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Research update: Issue 501

21 June 2021


Seeing Beyond Anatomy: Quality of Life with Geographic Atrophy

Ophthalmol Ther. 2021 Jun 5.

Dolores Caswell, William Caswell, Jill Carlton 

PMID: 34089491 DOI: 10.1007/s40123-021-00352-3

Quality of life (QoL) is a complex idea without a clear consensus definition. Generally speaking, QoL refers to several subjective measures of wellbeing that vary by individual and circumstance. QoL can decline noticeably as a disease progresses. This is particularly true for geographic atrophy (GA), an advanced form of age-related macular degeneration. GA leads to vision loss for which there is no currently approved pharmacological treatment. There is a lack of qualitative, patient-driven research on QoL in GA. There is also limited information available to both patients and physicians about GA, existing support groups and available assistive technologies. To address this, we have collated the experiences of a person with GA and those of her partner and carer with the current literature on QoL in GA. We have also outlined some of the wide range of developing technologies available to help people with GA carry out daily tasks and hobbies. It is clear that support, whether through informal or structured care, is vital to the wellbeing of people with GA. Despite this, the general public are often unaware of care work, which may result in this integral role being undervalued and under acknowledged. Furthermore, it is apparent that the general public have fundamental misunderstandings around what vision loss entails and are unaware that blindness is a vast spectrum. This feeds into the seemingly paradoxical mix of isolation and dependence on others that often results from GA and vision loss. Through this qualitative examination of a patient’s experiences, we hope to inform and educate both patients and physicians about GA as well as precipitate discussion around the frameworks that should be in place to support both newly diagnosed and long-term patients with GA and other retinal diseases. Seeing beyond anatomy: quality of life with geographic atrophy (WMV 29479 kb).

Plain Language Summary

Asking someone about their ‘quality of life’ is one way to understand their general wellbeing. Quality of life can mean different things to different people. For some people it may mean being able to do what they want to. For others it may include feelings such as happiness. Diseases that cause people to lose their vision can have a very big impact on quality of life. Geographic atrophy is an eye disease that leads to loss of vision and has no cure. In this article, Dolores, a person with geographic atrophy, Bill, her husband and carer, and Jill, a quality of life researcher, discuss how geographic atrophy can change quality of life. Vision loss often means that people are unable to keep up their hobbies and do daily tasks, like shopping or cooking. Learning to use smartphone apps and gadgets can help many people with their hobbies and tasks. Feeling alone also makes quality of life for people with geographic atrophy worse. The help and understanding of others—including friends, family and doctors—are very important. Treatment plans for patients with vision loss need to consider all parts of a patient’s life. Training for doctors should continue to emphasise that people with geographic atrophy are more than just eyes that cannot be treated.


COVID-19 morbidity and severity in patients with age-related macular degeneration: a Korean nationwide cohort study

Am J Ophthalmol. 2021 Jun 5;11881.

Jee Myung Yang, Sung Yong Moon, Joo Young Lee, Dritan Agalliu, Dong Keon Yon, Seung Won Lee

PMID: 34102151 PMCID: PMC8179838 DOI: 10.1016/j.ajo.2021.05.024

Objective: To determine the potential association of age-related macular degeneration (AMD), a representative chronic age-related degenerative disease of the retina associated with inflammation and aging, with susceptibility to SARS-CoV-2 infection and severe COVID-19 outcomes.

Design: Nationwide cohort study with propensity-score matching.

Setting: Population-based nationwide cohort in Korea.

Study population: Data were obtained from the Health Insurance Review & Assessment Service of Korea, including all patients older than 40 years who underwent SARS-CoV-2 testing in South Korea between January 1, 2020, and May 15, 2020 (excluding self-referral).

Main outcome measures: SARS-CoV-2 test positivity was the primary outcome and severe clinical outcome of COVID-19 was the secondary outcome.

Results: The unmatched cohort consisted of 135,435 patients who were tested for SARS-CoV-2; 4531 (3.3%) tested positive for SARS-CoV-2; 5493 (4.1%) patients had AMD. After propensity score matching, exudative AMD was associated with an increased likelihood of susceptibility to SARS-CoV-2 infection (adjusted odds ratio [aOR], 1.50; 95% confidence interval [CI], 1.03-2.25), and a considerably greater risk of severe clinical outcomes of COVID-19 (aOR, 2.26; 95% CI, 1.02 to 5.26), but not any AMD and non-exudative AMD.

Conclusions: In a Korean nationwide cohort, our data suggest that clinicians should be aware of the greater risk of susceptibility to severe clinical outcomes of COVID-19 in patients with exudative AMD. Our findings provide an improved understanding of the relationship between the pathogenesis of COVID-19 and chronic neurological disorders.


Geographic Atrophy Incidence and Progression Following Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Agents for Age-Related Macular Degeneration: A Meta-Analysis

Retina. 2021 May 17.

Arshia Eshtiaghi, Mariam Issa, Marko M Popovic, Rajeev H Muni, Peter J Kertes

PMID: 34101693 DOI: 10.1097/IAE.0000000000003207

Purpose: Geographic atrophy (GA) is a complication of advanced neovascular age-related macular degeneration (nAMD) that can lead to permanent vision loss. We sought to estimate the incidence and progression of GA following intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents in eyes with nAMD.

Methods: Ovid MEDLINE, EMBASE and Cochrane CENTRAL were searched from inception to May 2020. Included studies reported on the progression or development of GA in eyes with nAMD following anti-VEGF therapy.

Results: 31 articles and 4609 study eyes (4501 patients) were included. Eyes received a mean of 17.7 injections over 35.2 months. The prevalence of GA at baseline was 9.7%. The pooled incidence of GA was 30.5% at the end of follow-up. There was a positive, moderate linear correlation between the mean total number of injections and GA incidence at final follow-up (R2=0.30; P=0.01). Monthly treatment was associated with a significantly higher risk for GA development relative to PRN (RR=1.40, 95%CI=[1.21-1.61], P<0.001). Risk factors for GA development included GA in the fellow eye, retinal angiomatous proliferation, drusen, and reticular pseudodrusen.

Conclusion: We found an association between the frequency and number of treatments with anti-VEGF agents and the development of GA in nAMD. Future studies should clarify risk factors, population characteristics and relative contributions of treatment and disease progression on GA development in this context.

Long-term outcomes of anti-VEGF treatment of retinal vein occlusion

Eye (Lond). 2021 Jun 11.

Kimberly L Spooner, Samantha Fraser-Bell, Thomas Hong, James G Wong, Andrew A Chang

PMID: 34117379 DOI: 10.1038/s41433-021-01620-z

Background/objectives: To analyze the long-term outcomes of eyes with retinal vein occlusion (RVO) 8 years after commencing treatment with anti-vascular endothelial growth factor (VEGF) agents.

Subjects/methods: Retrospective, multicentre study of 221 eyes diagnosed with RVO, which were commenced on anti-VEGF therapy between 2009 and 2011. VA and CRT were recorded at baseline and at subsequent annual time points. The mean number of injections administered each year and the incidence of adverse events were recorded.

