during the study. Overall, the median baseline and follow-up area of GA were 1.42 [0.04-32.10] mm2 and 6.48 [0.25-47.40] mm2, respectively. The ER was similar between phakic and pseudophakic eyes (0.18 [0.01-1.03] vs 0.15 [0.01-0.65] mm/year, p = 0.62). In patients that underwent cataract surgery during the study, the GA ER remained stable (0.13 [0.01-0.92] vs 0.14 [0.01-0.63] mm/year, p = 0.43).

    Conclusion: These results suggest that cataract surgery does not increase the risk of pre-existing GA progression. Therefore, cataract surgery seems safe and a potential therapeutic weapon to improve visual acuity and consequently quality of life in GA patients.


    Differential Expression of Inflammasome-Related Genes in Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells with or without History of Age-Related Macular Degeneration

    Int J Mol Sci. 2021 Jun 24;22(13):6800.

    Maria Hytti, Eveliina Korhonen, Heidi Hongisto, Kai Kaarniranta, Heli Skottman, Anu Kauppinen

    PMID: 34202702 DOI: 10.3390/ijms22136800

    Inflammation is a key underlying factor of age-related macular degeneration (AMD) and inflammasome activation has been linked to disease development. Induced pluripotent stem-cell-derived retinal pigment epithelial cells (iPSC-RPE) are an attractive novel model system that can help to further elucidate disease pathways of this complex disease. Here, we analyzed the effect of dysfunctional protein clearance on inflammation and inflammasome activation in iPSC-RPE cells generated from a patient suffering from age-related macular degeneration (AMD) and an age-matched control. We primed iPSC-RPE cells with IL-1α and then inhibited both proteasomal degradation and autophagic clearance using MG-132 and bafilomycin A1, respectively, causing inflammasome activation. Subsequently, we determined cell viability, analyzed the expression levels of inflammasome-related genes using a PCR array, and measured the levels of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MCP-1 secreted into the medium. Cell treatments modified the expression of 48 inflammasome-related genes and increased the secretion of mature IL-1β, while reducing the levels of IL-6 and MCP-1. Interestingly, iPSC-RPE from an AMD donor secreted more IL-1β and expressed more Hsp90 prior to the inhibition of protein clearance, while MCP-1 and IL-6 were reduced at both protein and mRNA levels. Overall, our results suggest that cellular clearance mechanisms might already be dysfunctional, and the inflammasome activated, in cells with a disease origin.


    Plasma Lutein, a Nutritional Biomarker for Development of Advanced Age-Related Macular Degeneration: The Alienor Study

    Nutrients. 2021 Jun 15;13(6):2047.

    Bénédicte M J Merle, Audrey Cougnard-Grégoire, Jean-François Korobelnik, Wolfgang Schalch, Stéphane Etheve, Marie-Bénédicte Rougier, Catherine Féart, Cécilia Samieri, Marie-Noëlle Delyfer, Cécile Delcourt  

    PMID: 34203817 PMCID: PMC8232705 DOI: 10.3390/nu13062047

    Lutein and zeaxanthin may lower the risk of age-related macular degeneration (AMD). We evaluated the associations of plasma lutein and zeaxanthin with the incidence of advanced AMD in the Alienor study (Antioxydants Lipides Essentiels Nutrition et Maladies Oculaires). Alienor study is a prospective population-based cohort of 963 residents of Bordeaux, France, who were 73 years or older at baseline (2006-2008). The present study included 609 participants with complete ophthalmologic and plasma carotenoids data. Examinations were performed every two years over an eight-year period (2006 to 2017). Plasma lutein and zeaxanthin were determined at baseline from fasting blood samples using high-performance liquid chromatography. Cox proportional hazard models were used to assess associations between plasma lutein, zeaxanthin, and their (total cholesterol (TC) + triglycerides (TG)) ratios with AMD. Among the 609 included participants, 54 developed advanced incident AMD during a median follow-up time of 7.6 years (range 0.7 to 10.4). Participants with higher plasma lutein had a reduced risk for incident advanced AMD in the fully adjusted model (HR = 0.63 per 1-SD increase (95% CI, 0.41-0.97), p = 0.03). A similar association was observed using the lutein/(TC + TG) ratio (HR = 0.59 (95% CI, 0.39-0.90), p = 0.01). No associations were evidenced for other carotenoids. Higher plasma lutein was associated with a 37% reduced risk of incident advanced AMD.

    VEGF-R2/Caveolin-1 Pathway of Undifferentiated ARPE-19 Retina Cells: A Potential Target as Anti-VEGF-A Therapy in Wet AMD by Resvega, an Omega-3/Polyphenol Combination

    Int J Mol Sci. 2021 Jun 19;22(12):6590.

    Flavie Courtaut, Alessandra Scagliarini, Virginie Aires, Clarisse Cornebise, Jean-Paul Pais de Barros, Céline Olmiere, Dominique Delmas 

    PMID: 34205419 PMCID: PMC8234996 DOI: 10.3390/ijms22126590

    Age-related macular degeneration (AMD) is one of the main causes of deterioration in vision in adults aged 55 and older. In spite of therapies, the progression of the disease is often observed without reverse vision quality. In the present study, we explored whether, in undifferentiated ARPE-19 retinal cells, a disruption of the VEGF receptors (VEGF-R)/caveolin-1 (Cav-1)/protein kinases pathway could be a target for counteracting VEGF secretion. We highlight that Resvega®, a combination of omega-3 fatty acids with an antioxidant, resveratrol, inhibits VEGF-A secretion in vitro by disrupting the dissociation of the VEGF-R2/Cav-1 complex into rafts and subsequently preventing MAPK activation. Moreover, DNA ChIP analysis reveals that this combination prevents the interaction between AP-1 and vegf-a and vegf-r2 gene promoters. By these pathways, Resvega could present a potential interest as nutritional complementation against AMD.


    Management of Cataract in Patients with Age-Related Macular Degeneration

    J Clin Med. 2021 Jun 8;10(12):2538.

    Hemal Mehta 

    PMID: 34201114 PMCID: PMC8228734 DOI: 10.3390/jcm10122538

    Cataract and age-related macular degeneration (AMD) are two of the most common eye diseases of aging. This review addresses the pre-operative, intra-operative, and post-operative considerations in managing cataract in patients with age-related macular degeneration. Surgery for visually significant cataracts in patients with AMD can substantially improve the quality of life and reduce the risk of falls. Pre-operative optical coherence tomography is now recommended where possible to identify pre-existing macula disease. Careful counselling of patients is required before cataract surgery, especially with respect to the expected visual outcome, intraocular lens choice and potential risks of surgery. Real-world data has suggested 6 months of intravitreal anti-VEGF therapy for neovascular AMD before cataract surgery is compatible with optimum long-term visual outcomes. Patients receiving intravitreal therapy for neovascular AMD should be advised of the slightly higher risk of intraoperative complications and the surgeon should be prepared to manage these during the operation. During cataract surgery, unnecessary light exposure should be avoided to reduce phototoxicity. Careful planning of intravitreal therapy for neovascular AMD just before cataract surgery allows the eye greater recovery time in the post-operative period before further planned intravitreal therapy.