Macular Disease Foundation Australia logo

    Research update: 506

    The latest research highlights for 16 August 2021

    Research update 506


    Development of intraretinal fluid in neovascular age-related macular degeneration during anti-vascular endothelial growth factor treatment.

    Am J Ophthalmol. 2021 Jul 30:S0002-9394(21)00394-9.

    Cho HJ, Yoon W, Yoon J, Na SK, Lee J, Kim J, Kim CG, Kim JW.

    PURPOSE: To identify the risk factors of intraretinal fluid (IRF) development during anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD).

    DESIGN: Retrospective cohort study. METHODS: A total of 425 treatment-naïve patients with neovascular AMD who completed 24 months of follow-up were enrolled. All patients were treated with an initial series of 3-monthly loading doses of anti-VEGF injections, followed by further injections as required. Baseline characteristics were evaluated using multivariate modeling to determine the potential risk factors for IRF development.

    RESULTS: IRF occurred in 40.2% (171/425 eyes) of all participants during the maintenance phase after the loading injections. The development of IRF during follow-up negatively affected visual outcomes, irrespective of the presence of IRF at baseline. Multivariate analysis showed that larger areas of choroidal neovascularization (CNV) (odds ratio [OR], 1.360; P<0.001), the presence of IRF at baseline (OR, 5.469; P<0.001), and the presence of fibrovascular pigment epithelial detachment (PED) (OR, 2.043; P=0.022) were associated with an increased risk of IRF during follow-up. Type 1 (OR, 2.005; P<0.001) and type 2 macular neovascularization (MNV) (OR, 2.643; P<0.001) were also associated with a higher risk of IRF than aneurysmal type 1 MNV/polypoidal choroidal vasculopathy.

    CONCLUSIONS: The development of IRF during anti-VEGF treatment for neovascular AMD has additional negative effects on visual outcomes regardless of the presence of IRF at baseline. Baseline risk factors, including CNV size, presence of IRF at baseline, presence of fibrovascular PED, and MNV subtype, may influence the development of IRF during anti-VEGF treatment.

    DOI: 10.1016/j.ajo.2021.07.026

    Evaluation of Intravitreal Aflibercept for the Treatment of Severe Nonproliferative Diabetic Retinopathy: Results from the PANORAMA Randomized Clinical Trial.

    JAMA Ophthalmol. 2021 Aug 5.

    Brown DM, Wykoff CC, Boyer D, Heier JS, Clark WL, Emanuelli A, Higgins PM, Singer M, Weinreich DM, Yancopoulos GD, Berliner AJ, Chu K, Reed K, Cheng Y, Vitti R.

    IMPORTANCE: Proactive treatment of nonproliferative diabetic retinopathy (NPDR) reduces the risk of progression to vision-threatening complications.

    OBJECTIVE: To evaluate vascular endothelial growth factor blockade therapy with intravitreal aflibercept injections in eyes with severe NPDR without diabetic macular edema (DME).

    DESIGN, SETTING, AND PARTICIPANTS: The Study of the Efficacy and Safety of Intravitreal Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (PANORAMA) was a double-masked 100-week randomized clinical trial conducted in multiple centers worldwide. The study included 402 adults with Diabetic Retinopathy Severity Scale (DRSS) level 47 or 53 with no DME and best-corrected visual acuity of 20/40 or better.

    INTERVENTIONS: Intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval (aflibercept 2q16 group); intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56 (aflibercept 2q8/PRN group); or sham injections (control group).

    MAIN OUTCOMES AND MEASURES: Proportions of eyes with a 2-step or greater improvement in DRSS level, vision-threatening complications, and center-involved DME from baseline to weeks 24, 52, and 100.