Results: Of a total of 221 eyes which commenced treatment with anti-VEGF agents for RVO, 95 were diagnosed with BRVO and 126 with CRVO. 8-year data were available for 94 eyes (43%). The mean age of patients was 65.1 ± 12.0 years. Mean VA improved from baseline by 16.9 letters, (57.8-74.7 letters), (P < 0.001). For BRVO eyes, mean VA improved from 60.5 to 74.8 letters (p < 0.001) and for CRVO eyes from 52.0 to 66.4 letters (p < 0.001). In all RVO eyes, there was a reduction in mean CRT from 501.0 to 249.1 µm; in BRVO eyes from 472.4 to 284.7 µm and in CRVO eyes from 533.9 to 267.5 µm. In the 8th year after starting treatment, eyes with RVO were receiving a mean of four injections.

Conclusion: Good long-term outcomes of VEGF inhibition for eyes with RVO were found in this study. Patients maintained a gain of 3-lines of vision 8-years after the commencing therapy. This encouraging result contrasts with long-term studies of patients with neovascular age-related macular degeneration, where initial gains are lost over time.

The Relationship Between Stopper Position and Injection Volume in Ranibizumab and Aflibercept Prefilled Syringes

Retina. 2021 Jun 7.

John W Hinkle, Jason Hsu

PMID: 34111885 DOI: 10.1097/IAE.0000000000003232

Purpose: To determine the relationship between stopper position and injection volume in aflibercept and ranibizumab prefilled syringes (PFS).

Methods: Empty aflibercept 2.0 mg PFS and ranibizumab 0.3 mg and 0.5 mg PFS were collected and refilled with saline. The stopper was positioned relative to the preprinted mark and resulting injection volumes were recorded. The position for double the on-label volume was confirmed with repeated testing. The quantitative relationship between position and volume was calculated.

Results: In ranibizumab PFS, doubling the distance increased the volume injected by 2.6 times. Positioning the stopper 4.0, 3.0, 2.0, and 0 mm proximal to and 1.0 mm distal to the mark injected volumes of 0.13, 0.1, 0.08, 0.05 and 0.03 mL, respectively. The relationship between position (x) and volume (y) was y = 0.019x + 0.048.In aflibercept PFS, doubling the distance increased the volume injected by 3.2 times. Positioning the stopper 2.5, 2.0, 1.0, and 0 mm proximal to and 1.0 mm distal to the mark injected volumes of 0.16, 0.14, 0.11, 0.05 and 0.02 mL, respectively. The relationship between position (x) and volume (y) was y = 0.041x – 0.059.

Conclusions: Proper positioning of the stopper at the preprinted mark accurately delivers the on-label volume with both the ranibizumab and aflibercept PFS. However, small variations in stopper position appear to have substantial impacts on the volume of drug injected, particularly with the aflibercept PFS.

A Baseline Score to Predict Response to Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration

Transl Vis Sci Technol. 2021 May 3;10(6):11.

Cheikh Diack, Dietmar Schwab, Valerie Cosson, Vincent Buchheit, Norman Mazer, Nicolas Frey 

PMID: 34111259 PMCID: PMC8114000 DOI: 10.1167/tvst.10.6.11

Purpose: What are the patient characteristics predictive of response to ranibizumab treatment?

Methods: Model-based characterization of best-corrected visual acuity (BCVA) time profiles of patients with neovascular age-related macular degeneration under ranibizumab or sham treatment based on 24-month observations of BCVA in 2419 patients from randomized multicenter phase 3 trials of ranibizumab: ANCHOR, MARINA, PIER, and HARBOR. Goodness-of-fit plots and precision of parameter estimates were used for measure of accuracy.

Results: The model incorporates a long-term effect on disease progression and an additive and more potent short-term effect of ranibizumab. Response to ranibizumab treatment and progression of the disease were found to be a function of seven baseline characteristics (visual acuity, age, leakage size, central retinal lesion thickness, presence or absence of cyst, type of choroidal neovascularization (CNV), and size of pigment epithelium detachment). A composite score of these seven baseline characteristics was derived and used to categorize response to ranibizumab treatment. The ranibizumab treatment arms of two proof-of-concept studies held out from the model development were used to validate the methodology.

Conclusions: A composite score based on seven patient characteristics prior to treatment could be used to discriminate patients with predicted insufficient response to anti-vascular endothelial growth factor treatment.

Translational relevance: The method could be used to create a virtual ranibizumab treatment arm in clinical trials or to reduce the size of a ranibizumab active control arm.

ETOILE: Real-World Evidence of 24 Months of Ranibizumab 0.5 mg in Patients with Visual Impairment Due to Diabetic Macular Edema

Clin Ophthalmol. 2021 Jun 3;15:2307-2315.

Laurent Kodjikian, Amélie Lecleire-Collet, Corinne Dot, Marie-Laure Le Lez, Stéphanie Baillif, Ali Erginay, Eric Souied, Eric Fourmaux, Philippe Gain, Anne Ponthieux 

PMID: 34113074 PMCID: PMC8185131 DOI: 10.2147/OPTH.S313081

Purpose: To evaluate the real-world effectiveness of intravitreal ranibizumab 0.5 mg (Lucentis) in improving visual acuity (VA) in adults with decreased VA due to diabetic macular edema (DME).

Patients and methods: Real-world prospective observational 24-month study. Ranibizumab-naïve patients (n=116) were enrolled, treated and followed up according to investigators’ usual procedures. Outcomes included change from baseline to month 24 in best-corrected VA (BCVA; primary outcome), central retinal thickness (CRT), treatment exposure and safety.

Results: Overall, 62.9% of patients completed the study per protocol, 68.6% completed the induction phase (first three injections one month apart). On average, patients had 12.5 ophthalmologist visits and 5.74 injections in year 1, decreasing to 4.6 visits and 1.94 injections in year 2. Mean baseline BCVA was 58.4 letters, mean gain at M24 was +6.08 letters (95% CI: 2.95, 9.21). Gains were higher for patients who completed induction, and for patients who did not switch treatment. Mean CRT improved by 149.17 μm at M24. There were no new safety signals. BCVA variation of ≥6 letters by M3 was predictive of BCVA gains at M24 (p=0.007), as was hypertension medication at baseline (p=0.022).

Conclusion: Real-world ranibizumab treatment improved VA in DME patients, despite fewer injections than recommended.

Different Outcomes of Anti-VEGF Treatment for Neovascular AMD according to Neovascular Sutypes and Baseline Features: 2-Year Real-Life Clinical Outcomes

Biomed Res Int. 2021 May 24;2021:5516981.

Alessandro Arrigo, Andrea Saladino, Emanuela Aragona, Stefano Mercuri, Ugo Introini, Francesco Bandello, Maurizio Battaglia Parodi

PMID: 34124243 PMCID: PMC8169263 DOI: 10.1155/2021/5516981

Purpose: To evaluate the effects of anti-VEGF treatment of neovascular age-related macular degeneration (nAMD) in a real-life clinical setting.

Methods: Study design is a retrospective case series. Naïve nAMD patients treated with intravitreal injection of aflibercept or ranibizumab were analyzed over a 24-month follow-up. Each patient received the loading dose, followed by a PRN regimen. Patients were further subdivided into subgroups according to macular neovascularization type, best corrected visual acuity (BCVA) at baseline (BCVA > 0.3 LogMAR and BCVA ≤ 0.3 LogMAR), and different anti-VEGF drugs. Primary outcome was the changes in BCVA and central macular thickness (CMT) over 24 months. Secondary outcomes included the influence of the selected drug and of the baseline BCVA on the final outcomes.

