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    Research update: 518

    The latest research highlights for 8 November 2021.


    Physical activity, incidence and progression of age-related macular degeneration: A multi-cohort study 

    Am J Ophthalmol.2021 Oct 22;S0002-9394(21)00525-0.

    Matthias M Mauschitz, Marie-Therese Schmitz, Timo Verzijden, Matthias Schmid, Eric F Thee, Johanna M Colijn, Cécile Delcourt, Audrey Cougnard-Grégoire, Bénédicte M J Merle, Jean-François Korobelnik, Bamini Gopinath, Paul Mitchell, Hisham Elbaz, Alexander K Schuster, Philipp S Wild, Caroline Brandl, Klaus J Stark, Iris M Heid, Felix Günther, Annette Peters, Caroline C W Klaver, Robert P Finger, European Eye Epidemiology (E3) Consortium.

    Purpose: To investigate the impact of physical activity (PA) on the incidence or progression of age-related macular degeneration (AMD) in the general population. 

    Design: Meta-analysis of longitudinal cohort studies. 

    Methods: We included a total of 14,630 adults with no or early AMD at baseline from seven population-based studies and examined associations of PA with AMD incidence and progression using multi-state models (MSM) per study and subsequent random effects meta-analysis. Age effects were assessed using meta-regression. 

    Main outcome measure: Hazard ratio (HR) for incident early or progression to late AMD. 

    Results: At baseline, mean age ranged from 60.7± 6.9 to 76.4 ± 4.3 years and prevalence of early AMD was 7.7%, ranging from 3.6 to 16.9% between cohorts. During follow-up, 1461 and 189 events occurred for early and late AMD, respectively. In meta-analyses, no or low to moderate PA (high PA as reference) was associated with an increased risk for incident early AMD (HR 1.19; 95%CI=[1.01, 1.40]; p=0.04), but not for late AMD. In subsequent meta-regression, we found no association of age with the effect of PA on incident AMD. 

    Conclusions: Our study suggests high levels of PA to be protective for the development of early AMD across several population-based cohort studies. Our results establish PA as a modifiable risk factor for AMD and inform further AMD prevention strategies to reduce its public health impact. 

    DOI: 10.1016/j.ajo.2021.10.008 


    The Development of Macular Atrophy in Patients with Wet Age-Related Macular Degeneration Receiving Anti-VEGF Treatment 

    Ophthalmologica.2021 Oct 25. 

    Alexander Foss, Tryfon Rotsos, Theo Empeslidis, Victor Chong.


    Age-related macular degeneration (AMD) is a leading cause of blindness. Late AMD can be classified into exudative (commonly known as wet AMD [wAMD]) or dry AMD, both of which may progress to macular atrophy (MA). MA causes irreversible vision loss and currently has no approved pharmacological treatment. The standard of care for wAMD is treatment with anti-vascular endothelial growth factors (VEGF). However, recent evidence suggests that anti-VEGF treatment may play a role in the development of MA. Therefore, it is important to identify risk factors for the development of MA in patients with wAMD. For example, excessive blockade of VEGF through intense use of anti-VEGF agents may accelerate the development of MA. Patients with type III macular neovascularisation (retinal angiomatous proliferation) have a particularly high risk of MA. These patients are characterised as having a pre-existing thin choroid (age-related choroidopathy), suggesting that the choroidal circulation is unable to respond to increased VEGF expression. Evidence suggests that subretinal fluid (possibly indicative of residual VEGF activity) may play a protective role. Patients receiving anti-VEGF agents must be assessed for overall risk of MA and there is an unmet medical need to prevent the development of MA without undertreating wAMD. 

    DOI: 10.1159/000520171 

    Pigment Epithelial Detachment in Age-Related Macular Degeneration: Long-Term Visual Acuity May Improve with Higher Injection Index 

    Retina.2021 Nov 1;41(11):2229-2235. 

    Wei Gui, Adrian Au, Gilad Rabina, Noa Kapelushnik, Shai Cohen, Dua Masarwa, Hamid Hosseini, Gad Heilweil, Shulamit Schwartz, Anat Loewenstein, Steven D Schwartz.

    Purpose: To define injection index (II) and assess its impact on visual acuity (VA) in pigment epithelial detachment from age-related macular degeneration over 5 years. 

    Methods: Injection index is defined as the mean anti-vascular endothelial growth factor injections per year from presentation. A retrospective study of 256 eyes in 213 patients was performed. Patients were stratified by II (high: ≥9, low: <9). 