    RESULTS: Among 402 participants (1 eye per participant), the mean (SD) age was 55.7 (10.5) years; 225 (56.0%) were male, and 310 (77.1%) were White. A total of 135 were randomized to the aflibercept 2q16 group, 134 to the aflibercept 2q8/PRN group, and 133 to the control group. At 24 weeks, treatment with aflibercept resulted in a 2-step or greater improvement in DRSS level in 157 of 269 eyes (58.4%) in the combined aflibercept groups vs 8 of 133 eyes (6.0%) in the control group (adjusted difference, 52.3%; 95% CI, 45.2%-59.5%; P < .001). At 52 weeks, 88 of 135 eyes (65.2%) in the aflibercept 2q16 group (adjusted difference, 50.1%; 95% CI, 40.1%-60.1%) and 107 of 134 eyes (79.9%) in the aflibercept 2q8/PRN group (adjusted difference, 64.8%; 95% CI, 55.8%-73.9%) compared with 20 of 133 eyes (15.0%) in the control group (P < .001 for both comparisons) showed a 2-step or greater improvement in DRSS level. Fewer eyes treated with aflibercept vs sham injections developed vision-threatening complications and/or center-involved DME through week 100 (22 of 135 eyes [16.3%] in the 2q16 group [adjusted difference, -34.2%; 95% CI, -44.6 to -23.8] and 25 of 134 eyes [18.7%] in the 2q8/PRN group [adjusted difference, -31.7%; 95% CI, -42.5 to -20.9] compared with 67 of 133 eyes [50.4%] in the control group; P < .001 for both comparisons). No new safety signals were identified.

    CONCLUSIONS AND RELEVANCE: In this study, significantly more eyes with moderately severe to severe NPDR that were treated with aflibercept showed a 2-step or greater improvement in DRSS level at 24, 52, and 100 weeks, and significantly fewer eyes treated with aflibercept vs sham developed vision-threatening complications and center-involved DME. Outcomes on the DRSS between year 1 and 2 emphasize the need for ongoing vascular endothelial growth factor suppression and adherence. TRIAL REGISTRATION: Identifier: NCT02718326.

    DOI: 10.1001/jamaophthalmol.2021.2809

    Long-term outcomes of polypoidal choroidal vasculopathy in comparison with typical exudative age-related macular degeneration.

    Graefes Arch Clin Exp Ophthalmol. 2021 Aug 5.

    Roh HC, Kim SJ, Kang SW, Eun JS, Choi KJ.

    PURPOSE: To compare long-term outcomes between typical exudative age-related macular degeneration (TexAMD) and polypoidal choroidal vasculopathy (PCV), and to investigate factors related to the outcomes.

    METHODS: This retrospective study included 319 eyes (164 with TexAMD and 155 with PCV) treated with anti-vascular endothelial growth factor and followed more than 5 years. The primary outcome was visual acuity (VA) change from baseline to final visit. Linear regression analyses were used to determine factors associated with final VA.

    RESULTS: Baseline logMAR VA was 0.7 ± 0.5 in the TexAMD group and 0.5 ± 0.4 in the PCV group (p < 0.001). After a mean follow-up of 9 years, final VA was also significantly worse in the TexAMD group than in the PCV group (0.9 ± 0.6 vs. 0.6 ± 0.5; p < 0.001). The PCV group showed longer maintenance of improved vision and later onset of significant visual decline than the TexAMD group. In multivariate analysis, loss to follow-up, worse baseline VA, macular atrophy, and subretinal fibrosis were significantly associated with poor final VA in both groups.

    CONCLUSION: PCV eyes showed relatively favorable long-term visual outcome than TexAMD eyes. The results of this study emphasized the importance of compliance with treatment, along with other well-known prognostic factors.

    DOI: 10.1007/s00417-021-05190-4


    OCT Biomarkers in Neovascular Age-Related Macular Degeneration: A Narrative Review.

    J Ophthalmol. 2021 Jul 17;2021:9994098.

    Metrangolo C, Donati S, Mazzola M, Fontanel L, Messina W, D’alterio G, Rubino M, Radice P, Premi E, Azzolini C.

    Age-related macular degeneration (AMD) is the leading cause of legal blindness in elderly people. Neovascular AMD (nAMD) is responsible for the majority of cases of severe visual loss in eyes with AMD. Optical coherence tomography (OCT) is the most widely used technology for the diagnosis and follow-up of nAMD patients, which is widely used to study and guide the clinical approach, as well as to predict and evaluate treatment response. The aim of this review is to describe and analyze various structural OCT-based biomarkers, which have practical value during both initial assessment and treatment follow-up of nAMD patients. While central retinal thickness has been the most common and one of the first OCT identified biomarkers, today, other qualitative and quantitative biomarkers provide novel insight into disease activity and offer superior prognostic value and better guidance for tailored therapeutic management. The key importance of retinal fluid compartmentalization (intraretinal fluid, subretinal fluid, and subretinal pigment epithelium (RPE) fluid) will be discussed firstly. In the second part, the structural alterations of different retinal layers in various stages of the disease (photoreceptors layer integrity, hyperreflective dots, outer retinal tubulations, subretinal hyperreflective material, and retinal pigment epithelial tears) will be analyzed in detail. The last part of the review will focus on how alterations of the vitreoretinal interface (vitreomacular adhesion and traction) and of the choroid (sub-RPE hyperreflective columns, prechoroidal clefts, choroidal caverns, choroidal thickness and choroidal volume, and choroidal vascular index) interact with nAMD progression. OCT technology is evolving very quickly, and new retinal biomarkers are continuously described. This up-to-date review article provides a comprehensive description on how structural OCT-based biomarkers provide a valuable tool to monitor the progression of the disease and the treatment response in nAMD patients. Thus, in this perspective, clinicians will be able to allocate hospital resources in the best possible way and tailor treatment to the individual patient’s needs.