Results: 439 patients (224 males; 51%) with naïve AMD-related macular neovascularization were included in the analyses. Mean age was 78 ± 8 years old. Compared to baseline evaluations, not significant BCVA changes were found at 1-year and 2-year examinations. CMT was significantly reduced at both 1-year and 2-year follow-ups (p < 0.01). Classic, polypoidal choroidal vasculopathy and mixed subtypes significantly correlated with worse visual outcome (p < 0.01). Overall, baseline BCVA significantly correlated with both 1-year and 2-year follow-up changes (p < 0.01). Moreover, BCVA at 1-year significantly correlated with BCVA changes at 2-year follow-up (p < 0.01). Furthermore, CMT changes from baseline significantly correlated with both 1-year and 2-year follow-up measurements (p < 0.01).

Conclusion: Anti-VEGF approach is generally effective in stopping nAMD progression in our real-life analysis. No difference was found comparing patients treated with ranibizumab and aflibercept, nor in patients with drug switching.

Observational outcomes in proliferative diabetic retinopathy patients following treatment with ranibizumab, panretinal laser photocoagulation or combination therapy – The non-interventional second year follow-up to the PRIDE study

Acta Ophthalmol. 2021 Jun 14.

Gabriele E Lang, Andreas Stahl, Jessica Voegeler, Claudia Quiering, Laureen Zaremba, Katrin Lorenz, Georg Spital, Sandra Liakopoulos 

PMID: 34121335 DOI: 10.1111/aos.14907

Purpose: Ranibizumab monotherapy showed stronger effects on area of retinal neovascularization (NV) reduction while offering better visual acuity (VA) results than panretinal laser photocoagulation (PRP) monotherapy during the first 12 months of the PRIDE study. The second year of PRIDE was an observational, non-interventional follow-up, performed to evaluate long-term anatomical and functional outcomes in proliferative diabetic retinopathy (PDR) patients under real-life conditions, prior to the approval of ranibizumab for PDR.

Methods: Seventy-three PDR patients (28 from the ranibizumab group; 20 from the PRP group; 25 from the combination group) were included in the observational follow-up phase and treated at the investigators discretion. Visual acuity (VA) measurements and retinal imaging were performed at Months 12, 18 and 24.

Results: Mean (± SD) NV area in the ranibizumab monotherapy and combination follow-up groups increased from 3.16 ± 4.30 mm2 and 1.13 ± 2.78 mm2 at Month 12 to 6.09 ± 10.79 mm2 and 2.14 ± 4.41 mm2 at Month 18 and 10.00 ± 17.63 mm2 and 3.26 ± 7.05 mm2 at Month 24, respectively. In the PRP follow-up group, NV area declined from 5.44 ± 14.55 mm2 at Month 12 to 1.22 ± 1.67 mm2 at Month 18, but increased again to 4.05 ± 11.66 mm2 at Month 24. During the observational phase, only 2 (6;8) patients in the ranibizumab (PRP;combination) follow-up group were treated with anti-VEGF medications, while 17 (6;10) patients received PRP laser therapy.

Conclusion: Discontinuation of ranibizumab treatment in PDR patients may result in an increase of NV area and VA loss. Tight monitoring of disease activity and continued treatment beyond the first year is needed to maintain disease control.

Incidence of elevated intraocular pressure after intravitreal injection in Japanese patients with age-related macular degeneration

Sci Rep. 2021 Jun 10;11(1):12246.

Maiko Maruyama-Inoue, Tatsuya Inoue, Shaheeda Mohamed, Yoko Kitajima, Shoko Ikeda, Arisa Ito, Kazuaki Kadonosono  

PMID: 34112856 PMCID: PMC8192945 DOI: 10.1038/s41598-021-91832-w

The purpose of this study was to report the incidence of elevated intraocular pressure (IOP) after intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) in Japanese patients with age-related macular degeneration (AMD). A retrospective study of chart review of patients who underwent ≥ 10 intravitreal anti-VEGF injections between April 2009 and December 2019 was conducted. Elevated IOP was defined as IOP ≥ 25 mmHg at one visit. Cases with elevated IOP resulting from IVI were identified. Furthermore, the association between elevated IOP and some parameters, as the risk factors that influence elevated IOP, was investigated. A total of 402 eyes of 370 patients were included in this study. Twenty-eight eyes of 26 patients (7.0%) were identified as cases with elevated IOP after IVI. The mean time of elevation after baseline was 50.6 ± 26.5 months. History of glaucoma (p = 0.021; odds ratio, 5.85), treatment modality (p = 0.019; odds ratio, 6.32), and total number of injections (p = 0.003; odds ratio, 1.03) were significantly associated with elevated IOP. A late complication of elevated IOP is associated with IVI in patients with AMD. Particularly, history of glaucoma and treat and extend regimen with frequent injections were found to be risk factors of elevated IOP.

Efficacy of anti-vascular endothelial growth factor agents for treating neovascular age-related macular degeneration in vitrectomized eyes

PLoS One. 2021 Jun 10;16(6):e0252006.

Yongseok Mun, Kyu Hyung Park, Sang Jun Park, Se Joon Woo 

PMID: 34111133 PMCID: PMC8191940 DOI: 10.1371/journal.pone.0252006

Purpose: To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents for treatment of neovascular age-related macular degeneration (nAMD) in vitrectomized eyes.

Methods: The medical records were reviewed of nAMD patients treated with anti-VEGF agents who previously underwent pars plana vitrectomy (PPV). PPV was performed with complete posterior vitreous detachment induction.

Results: A total of 44 eyes from 44 patients were included. The mean central foveal thickness (CFT) was 478.50 ± 156.93 μm at baseline, 414.25 ± 143.55 μm (86.6% of baseline) at 1 month after first injection (P < 0.001), and 386.75 ± 141.45 μm (80.8% of baseline) after monthly multiple injections (2.30 ± 1.07; range, 1-5) (P < 0.001). The mean logarithm of the minimum angle of resolution best-corrected visual acuity visual acuity (BCVA) was 0.85 ± 0.57 at baseline, 0.86 ± 0.63 after the first injection, and 0.84 ± 0.64 after monthly multiple injections. BCVA improved in 39.5% at 1 month after first injection and 45.2% at 1 month after monthly multiple injections. In the subgroup analysis, CFT of eyes with the posterior capsule decreased significantly to 85.8% and 79.8% of baseline values at 1 month after the first injection and after monthly multiple injections, respectively. CFT of eyes without the posterior capsule decreased to 91.6% and 87.4% of baseline values at 1 month after the first injection and after monthly multiple injections, respectively, without statistical significance.

Conclusion: Monthly injections of Intravitreal anti-VEGF agents induced favorable anatomical improvement and vision maintenance in vitrectomized eyes with nAMD.

Long-term outcome of intravitreal anti-vascular endothelial growth factor treatment for pachychoroid neovasculopathy

Sci Rep. 2021 Jun 8;11(1):12052.