    Results: Baseline characteristics showed no differences across II groups. Mean (range) follow-up, in years, was 5.02 (1.04-12.74) for all patients. Mean logMAR VA (Snellen VA) were 0.60 (20/80) and 0.56 (20/73) at baseline, 0.52 (20/66) and 0.59 (20/78) at Year 1, 0.45 (20/56) and 0.67 (20/94) at Year 2, 0.38 (20/48) and 0.66 (20/91) at Year 3, 0.41 (20/51) and 0.89 (20/155) at Year 4, and 0.35 (20/45) and 0.79 (20/123) at Year 5 for the high and low II groups, respectively. Linear regression analysis showed a gain of 0.5 approxETDRS letters with each additional injection per year. 

    Conclusion: Increased II was associated with better mean VA, suggesting that long-term continuous vascular endothelial growth factor suppression may improve VA in eyes thought to carry poor prognoses. 

    DOI: 10.1097/IAE.0000000000003224 

    Intraocular Pressure-Related Events After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal Vein Occlusion or Hemiretinal Vein Occlusion: SCORE2 Report 16 on a Secondary Analysis of a Randomized Clinical Trial 

    JAMA Ophthalmol.2021 Oct 28. 

    Ahmad A Aref, Ingrid U Scott , Paul C VanVeldhuisen, Jacquie King, Michael S Ip, Barbara A Blodi, Neal L Oden, Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) Investigator Group.

    Importance: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are used to treat a variety of posterior segment conditions, including some associated with glaucoma, such as macular edema due to central retinal vein occlusion (CRVO). Therefore, information regarding intraocular pressure (IOP)-related events associated with anti-VEGF therapies is important to help balance the risks and benefits over the course of therapy. 

    Objective: To investigate IOP-related events among participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2). 

    Design, setting, and participants: Secondary analysis of a randomized clinical trial that included 312 participants with macular edema secondary to CRVO or hemiretinal vein occlusion (HRVO) who were not taking IOP-lowering medications at baseline. First randomization occurred on September 14, 2014, and contained data through data freeze on April 1, 2020. Analysis took place from April 2020 through December 2020. 

    Interventions: Study participants were initially randomized to 6 monthly intravitreal injections of aflibercept or bevacizumab. At month 6, protocol-defined good responders were rerandomized to continued monthly or treat-and-extend dosing of their originally assigned study drug, and protocol-defined poor or marginal responders were switched to alternative treatment. After month 12, participants were treated as per investigator discretion. 

    Main outcomes and measures: Three different outcomes: (1) IOP elevation more than 10 mm Hg from baseline, (2) IOP to a level higher than 35 mm Hg, and (3) IOP-lowering incisional or laser surgery. 

    Results: Of the 312 participants meeting inclusion criteria (138 [44.2%] were female; mean [SD] age, 67.8 [12.1] years), 25 (8.0%) had IOP elevation more than 10 mm Hg over baseline through month 60, and 5 (1.6%) had IOP higher than 35 mm Hg. The 60-month Kaplan-Meier cumulative incidence of IOP elevation more than 10 mm Hg over baseline was 0.13 (95% CI, 0.08-0.19), and the 60-month Kaplan-Meier cumulative incidence of IOP higher than 35 mm Hg was 0.02 (95% CI, 0.01-0.06), and did not differ among participants initially randomly assigned to receive aflibercept or bevacizumab. Three participants (1.0%) underwent IOP-lowering incisional surgery, and 3 participants (1.0%) underwent IOP-lowering glaucoma laser surgery. 

    Conclusions and relevance: Intravitreal anti-VEGF injections are used to treat some conditions associated with glaucoma, such as macular edema due to CRVO, and the rates of IOP-related events in this trial support monitoring IOP in eyes treated with anti-VEGF therapy for macular edema associated with CRVO or HRVO for up to 60 months. 

    DOI: 10.1001/jamaophthalmol.2021.4395 

    Early Residual Fluid-free Status and Long-term BCVA outcomes: A Treatment Agnostic, Post-hoc Analysis of Pooled HAWK and HARRIER Data 

    Am J Ophthalmol.2021 Oct 22;S0002-9394(21)00528-6. 

    Chirag Jhaveri, Charles C Wykoff, Arshad M Khanani, Chiara M Eandi, Andrew Chang, Guruprasad B, Kinfemichael A Gedif, Michael Singer.

    Purpose: Determine associations between early residual fluid (ERF)-free status and improved long-term visual outcomes. 

    Design: Clinical cohort study from post hoc analysis of two phase 3 clinical trials’ data. 