    DOI: 10.1155/2021/9994098

    Intraretinal, sub-retinal, and sub-retinal pigmented epithelium fluid in non-exudative age-related macular degeneration: follow-up with OCT imaging.

    Eur J Ophthalmol. 2021 Aug 2:11206721211036289.

    Samanta A, Jhingan M, Arora S, Singh S, Tucci D, Cagini C, Lupidi M, Chhablani J.

    BACKGROUND/OBJECTIVES: To evaluate the presence and evolution of fluid in non-exudative age-related macular degeneration (AMD) through serial OCT.

    SUBJECTS/METHODS: A retrospective analysis of eyes with non-exudative AMD with a minimum of 4 year follow-up was done. Parameters including intraretinal fluid (IRF), subretinal fluid (SRF), and sub-retinal pigment epithelium (RPE) fluid (SRPEF); subfoveal choroidal thickness (SFCT) and type of drusen were evaluated using optical coherence tomography (OCT) scans at baseline and follow up visits.

    RESULTS: Seventy-two eyes (in 63 patients) were followed up for an average of 5.83 ± 2.17 years. A total of 26/72 (36%) and 29/65 (52%) of the non-exudative eyes had fluid during baseline and the last visit. Seven eyes (10%) out of 72 eyes converted into exudative AMD or neo-vascular AMD (nAMD) during the study period. SRPEF at baseline was most common fluid location for non-exudative eyes that eventually converted to nAMD.

    CONCLUSION: Non-exudative fluid including IRF, SRF, and SRPEF is seen in patients with non-exudative AMD with increasing incidence during long term follow-up.

    DOI: 10.1177/11206721211036289

    The Effect of Age-Related Macular Degeneration on Polarization Pattern Perception.

    Transl Vis Sci Technol. 2021 Aug 2;10(9):8.

    Misson GP, Anderson SJ, Armstrong RA, Gilett M, Reynolds D.

    PURPOSE: The purpose of this study was to determine if a battery of polarization-modulated stimuli, quantified as a single metric, is effective in identifying macular disease in the presence/absence of cataract or pseudophakia.

    METHODS: Using a modified liquid crystal display, polarization pattern perception (PPP) for a formulated battery of geometric and logMAR stimuli was evaluated in participants that had either no eye pathology (healthy participants) or were grouped according to the presence of cataract, pseudophakia, and/or age-related macular degeneration (AMD). PPP was quantified as response frequencies to individual stimuli, and as a novel monocular polarization sensitivity score (Ps) based on perception of the stimulus battery set.

    RESULTS: Stimulus response frequencies were pattern-dependent and, compared with healthy participants, reduced for cataract and AMD groups but not for subjects with pseudophakia. Compared with healthy eyes (n = 47, median Ps = 17), Ps was significantly reduced by AMD (n = 59, median Ps = 1, P < 0.001) and, to a lesser extent, by cataracts (n = 80, median Ps = 6, P < 0.001). There was no significant difference between Ps for healthy and pseudophakic eyes (n = 47, median Ps = 13, P = 0.323). There was no significant correlation between Ps and logMAR visual acuity.

    CONCLUSIONS: In the absence of significant cataract, or in pseudophakia, a set of polarization-modulated visual stimuli, quantified as the Ps score, distinguishes AMD from healthy maculae.

    TRANSLATIONAL RELEVANCE: Perception of polarization-modulated stimuli, previously shown to be macula-dependent in a laboratory setting, is effective as a test of macular function in health and disease in a clinic setting.

    DOI: 10.1167/tvst.10.9.8

    Impact of large choroidal vessels on choriocapillaris flow deficit analyses in optical coherence tomography angiography.

    PLoS One. 2021 Aug 3;16(8):e0254955.