Jihyun Yoon, Wontae Yoon, Seung Kwan Na, Jihyun Lee, Chul Gu Kim, Jong Woo Kim, Han Joo Cho 

PMID: 34103603 PMCID: PMC8187411 DOI: 10.1038/s41598-021-91589-2

To compare the long-term effectiveness of intravitreal anti-vascular endothelial growth factor (VEGF) treatment for pachychoroid neovasculopathy (PNV), polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization (PCV/AT1), and typical neovascular age-related macular degeneration (nAMD). Forty-one eyes with PNV, 68 eyes with PCV/AT1, and 56 eyes with typical nAMD were retrospectively included for analysis. All patients were treatment-naïve and received a three-monthly loading injection of anti-VEGF, followed by further injections, as required. The visual and anatomical outcomes after treatment were evaluated up to 36 months from baseline. No significant intergroup difference was found in terms of best-corrected visual acuity (BCVA) and changes in central foveal thickness at 12, 24, and 36 months after the baseline. In addition, no significant difference was found between the groups regarding the proportions of improved or worsened (increased or decreased more than 3-lines) visual acuity. However, the PNV group participants received significantly fewer anti-VEGF injections (11.7 ± 6.9) than those in the PCV/AT1 (12.4 ± 7.0; P = 0.031) and typical nAMD groups (13.2 ± 7.4; P = 0.016). The incidence of macular atrophy (MA) development was also significantly lower for the PNV (4/41 eyes, 9.8%) than the typical nAMD (15/56 eyes, 26.8%; P = 0.033) eyes. There was no significant difference between PNV, PCV/AT1, and typical nAMD regarding visual acuity improvement after anti-VEGF treatment over 36 months. However, the number of injections for PNV was significantly lower compared to that for PCV/AT1 and typical nAMD, and the incidence of MA development was significantly lower than in typical nAMD.

Predominantly Persistent Subretinal Fluid in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)

Ophthalmol Retina. 2021 Jun 11;S2468-6530(21)00192-5.

Jason Q Core, Maxwell Pistilli, Ebenezer Daniel, Juan E Grunwald, Cynthia A Toth, Glenn J Jaffe, Peiying Hua, Daniel F Martin, Gui-Shuang Ying, Maureen G Maguire, Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group

PMID: 34126249 DOI: 10.1016/j.oret.2021.06.003

Objective: To describe predominantly persistent subretinal fluid (SRF) in eyes receiving ranibizumab or bevacizumab for neovascular age-related macular degeneration and compare visual acuity (VA) to eyes with non-persistent SRF.

Design: Cohort within randomized clinical trial PARTICIPANTS: Comparison of Age-related Macular Degeneration Treatments Trials patients assigned to pro re nata (PRN) treatment.

Methods: Reading center graders evaluated optical coherence tomography scans at baseline and monthly follow-up visits for SRF. Predominantly persistent SRF through week 12 was defined as SRF at baseline, weeks 4, 8, and 12. Predominantly persistent SRF through 1 or 2 years was defined as SRF in ≥80% of visits by year 1 or year 2, respectively. Adjusted mean VA score and VA change from baseline were compared between eyes with predominantly persistent SRF and eyes non-persistent SRF over the same duration using linear regression models including baseline predictors of VA and predominantly persistent intraretinal fluid (IRF).

Primary outcome measures: Predominantly persistent SRF through year 1, adjusted VA score and VA change, and SRF thickness at the foveal center.

Results: Among 406 eyes with baseline SRF, SRF persisted in 108 (26.6%) through week 12, 94 (23.2%) through year 1, and 77 (19.0%) through year 2. Adjusted VA means (letters) at year 1 were similar between eyes with predominantly persistent vs. non-persistent SRF by week 12, (68.1 vs. 70.2; P=0.18), year 1 (67.6 vs. 70.2; P=0.11), and year 2 (71.4 vs. 70.9; P=0.78). Adjusted change in VA at year 1 means were similar between eyes with predominantly persistent vs. non-persistent SRF by week 12 (6.3 vs. 7.6; P=0.38), year 1 (5.5 vs. 7.8; P=0.14), and year 2 (8.1 vs. 7.7; P=0.78). Among eyes with predominantly persistent SRF through year 1, SRF was absent in the foveal center in 46 (48.9%), thickness was 1-200 μm in 48 (50.0%) and >200 μm in 1 (1.1%) at year 1.

Conclusions: Eyes with predominantly persistent and non-persistent SRF through week 12, year 1, or year 2 had similar VA outcomes after adjustment for baseline covariates and persistent IRF. At the foveal center, predominantly persistent SRF was most commonly absent or present in small quantities.


Smartphone-based remote monitoring of vision in macular disease enables early detection of worsening pathology and need for intravitreal therapy

BMJ Health Care Inform. 2021 May;28(1):e100310.

Meriam Islam, Stafford Sansome, Radha Das, Marko Lukic, Kelvin Yi Chong Teo, Gavin Tan, Konstantinos Balaskas, Peter B M Thomas, Lucas M Bachmann, Andrew M Schimel, Dawn A Sim 

PMID: 34035050 PMCID: PMC8154994 DOI: 10.1136/bmjhci-2020-100310

Background/aims: To assess the outcomes of home monitoring of distortion caused by macular diseases using a smartphone-based application (app), and to examine them with hospital-based assessments of visual acuity (VA), optical coherence tomography-derived central macular thickness (CMT) and the requirement of intravitreal injection therapy.

Design: Observational study with retrospective analysis of data.

Methods: Participants were trained in the correct use of the app (Alleye, Oculocare, Zurich, Switzerland) in person or by using video and telephone consultations. Automated threshold-based alerts were communicated based on a traffic light system. A ‘threshold alarm’ was defined as three consecutive ‘red’ scores, and turned into a ‘persistent alarm’ if present for greater than a 7-day period. Changes of VA and CMT, and the requirement for intravitreal therapy after an alarm were examined.

Results: 245 patients performing a total of 11 592 tests (mean 46.9 tests per user) were included and 85 eyes (164 alarms) examined. Mean drop in VA from baseline was -4.23 letters (95% CI: -6.24 to -2.22; p<0.001) and mean increase in CMT was 29.5 µm (95% CI: -0.08 to 59.13; p=0.051). Sixty-six eyes (78.5%) producing alarms either had a drop in VA, increase in CMT or both and 60.0% received an injection. Eyes with persistent alarms had a greater loss of VA, -4.79 letters (95% CI: -6.73 to -2.85; p<0.001) or greater increase in CMT, +87.8 µm (95% CI: 5.2 to 170.4; p=0.038).

Conclusion: Smartphone-based self-tests for macular disease may serve as reliable indicators for the worsening of pathology and the need for treatment.

Imaging Biomarkers of 1-Year Activity in Type 1 Macular Neovascularization

Transl Vis Sci Technol. 2021 May 3;10(6):18.

Eliana Costanzo, Mariacristina Parravano, Daniela Giannini, Enrico Borrelli, Riccardo Sacconi, Giuseppe Querques  

PMID: 34111264 PMCID: PMC8131998 DOI: 10.1167/tvst.10.6.18

Purpose: The purpose of this study was to evaluate the predictive value of optical coherence tomography (OCT) and OCT angiography (OCTA) parameters at baseline on lesion’s activity at the 1-year follow-up in type 1 macular neovascularizations (MNVs) treated with 1-year fixed regimen of intravitreal aflibercept injections (q8 IAIs).

Methods: All patients were imaged by structural OCT to evaluate central macular thickness (CMT), subretinal fluid (SRF), subretinal hyper-reflective material (SHRM), intraretinal fluid (IRF) and intraretinal hyper-reflective dots (HRDs), and by Swept-Source OCTA to measure baseline MNV area, perfusion density (PD), vessel length density (VLD), and vessel diameter index. At the end of q8 IAI, patients were classified in two groups: active-MNV (A-MNV) and inactive-MNV (I-MNV), considering the OCT signs of activity. Three binary logistic regression models were developed: (1) OCT-based, (2) OCTA-based, and (3) OCT/OCTA-based model.