    Methods: Independent of treatment allocation, patients from the multicenter, prospective, randomized, double-masked HAWK and HARRIER trials who received either brolucizumab 6 mg or aflibercept 2 mg were split into two cohorts dependent on presence or absence of ERF at week 12. Additionally, similar analyses were performed on presence or absence of early residual intraretinal fluid (IRF) and subretinal fluid (SRF) at week 12. The two groups, ERF-free (N=1051) and ERF (N=366) were compared. Changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST) were determined. 

    Results: From week 12 to 96, patients who were ERF-free had greater least square (LS) mean increases from baseline for BCVA and CST compared to ERF patients. Greater LS mean differences in BCVA from week 12 to 96 were noted between ERF-free and ERF patients. A greater proportion of patients in the ERF-free cohort reported a ≥5, ≥10, or ≥15 letter improvement and a higher proportion reported BCVA ≥70 letters from baseline to week 96 compared to those with fluid. 

    Conclusions: Improvements in visual outcomes in ERF-free patients were greater than in ERF patients occurring as early as 4 weeks (week 12) following the last loading dose and continued to week 96. Therefore, ERF status may be a useful indicator of anti-vascular endothelial growth factor treatment response. 

    DOI: 10.1016/j.ajo.2021.10.017 

    Subfoveal choroidal thickness as a potential predictor of treatment response after intravitreal ranibizumab injections for polypoidal choroidal vasculopathy 

    Can J Ophthalmol.2021 Oct 19;S0008-4182(21)00358-6. 

    Maria Jiménez-Santos, Federico Saenz-Francés, Cristina Calvo González, José I Fernández-Vigo, Juan Donate-Lopez, Lorenzo López-Guajardo.

    Objective: To evaluate the impact of subfoveal choroidal thickness (SFCT) and other clinical biomarkers in intravitreal anti-vascular endothelial growth factor response in treatment-naive Caucasian patients diagnosed with polypoidal choroidal vasculopathy (PCV/AT1). 

    Design: Cross-sectional study. 

    Participants: Treatment-naive patients diagnosed with PCV/AT1 recruited in a single centre from January 2013 to December 2020. 

    Methods: Eligibility was determined in treatment-naive PCV patients who received a loading dose of 3 injections of 0.5 mg ranibizumab. A diagnosis of PCV/AT1 was made based on the diagnostic criteria in the EVEREST study. Choroidal thickness was manually measured by enhanced depth imaging technology in Spectralis spectral domain optical coherence tomography. 

    Results: Eighty-three eyes of 83 patients were included in this study, 47 patients diagnosed with PCV/AT1 with a good response to 3 intravitreal injections of ranibizumab and 36 with a poor response. The receiver operating characteristic curve of treatment effect against the SFCT revealed that the area under the curve was 0.85 (range, 0.74-0.96). Based on the Youden index, the optimal SFCT cut-off point for predicting a poor response to anti-vascular endothelial growth factor is 257 µm. In the multivariate analysis, the SFCT remained statistically significant (odds ratio 1.02 [range, 1.01-1.04]; P = 0.008). The combined effect of treatment effect against clinical biomarkers produced an area under the curve of 0.90 (range, 0.82-0.98). 

    Conclusion: SFCT is a risk factor for a poor response to the 3 loading injections of ranibizumab in treatment-naive PCV/AT1 Caucasian patients. A cut-off point of 257 µm could be a valuable parameter for defining the population at risk for an inadequate response to ranibizumab. 

    DOI: 10.1016/j.jcjo.2021.09.008 


    Posterior Segment Ophthalmic Drug Delivery: Role of Muco-Adhesion with a Special Focus on Chitosan 

    Pharmaceutics.2021 Oct 14;13(10):1685. 

    Ayah Mohammad Burhan, Butsabarat Klahan, Wayne Cummins, Vanessa Andrés-Guerrero, Mark E Byrne, Niall J O’Reilly, Anuj Chauhan, Laurence Fitzhenry, Helen Hughes.