    Hacker V, Reiter GS, Schranz M, Told R, Reumüller A, Hofer D, Steiner I, Schmidt-Erfurth U, Sacu S.

    PURPOSE: To investigate the impact of large choroidal vessels (LCV) on Choriocapillaris (CC) flow deficit (FD) analyses with swept-source optical coherence tomography angiography (SS-OCTA).

    DESIGN: Prospective, cross-sectional study. METHODS: Macular 6x6mm SS-OCTA scans were obtained from intermediate age-related macular degeneration (iAMD) and healthy eyes. Images were captured and processed according to most common standards and analyzed for percentage of flow-deficits (FD%) within four 1x1mm squares at the corners of each image. Choroidal thickness (CT), iris color and refraction error were considered as potential influential factors for LCV visibility. A linear mixed model and logistic regression models were calculated for statistical evaluation.

    RESULTS: Sixty-nine iAMD and 49 age-matched healthy eyes were enrolled. LCV were visible in at least one sector in 52% of iAMD and 47% of healthy eyes. Within the iAMD group FD% were significantly lower in areas containing LCV (p = 0.0029). Increasing CT resulted in an odds ratio decrease of LCV (OR: 0.94, p<0.0001). Below a CT value of ≤118μm LCV could be expected with a sensitivity of 86% and a specificity of 85%.

    CONCLUSIONS: LCV can significantly affect CC FD analyses of SS-OCTA images. Their visibility is negatively associated with CT. The impact of LCV should be taken into account when performing CC FD assessments, especially in patients where reduced CT is to be expected and inclusion of affected areas should be considered carefully.

    DOI: 10.1371/journal.pone.0254955


    Statins and the progression of age-related macular degeneration in the United States.

    PLoS One. 2021 Aug 4;16(8):e0252878.

    Ludwig CA, Vail D, Rajeshuni NA, Al-Moujahed A, Rosenblatt T, Callaway NF, Veerappan Pasricha M, Ji MH, Moshfeghi DM.

    PURPOSE: To study the effect of statin exposure on the progression from non-exudative to exudative age-related macular degeneration (AMD).

    METHODS: Retrospective cohort study of commercially insured patients diagnosed with non-exudative AMD (n = 231,888) from 2007 to 2015. Time-to-event analysis of the association between exposure to lipid-lowering medications and time from non-exudative AMD to exudative AMD diagnosis was conducted. Outcome measures included progression to exudative AMD, indicated by diagnosis codes for exudative AMD or procedural codes for intravitreal injections.

    RESULTS: In the year before and after first AMD diagnosis, 11,330 patients were continuously prescribed lipid-lowering medications and 31,627 patients did not take any lipid-lowering medication. Of those taking statins, 21 (1.6%) patients were on very-high-dose lipophilic statins, 644 (47.6%) on high-dose lipophilic statins, and 689 (50.9%) on low-dose lipophilic statins. We found no statistically significant relationship between exposure to low (HR 0.89, 95% CI 0.83 to 1.38) or high-dose lipophilic statins (HR 1.12, 95% CI 0.86 to 1.45) and progression to exudative AMD. No patients taking very-high-dose lipophilic statins converted from non-exudative to exudative AMD, though this difference was not statistically significant due to the subgroup size (p = .23, log-rank test).

    CONCLUSIONS: No statistically significant relationship was found between statin exposure and risk of AMD progression. Interestingly, no patients taking very-high-dose lipophilic statins progressed to exudative AMD, a finding that warrants further exploration.

    DOI: 10.1371/journal.pone.0252878


    Stem Cell Based Treatment Strategies for Degenerative Diseases of the Retina.

    Curr Stem Cell Res Ther. 2021 Aug 3.

    Nair DR, Thomas B.

    The main cause of progressive vision impairment in retinal degenerative diseases is the dysfunction of photoreceptors and the underlying retinal pigment epithelial cells. The inadequate regenerative capacity of the neural retina and lack of established therapeutic options demand the development of clinical grade protocols to halt degenerative process in the eye or to replace the damaged cells by using stem cell derived products. Recently, stem cell-based regenerative therapies are at the forefront of clinical investigations for retinal dystrophies.

    Objective: This article will review different stem cell-based therapies currently employed for retinal degenerative diseases, recent clinical trials, and major challenges in the translation of these therapies from bench to bedside.