Results: Thirty-one treatment-naïve type 1 MNVs were enrolled (13 A-MNV and 18 I-MNV). No differences were observed in baseline OCT and OCTA characteristics between A-MNV and I-MNV. Among the models developed, model 3 that combined OCT/OCTA parameters showed a performance of 87.5% and excellent sensitivity for A-MNV lesions (100%). By analyzing the model, the A-MNV group appears more likely to show at baseline SRF, greater CMT, wider MNV area, and lower PD and VLD compared to I-MNV.

Conclusions: Our study demonstrated that the combination of baseline OCT and OCTA parameters allowed to achieve a good models’ performance in the prediction of MNV activity permitting to correctly classifying the active lesions at the end of follow-up period, with excellent sensitivity.

Translational relevance: OCT/OCTA could integrate statistical models potentially useful for artificial intelligence.

Comparing Fluorescence Lifetime Imaging Ophthalmoscopy in Atrophic Areas of Retinal Diseases

Transl Vis Sci Technol. 2021 Jun 1;10(7):11.

Lukas Goerdt, Lydia Sauer, Alexandra S Vitale, Natalie K Modersitzki, Monika Fleckenstein, Paul S Bernstein 

PMID: 34110387 DOI: 10.1167/tvst.10.7.11

Purpose: Fluorescence lifetime imaging ophthalmoscopy (FLIO) is a non-invasive imaging modality to investigate the human retina. This study compares FLIO lifetimes in different degenerative retinal diseases.

Methods: Included were eyes with retinal pigment epithelium (RPE) and/or photoreceptor atrophy due to Stargardt disease (n = 66), pattern dystrophy (n = 18), macular telangiectasia type 2 (n = 49), retinitis pigmentosa (n = 28), choroideremia (n = 26), and geographic atrophy (n = 32) in age-related macular degeneration, as well as 37 eyes of 37 age-matched healthy controls. Subjects received Heidelberg Engineering FLIO, autofluorescence intensity, and optical coherence tomography imaging. Amplitude-weighted mean FLIO lifetimes (τm) were calculated and analyzed.

Results: Retinal FLIO lifetimes show significant differences depending on the disease. Atrophic areas in geographic atrophy and choroideremia showed longest mean FLIO lifetimes. τm values within areas of RPE and outer nuclear layer atrophy were significantly longer than within areas with preserved outer nuclear layer (P < 0.001) or non-atrophic areas (P < 0.001).

Conclusions: FLIO is able to contribute additional information regarding differences in chronic degenerative retinal diseases. Although it cannot replace conventional autofluorescence imaging, FLIO adds to the knowledge in these diseases and may help with the correct differentiation between them. This may lead to a more in-depth understanding of the pathomechanisms related to atrophy and types of progression.

Translational relevance: Differences between atrophic retinal diseases highlighted by FLIO may indicate separate pathomechanisms leading to atrophy and disease progression.

Microperimetry Hill of Vision and Volumetric Measures of Retinal Sensitivity

Transl Vis Sci Technol. 2021 Jun 1;10(7):12.

Amandeep Singh Josan, Thomas M W Buckley, Laura J Wood, Jasleen K Jolly, Jasmina Cehajic-Kapetanovic, Robert E MacLaren  

PMID: 34110386 DOI: 10.1167/tvst.10.7.12

Purpose: Mean retinal sensitivity is the main output measure used in microperimetry. It is, however, of limited use in patients with poor vision because averaging is weighted toward zero in those with significant scotomas creating an artificial floor effect. In contrast, volumetric measures avoid these issues and are displayed graphically as a hill of vision.

Methods: An open-source program was created to manipulate raw sensitivity threshold data files obtained from MAIA microperimetry. Thin plate spline interpolated heat maps and three-dimensional hill of vision plots with an associated volume were generated. Retrospective analyses of microperimetry volumes were undertaken in patients with a range of retinal diseases to assess the qualitative benefits of three-dimensional visualization and volumetric measures. Simulated pathology was applied to radial grid patterns to investigate the performance of volumetric sensitivity in nonuniform grids.

Results: Volumetric analyses from microperimetry in RPGR-related retinitis pigmentosa, choroideremia, Stargardt disease, and age-related macular degeneration were analyzed. In simulated nonuniform testing grids, volumetric sensitivity was able to detect differences in retinal sensitivity where mean sensitivity could not.

Conclusions: Volumetric measures do not suffer from averaging issues and demonstrate superior performance in nonuniform testing grids. Additionally, volume measures enable detection of localized retinal sensitivity changes that might otherwise be undetectable in a mean change.

Translational relevance: As microperimetry has become an outcome measure in several gene-therapy clinical trials, three-dimensional visualization and volumetric sensitivity enables a complementary analysis of baseline disease characteristics and subsequent response to treatment, both as a signal of safety and efficacy.


Association of Aberrant Posterior Vitreous Detachment and Pathologic Tractional Forces With Myopic Macular Degeneration

Invest Ophthalmol Vis Sci. 2021 Jun 1;62(7):7.

Kai Yuan Tey, Qiu Ying Wong, Yee Shan Dan, Andrew S H Tsai, Daniel S W Ting, Marcus Ang, Gemmy Chiu Ming Cheung, Shu Yen Lee, Tien Yin Wong, Quan V Hoang, Chee Wai Wong

PMID: 34096974 DOI: 10.1167/iovs.62.7.7

Purpose: The purpose of this study was to assess whether the tractional elements of pathologic myopia (PM; e.g. myopic traction maculopathy [MTM], posterior staphyloma [PS], and aberrant posterior vitreous detachment [PVD]) are associated with myopic macular degeneration (MMD) independent of age and axial length, among highly myopic (HM) eyes.

Methods: One hundred twenty-nine individuals with 239 HM eyes from the Myopic and Pathologic Eyes in Singapore (MyoPES) cohort underwent ocular biometry, fundus photography, swept-source optical coherence tomography, and ocular B-scan ultrasound. Images were analyzed for PVD grade, and presence of MTM, PS, and MMD. The χ² test was done to determine the difference in prevalence of MMD between eyes with and without PVD, PS, and MTM. Multivariate probit regression analyses were performed to ascertain the relationship between the potential predictors (PVD, PS, and MTM) and outcome variable (MMD), after accounting for possible confounders (e.g. age and axial length). Marginal effects were reported.

Results: Controlling for potential confounders, eyes with MTM have a 29.92 percentage point higher likelihood of having MMD (P = 0.003), and eyes with PS have a 25.72 percentage point higher likelihood of having MMD (P = 0.002). The likelihood of MMD increases by 10.61 percentage points per 1 mm increase in axial length (P < 0.001). Subanalysis revealed that eyes with incomplete PVD have a 22.54 percentage point higher likelihood of having MMD than eyes with early PVD (P = 0.04).

Conclusions: Our study demonstrated an association between tractional (MTM, PS, and persistently incomplete PVD) and degenerative elements of PM independent of age and axial length. These data provide further insights into the pathogenesis of MMD.

Elevated YKL-40 serum levels may contribute to wet age-related macular degeneration via the ERK1/2 pathway

FEBS Open Bio. 2021 Jun 10.