    Posterior segment eye diseases (PSEDs) including age macular degeneration (AMD) and diabetic retinopathy (DR) are amongst the major causes of irreversible blindness worldwide. Due to the numerous barriers encountered, highly invasive intravitreal (IVT) injections represent the primary route to deliver drugs to the posterior eye tissues. Thus, the potential of a more patient friendly topical route has been widely investigated. Mucoadhesive formulations can decrease precorneal clearance while prolonging precorneal residence. Thus, they are expected to enhance the chances of adherence to corneal and conjunctival surfaces and as such, enable increased delivery to the posterior eye segment. Among the mucoadhesive polymers available, chitosan is the most widely explored due to its outstanding mucoadhesive characteristics. In this review, the major PSEDs, their treatments, barriers to topical delivery, and routes of topical drug absorption to the posterior eye are presented. To enable the successful design of mucoadhesive ophthalmic drug delivery systems (DDSs), an overview of mucoadhesion, its theory, characterization, and considerations for ocular mucoadhesion is given. Furthermore, chitosan-based DDs that have been explored to promote topical drug delivery to the posterior eye segment are reviewed. Finally, challenges of successful preclinical to clinical translation of these DDSs for posterior eye drug delivery are discussed. 

    DOI: 10.3390/pharmaceutics13101685 


    Exacerbation of pigment epithelial detachment following aflibercept: A case of bevacizumab rescue 

    Am J Ophthalmol Case Rep.2021 Oct 5;24:101216.

    Samaneh Davoudi, Ramak Roohipourmoallai, Cynthia M Guerin, Siva S R Iyer.

    Purpose: We describe a 61-year-old female patient with a retinal pigment epithelial detachment (PED) of the left eye in the setting of neovascular aged-macular degeneration (nAMD) with unanticipated responses to aflibercept and bevacizumab. 

    Observations: A reduction of PED size from 423 μm to 309 μm and vision improvement (20/150- to 20/40) were observed after five consecutive monthly injections of bevacizumab. A switch to aflibercept for the following two consecutive months showed an unanticipated incremental decline in vision (20/80- at month 1, 20/150- at month 2), increased PED size (749 μm), and the development of subretinal fluid (SRF). After a switch back to bevacizumab, the subretinal fluid resolved. After nine consecutive monthly injections of bevacizumab, final vision in the left eye was 20/25, and final PED height was 84 μm. 

    Conclusions: Different anti-VEGFs may induce varied and unpredictable responses among the most recalcitrant cases of nAMD. Unpredictably, PED size in our patient worsened with aflibercept treatment. 

    Importance: Treatment for nAMD with large PEDs has poor level 1 evidence for guidance, and customized treatment should be considered. 

    DOI: 10.1016/j.ajoc.2021.101216 


    Cytokine profiles of macular neovascularization in the elderly based on a classification from a pachychoroid/drusen perspective 

    Graefes Arch Clin Exp Ophthalmol.2021 Oct 29.  

    Satoru Inoda, Hidenori Takahashi, Yuji Inoue, Xue Tan, Hironobu Tampo, Yusuke Arai, Yasuo Yanagi, Hidetoshi Kawashima.

    Purpose: To classify macular neovascularization (MNV) based on pachychoroid and drusen features and to examine the aqueous humor cytokine signatures of each group. 

    Methods: In total, 106 consecutive eyes with treatment-naïve MNV and 104 control eyes were examined. The aqueous humor concentrations of 15 cytokines were compared among the MNV groups classified based on the presence of drusen and/or pachychoroid features. Multidimensional scaling analysis was used to visualize the similarity level of the MNV subtypes according to their cytokine profiles. 

    Results: Thirty-one, 18, 43, and 10 eyes were classified into the pachychoroid-associated, drusen-associated, pachychoroid/drusen-associated, and non-drusen/non-pachychoroid MNV groups, respectively. Compared with the control group, cytokines were differently upregulated among the MNV groups. CRP and CXCL12 were significantly upregulated in all MNV groups, whereas CXCL13 and IL-8 were significantly upregulated in three MNV groups, excluding the non-pachychoroid/non-drusen-associated MNV group. Ang-2 was significantly upregulated in three MNV groups except the drusen-associated MNV group. PlGF was significantly upregulated in the pachychoroid-associated and drusen-associated MNV groups. CCL-2 was significantly upregulated in the pachychoroid-associated and pachychoroid/drusen-associated MNV groups. VEGF was downregulated in the pachychoroid-associated and drusen-associated MNV groups, respectively. Multidimensional scaling analysis showed a distinct cytokine profile for each MNV group. 

    Conclusion: All MNV groups showed distinct cytokine profiles. Eyes with “neovascular age-related macular degeneration with drusen and concomitant pachychoroid” may share a similar etiology to those with “pachychoroid neovasculopathy” and “choroidal neovascularization with drusen,” but have a distinct etiology to those without these. These findings suggest the importance of evaluating drusen and the choroid during the diagnosis of neovascular age-related macular degeneration. 

    DOI: 10.1007/s00417-021-05445-0