    Methodology: A systematic literature review was carried out to identify potentially relevant articles published in MEDLINE/PubMed, Embase,, Drugs@FDA, European Medicines Agency, World Health Organization International Clinical Trials Registry Platform and CENTRAL

    Result: Transplantation of healthy cells to replace the damaged cells in the outer retina is a clinically relevant concept because the inner retina that communicates with the visual areas of the brain remains functional even after the photoreceptors are completely lost. Different methods have been established for the differentiation of pluripotent stem cells into different retinal cell types that can be used for therapies. Factors released from transplanted somatic stem cells showed trophic support and photoreceptor rescue during early stages of the disease. Several preclinical and phase I/II clinical studies using terminally differentiated photoreceptor/ retinal pigment epithelial cells derived from pluripotent stem cells have shown proof of concept for visual restoration in Age-related macular degeneration (AMD), Stargardt disease and Retinitis pigmentosa (RP).

    Conclusion: Cell replacement therapy has great potential for vision restoration. The results obtained from the initial clinical trials are encouraging and indicates its therapeutic benefits. The current status of the therapies suggests that there is a long way to go before these results can be applied to routine clinical practice. Input from the ongoing multicentre clinical trials will give a more refined idea for the future design of clinical- grade protocols to transplant GMP level HLA matched cells.

    DOI: 10.2174/1574888X16666210804112104

    A phase I clinical trial of human embryonic stem cell-derived retinal pigment epithelial cells for early-stage Stargardt macular degeneration: 5-years’ follow-up.

    Cell Prolif. 2021 Aug 4:e13100.

    Li SY, Liu Y, Wang L, Wang F, Zhao TT, Li QY, Xu HW, Meng XH, Hao J, Zhou Q, Wang L, Yin ZQ.

    OBJECTIVES: To evaluate the long-term biosafety and efficacy of transplantation of human embryonic stem cells-derived retinal pigment epithelial (hESC-RPE) cells in early-stage of Stargardt macular degeneration (STGD1).

    MATERIALS AND METHODS: Seven patients participated in this prospective clinical study, where they underwent a single subretinal transplantation of 1 × 105 hESC-RPE cells in one eye, whereas the fellow eye served as control. These patients were reassessed for a 60-month follow-up through systemic and ophthalmic examinations.

    RESULTS: None of the patients experienced adverse reactions systemically or locally, except for two who had transiently high intraocular pressure post-operation. Functional assessments demonstrated that all of the seven operated eyes had transiently increased or stable visual function 1-4 months after transplantation. At the last follow-up visit, two of the seven eyes showed visual function loss than the baseline; however, one of them showed a stable visual acuity when compared with the change of fellow eye. Obvious small high reflective foci in the RPE layer were displayed after the transplantation, and maintained until the last visit. Interestingly, three categories of patients who were classified based on autofluorescence, exhibited distinctive patterns of morphological and functional change.

    CONCLUSIONS: Subretinal transplantation of hESC-RPE in early-stage STGD1 is safe and tolerated in the long term. Further investigation is needed for choosing proper subjects according to the multi-model image and function assessments.

    DOI: 10.1111/cpr.13100


    Internal limiting membrane graft in full-thickness macular hole secondary to macular telangiectasia type 2.

    J Fr Ophtalmol. 2021 Jul 29:S0181-5512(21)00391-0.

    Bozdogan YC, Erol MK, Suren E, Gedik B.

    We present a case report of an autologous internal limiting membrane (ILM) graft transposition technique in a 60-years-old female patient who with a full-thickness macular hole (FTMH) secondary to idiopathic macular telangiectasia type 2 (MacTel type 2). To our knowledge, our case is the first report of ILM graft transposition to treat persistent FTMH secondary to MacTel type 2. MacTel type 2 is an acquired disease characterized by macular capillary abnormalities and retinal neurodegeneration. FTMH is an infrequent complication of MacTel type 2. Pars plana vitrectomy (PPV) with ILM peeling and gas endotamponade is the standard treatment of FTMH to help restore macular anatomy and visual function. The technique of autologous ILM graft transposition is a useful alternative to repair large, persistent macular holes that have failed to close with previous ILM peeling. In the present case, our patient with persistent FTMH secondary to MacTel type 2 after the previous standard macular hole surgery was admitted to our clinic. We performed 23-gauge PPV with extramacular ILM peeling and ILM graft transposition into the macular hole. 2 months after the surgery, her visual acuity had improved and anatomic closure of the FTMH was observed. In our opinion, ILM grafting might support reorganization of the retinal structure that has been affected by Muller cell degeneration.

    DOI: 10.1016/j.jfo.2021.05.003