Yue Bin, Yanyao Liu, Shaoqiu Jiang, Hui Peng  

PMID: 34110111 DOI: 10.1002/2211-5463.13223

Choroidal neovascularization (CNV) is a key characteristic of wet age-related macular degeneration (AMD) that can lead to severe vision loss in the elderly. Anti-VEGF therapy is currently the premier strategy for wet AMD, but it has limited efficacy. Previous studies have shown that chitinase-3-like-1 (YKL-40) can promote microangiogenesis and inflammation, but its effect on CNV formation has not yet been studied. Here, we investigated the potential role of YKL-40 in wet AMD and the underlying mechanism(s). We report that the serum expression of YKL-40 in wet AMD patients was significantly higher than that in control patients and was positively correlated with VEGF expression, indicating that YKL-40 may participate in the development of wet AMD. In addition, YKL-40 and VEGF expression levels were observed to be increased and the ERK1/2 pathway activated in the neuroretinal (NR) and RPE/choroid tissues of mice with laser-induced CNV. The YKL-40 and phosphorylated protein levels of the ERK1/2 pathway were decreased after intravitreal injection with an anti-YKL-40 antibody, suggesting that anti-YKL-40 could inhibit the activation of the ERK1/2 pathway. These results indicate that YKL-40 may serve as a novel target for the diagnosis and treatment of wet AMD.

Altered serum levels of autophagy proteins Beclin-1 and mTOR in patients with exudative age-related macular degeneration

J Physiol Pharmacol. 2021 Feb;72(1).

A Kubicka-Trzaska, K Zuber-Laskawiec, H Plutecka, B Romanowska-Dixon, M Sanak, I Karska-Basta  

PMID: 34099588 DOI: 10.26402/jpp.2021.1.09

Autophagy is a key process in the maintenance of cellular survival and homeostasis. Inhibition of autophagy results in degenerative changes resembling ageing. We wondered if autophagy can contribute to the pathogenesis of age-related macular degeneration (AMD). We aimed to investigate the serum concentrations of two key autophagy regulators, Beclin-1 and mechanistic target of rapamycin (mTOR), in patients with exudative AMD. This retrospective case-control study included 38 patients with exudative AMD and 36 sex- and age-matched controls selected among senile cataract patients. Circulating Beclin-1 and mTOR were assessed using an enzyme-linked immunosorbent assay. The proteins levels were correlated with age, sex, duration of ocular symptoms, as well as angiographic and optical coherence tomography findings. Serum Beclin-1 levels were much lower in patients with AMD than in controls (median, 0.100 ng/ml versus 1.123 ng/ml; p = 0.0033), while mTOR levels did not differ (median, 4.377 ng/ml versus 3.608 ng/ml; p = 0.4522). Participants of the study older than 70 years had lower Beclin-1 levels than younger ones (p = 0.0444). However, this difference was the most evident in patients with AMD (p = 0.0024). Serum mTOR levels increased with age. In patients with AMD, lower mTOR levels were associated with drusen, while higher levels were observed in those with a fibrous scar in the contralateral eye (p = 0.0212). Our findings suggest that circulating Beclin-1 decreases with age and that is downregulated in patients with AMD.

Inhibition of epithelial-mesenchymal transition in retinal pigment epithelial cells by a retinoic acid receptor-α agonist

Sci Rep. 2021 Jun 4;11(1):11842.

Yuka Kobayashi, Kazuhiro Tokuda, Chiemi Yamashiro, Fumiaki Higashijima, Takuya Yoshimoto, Manami Ota, Tadahiko Ogata, Atsushige Ashimori, Makoto Hatano, Masaaki Kobayashi, Sho-Hei Uchi, Makiko Wakuta, Kazuhiro Kimura  

PMID: 34088917 PMCID: PMC8178299 DOI: 10.1038/s41598-021-90618-4

Epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a key role in proliferative retinal diseases such as age-related macular degeneration by contributing to subretinal fibrosis. To investigate the potential role of retinoic acid receptor-α (RAR-α) signaling in this process, we have now examined the effects of the RAR-α agonist Am580 on EMT induced by transforming growth factor-β2 (TGF-β2) in primary mouse RPE cells cultured in a three-dimensional type I collagen gel as well as on subretinal fibrosis in a mouse model. We found that Am580 inhibited TGF-β2-induced collagen gel contraction mediated by RPE cells. It also attenuated the TGF-β2-induced expression of the mesenchymal markers α-smooth muscle actin, fibronectin, and collagen type I; production of pro-matrix metalloproteinase 2 and interleukin-6; expression of the focal adhesion protein paxillin; and phosphorylation of SMAD2 in the cultured RPE cells. Finally, immunofluorescence analysis showed that Am580 suppressed both the TGF-β2-induced translocation of myocardin-related transcription factor-A (MRTF-A) from the cytoplasm to the nucleus of cultured RPE cells as well as subretinal fibrosis triggered by laser-induced photocoagulation in a mouse model. Our observations thus suggest that RAR-α signaling inhibits EMT in RPE cells and might attenuate the development of fibrosis associated with proliferative retinal diseases.

Cynaroside protects the blue light-induced retinal degeneration through alleviating apoptosis and inducing autophagy in vitro and in vivo

Phytomedicine. 2021 Jul 15;88:153604.

Jia-Hao Feng, Xiao-Wei Dong, Hao-Li Yu, Wei Shen, Xian-Yu Lv, Rong Wang, Xue-Xiang Cheng, Fei Xiong, Xiao-Long Hu, Hao Wang  

PMID: 34130054 DOI: 10.1016/j.phymed.2021.153604

Background: Blue light can directly penetrate the lens and reach the retina to induce retinal damage, causing dry age-related macular degeneration (dAMD). Cynaroside (Cyn), a flavonoid glycoside, was proved to alleviate the oxidative damage of retinal cells in vitro. However, whether or not Cyn also exerts protective effect on blue light-induced retinal degeneration and its mechanisms of action are unclear.

Purpose: This study aims to evaluate the protective effects of Cyn against blue-light induced retinal degeneration and its underlying mechanisms in vitro and in vivo.

Study design/methods: Blue light-induced N-retinylidene-N-retinylethanolamine (A2E)-laden adult retinal pigment epithelial-19 (ARPE-19) cell damage and retinal damage in SD rats were respectively used to evaluate the protective effects of Cyn on retinal degeneration in vitro and in vivo. MTT assay and AnnexinV-PI double staining assay were used to evaluate the in vitro efficacy. Histological analysis, TUNEL assay, and fundus imaging were conducted to evaluate the in vivo efficacy. ELISA assay, western blot, and immunostaining were performed to investigate the mechanisms of action of Cyn.

Results: Cyn decreased the blue light-induced A2E-laden ARPE-19 cell damage and oxidative stress. Intravitreal injection of Cyn (2, 4 μg/eye) reversed the retinal degeneration induced by blue light in SD rats. Furthermore, Cyn inhibited the nuclear translocation of NF-κB and induced autophagy, which led to the clearance of overactivated pyrin domain containing 3 (NLRP3) inflammasome in vitro and in vivo.

Conclusion: Cyn protects against blue light-induced retinal degeneration by modulating autophagy and decreasing the NLRP3 inflammasome.


Neovascular age-related macular degeneration at treatment intervals of 14 weeks or greater

Clin Exp Ophthalmol. 2021 Jun 15.

Elisa E Cornish, Vuong Nguyen, Stephanie Young, Samantha Fraser-Bell, Robyn Guymer, David Squirrell, Daniel Barthelmes, Mark C Gillies  

PMID: 34129283 DOI: 10.1111/ceo.13962

Background: We assessed the proportion of eyes with neovascular age-related macular degeneration (nAMD) in routine clinical practice that reach ≥14 week treatment intervals and their outcomes.

Method: We analysed data from the Fight Retinal Blindness! (FRB!) Project database, a prospectively designed registry of “real-world” outcomes. Treatment-naive eyes starting vascular endothelial growth factor (VEGF) inhibitors for nAMD from 1st January 2006 were included. Eyes were defined to have reached the ≥14 week treatment interval if they received ≥2 consecutive injections at treatment intervals of ≥14 week but not exceeding 26 weeks. Outcomes were reported in a subgroup of eyes that had 12 months of follow-up from reaching this interval.

Results: Of the 3907 treatment-naïve eyes that started treatment during the identified periods on a treat-and-extend regimen and received at least 8 injections over the first 2 years, 402 (10%) eyes received at least 2 consecutive injections at an interval of ≥14 week during their follow-up. Fifty-two percent of these eyes maintained vision to 12 months, however only 40% stayed at this interval and 25% of the lesions reactivated.

Conclusion: We found that only 10% of eyes with nAMD were extended beyond a 13-week injection interval and that over half had returned to a shorter interval by 12 months. Eyes that stayed at this extended treatment interval maintained stable vision. More data on the outcomes of eyes treated with intervals longer than 3 months are required to establish whether emerging VEGF inhibitors provide a more sustained effect than the currently available drugs.

Intravitreal anti-VEGF use in France: a cross-sectional and longitudinal Nationwide observational study

Acta Ophthalmol. 2021 Jun 14.

Sophie Billioti de Gage, Marion Bertrand, Sébastien Grimaldi, Mahmoud Zureik  

PMID: 34126649 DOI: 10.1111/aos.14929

Purpose: To describe the sociodemographic, medical and management characteristics of patients using intravitreal (IVT) anti-vascular endothelial growth factors (VEGF) in France.

Methods: An observational study was conducted in patients treated with IVT ranibizumab or aflibercept, aged 18 years or older using the French National Health Insurance Databases covering 99% of the French population. Patients currently treated in 2018 were included in a cross-sectional approach to describe treatment history over the previous 6 years. Patients newly treated between 2014 and 2018 were included in a longitudinal approach to describe treatment management during up to 6 years of follow-up. Sociodemographic characteristics and medical history were described in both populations. The analyses were performed at the patient level, as no distinction between the eyes could be made.

Results: A total of 224 775 current users of IVT anti-VEGF in 2018 (mean age 78.1 ± 11.3 years, 60% female) and 330 969 new users between 2014 and 2018 (mean age 75.9 ± 12.0 years, 59% female) were included. In both populations cardiovascular comorbidities or risk factors were frequent and the main treatment indications were age-related macular degeneration and diabetic macular oedema. Among current users of IVT anti-VEGF in 2018, the mean number of years receiving a treatment was 2.9 ± 2.0 years, with a mean of 13.7 ± 11.8 dispensations. In the longitudinal approach, a 26% increase in IVT anti-VEGF initiation was observed between 2014 and 2018. For new users, the mean number of years receiving a treatment was 1.6 ± 1.6 and 67% had at least three dispensations within the first three months. A treatment interruption was observed for 83% of new users and occurred on average of 6.1 ± 8.1 months after initiation. The mean number of dispensations was 4.8 ± 2.8 in the first year and 2.2 ± 2.9 in the second year. The mean number of eye monitoring examinations was 6.5 ± 4.7 in the first year and 4.6 ± 4.4 in the second year.

Conclusion: This study described the real-world conditions of IVT anti-VEGF dispensing at the entire French population scale. Less frequent dispensations and surveillance examinations were observed than in monthly schemes applied in registration trials for IVT anti-VEGF. These results may indicate a lack of systematic monitoring associated with fewer injections and/or clinicians’ preference for more flexible and personalized injection schemes than those originally recommended.


Transcription factor overexpression drives reliable differentiation of retinal pigment epithelium from human induced pluripotent stem cells

Stem Cell Res. 2021 May;53:102368.

Tessa E Dewell, Ketrin Gjoni, Angela Z Liu, Ashley R G Libby, Anthony T Moore, Po-Lin So, Bruce R Conklin  

PMID: 34087997 DOI: 10.1016/j.scr.2021.102368

Age-related macular degeneration and genetic forms of blindness such as Best Disease and Retinitis Pigmentosa can be caused by degeneration of the Retinal Pigment Epithelium (RPE). RPE generated from patient-derived induced pluripotent stem cells (iPSCs) is valuable for both the study of disease mechanisms and development of therapeutic strategies. However, protocols to produce iPSC-derived RPE in vitro are often inefficient, labor-intensive, low-throughput, and highly variable between cell lines and within batches. Here, we report a robust, scalable method to generate iPSC-RPE using doxycycline-inducible expression of eye field transcription factors OTX2, PAX6 and MITF paired with RPE-permissive culture media. Doxycycline addition induces exogenous expression of these transcription factors in Best Disease patient- and wildtype iPSCs to efficiently produce monolayers of RPE with characteristic morphology and gene expression. Further, these RPE monolayers display functionality features including light absorption via pigmentation, polarity-driven fluid transport, and phagocytosis. With this method, we achieve a highly efficient and easily scalable differentiation without the need for mechanical isolation or enrichment methods, generating RPE cultures applicable for in vitro studies.


Alcohol consumption and age-related macular degeneration: A systematic review and dose-response meta-analysis

Curr Eye Res. 2021 Jun 11.

Jingjing Zhang, Toshiharu Mitsuhashi, Toshihiko Matsuo, Takashi Yorifuji, Jun Hamada, Yangyang Liu 

PMID: 34115943 DOI: 10.1080/02713683.2021.1942070

Purpose: To perform a systematic review on the association between alcohol consumption and risk of age-related macular degeneration (AMD) using a meta-analytical approach.

Method: Systematic literature research was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Both categorical and dose-response meta-analysis was performed separately for early and late AMD. A fixed-effect model was used to calculate pooled effect estimates with 95% confidence interval (CI).

Result: Seven studies were included in the analysis with 4,566 and 440 cases of early and late AMD, respectively. Compared to the nondrinkers or occasional drinkers, the pooled effect estimates for early AMD with moderate (1.19, 95% CI [1.03-1.37]) and heavy (1.24, [1.10-1.39]) alcohol consumption, but not light (0.95, [0.90-1.06]) alcohol consumption, were statistically significant. However, the pooled effect estimates for late AMD with light (1.03, [0.79-1.33]), moderate (1.13, [0.83-1.55]), and heavy (0.98, [0.63-1.53]) alcohol consumption were found to be insignificant. A linear dose-response relationship was established (P < 0.05) between alcohol consumption and risk of early AMD, and the pooled effect estimate for an increase in alcohol consumption of 10 g/day was 1.14 (1.08-1.21).

Conclusion: Moderate and heavy alcohol consumption could increase the risk of early AMD, but not late AMD, with a linear dose-response relationship.


Photobiomodulation for non-exudative age-related macular degeneration

Cochrane Database Syst Rev. 2021 May 6;5:CD013029.

Christin Henein, David Hw Steel 

PMID: 34097768 DOI: 10.1002/14651858.CD013029.pub2

Background: Age-related macular degeneration (AMD) is one of the leading causes of blindness in high-income countries. The majority of cases of AMD are of the non-exudative type. Experts have proposed photobiomodulation (PBM) therapy as a non-invasive procedure to restore mitochondrial function, upregulate cytoprotective factors and prevent apoptotic cell death in retinal tissue affected by AMD.

Objectives: To assess the effectiveness and safety of PBM compared to standard care, no treatment or sham treatment for people with non-exudative AMD.

Search methods: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 5, 2020), Ovid MEDLINE, Embase, ISRCTN, and the WHO ICTRP to 11 May 2020 with no language restrictions.

Selection criteria: The review included randomised controlled trials (RCTs) on participants receiving any type of PBM therapy for non-exudative AMD compared to standard care, sham treatment or no treatment.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. We considered the following outcome measures at 12 months: best-corrected visual acuity (BCVA) ; contrast sensitivity; near vision; low luminance density score; reading speed; vision-related quality of life score; and adverse events such as progression of AMD and conversion to exudative AMD. We graded the certainty of the evidence using GRADE.

Main results: We included two published RCTs from single centres in the UK and Canada, which recruited 60 participants (60 eyes) and 30 participants (46 eyes) respectively. Participants in these trials were people with non-exudative AMD with Age-Related Eye Disease Study (AREDS) categories 2 to 4. One study compared single wavelength PBM with no treatment. This study was at risk of performance bias because the study was not masked, and there was attrition bias. One study compared multi-wavelength PBM with sham treatment and conflicts of interest were reported by study investigators. We also identified three eligible ongoing RCTs from searching the clinical trials database. When comparing PBM with sham treatment or no treatment for non-exudative AMD, there was no evidence of any meaningful clinical difference in BCVA at 12 months (mean difference (MD) 0.02 logMAR, 95% confidence interval (CI) -0.02 to 0.05; 2 RCTs, 90 eyes; low-certainty evidence). One study comparing multi-wavelength PBM with sham treatment showed an improvement in contrast sensitivity at Level E (18 cycles/degree) at 12 months (MD 0.29 LogCS, 95% CI 0.23 to 0.35; 1 RCT, 46 eyes; low-certainty evidence). Visual function and health-related quality of life scores were comparable between single wavelength PBM and no treatment groups at 12 months (VFQ-48 score MD 0.43, 95% CI -0.17 to 1.03; P = 0.16; 1 RCT, 47 eyes; low-certainty evidence). When comparing PBM with sham treatment or no treatment for non-exudative AMD, there was no evidence of any meaningful clinical difference in conversion to exudative AMD (risk ratio (RR) 0.97, 95% CI 0.17 to 5.44; 2 RCTs, 96 eyes; very low-certainty evidence) at 12 months. There was inconclusive evidence that single wavelength PBM prevents the progression of AMD (RR 0.79, 95% CI 0.41 to 1.53; P = 0.48; 1 RCT, 50 eyes; low-certainty evidence). Disease progression was defined as the development of advanced AMD or significant increase in drusen volume. No included study reported near vision, low luminance vision or reading speed outcomes.

Authors’ conclusions: Currently there remains uncertainty whether PBM treatment is beneficial in slowing progression of non-exudative macular degeneration. There is a need for further well-designed controlled trials assessing dosimetry, powered for both effectiveness and safety outcomes. Consideration should be given to the adoption of agreed clinical outcome measures and patient-based outcome measures for AMD.

Pachychoroid Spectrum Disease: Underlying Pathology, Classification, and Phenotypes

Curr Eye Res. 2021 Jun 11.

Rui Hua, Jianan Duan, Meixia Zhang

PMID: 34114902 DOI: 10.1080/02713683.2021.1942073

Purpose: Pachychoroid spectrum disease encompasses a set of macular disorders secondary to an abnormally thick choroid. However, the pathological process underlying pachychoroid spectrum disease and its overlap with age-related macular degeneration (AMD) remain unclear. This review aimed to understand the underlying pathology, classification, and phenotypes of pachychoroid spectrum disease.

Methods: This comprehensive literature review was performed based on a search of peer-reviewed published papers relevant to the current knowledge of pachychoroid disease spectrum.

Results: Pachychoroid is primarily a bilateral phenomenon; the main pathological lesions include choriocapillaris attenuation and abnormally dilated pachyvessels. Chronic central serous chorioretinopathy (CSC) and pachychoroid neovasculopathy (PNV) show similar morphological changes and angiogenic cytokine levels. The subretinal fluid in PNV may not accurately indicate PNV activity. Besides, types 1 and 2 of choroidal neovascularization (CNV) may be involved in primary pachychoroidal disease. Both choroidal arteriosclerosis and higher hydrostatic pressure contribute to hyalinized choroidal arteries and aneurysmal dilatations, resulting in PNV progression to polypoidal choroidal vasculopathy (PCV). Thus, pachychoroid-related type 2 CNV and chronic CSC could be considered as PNV (IIIc) and as a precursor of PNV (IIIa), respectively. Tangled PCV on optical coherence tomography angiography that fails to develop aneurysms should be classified as a subtype of PNV or a forme fruste of PCV.

Conclusions: Multiple disorders of the pachychoroid spectrum are considered as a continuous disease process, ultimately stimulated by choroidal malfunction. PCV overlaps both AMD and pachychoroid disease, especially for thin-choroid and bilateral types. The terminology and classification of pachychoroid spectrum disease should be used cautiously.


The Influence of Blue-Filtering Intraocular Lenses Implant on Exudative Age-Related Macular Degeneration: A Case-Control Study

Clin Ophthalmol. 2021 Jun 1;15:2287-2292.

Thierry Hamel, Justine Rheault, David Simonyan, Serge Bourgault, Patrick J Rochette

PMID: 34103892 PMCID: PMC8179786 DOI: 10.2147/OPTH.S300461

Purpose: To determine whether the use of a blue light-filtering intraocular lens (IOL) prevents the onset of wet age-related macular degeneration (AMD). More precisely, we examined the proportion of blue light-filtering IOL in a wet AMD patients’ sample and compared it with a general North American pseudophakic population sample.

Design: Retrospective case-control study.

Methods: Case patients were diagnosed and treated for wet AMD and had prior IOL implantation at least 3 years before the diagnosis of wet AMD. Control patients were randomly selected among patients who had cataract surgery at our institution. They were exempt of AMD and paired for the year of surgery, sex and age at cataract surgery. A total of 196 patients were included in each study group.

Results: Among patients with wet AMD, 62.8% had a blue light-filtering IOL compared with 63.3% among control patients (p = 0.92). Mean time between implantation and injection of anti-VEGF in AMD patients was 6.62 years (95% confidence interval (CI): 6.04-7.19) in non-blue light-filtering IOL group and 5.76 years (95% CI: 5.41-6.11) in blue light-filtering IOL group (p = 0.0120).

Conclusion: No correlations could be established between the presence of a blue light filter in the IOL and the occurrence of wet AMD. AMD patients without blue light-filtering IOL were injected significantly later than patients with an IOL filtering blue light, which contradict the potential clinical benefit of the blue light filter.