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    Research update: 509

    The latest research highlights for 6 September 2021


    Intravitreal Ranibizumab Treatment for Advanced Familial Exudative Vitreoretinopathy with High Vascular Activity

    Retina. 2021 Sep 1;41(9):1976-1985.

    Lyu J, Zhang Q, Xu Y, Zhang X, Fei P, Zhao P.

    PURPOSE: To determine the efficacy of intravitreal ranibizumab (IVR) treatment for advanced familial exudative vitreoretinopathy with high vascular activity.

    METHODS: The retrospective interventional case series included 28 eyes (20 patients) that had IVR in combination or not with other treatment, for Stage 3 to 5 familial exudative vitreoretinopathy with active fibrovascular proliferation and prominent subretinal exudation. Outcome measures were fundus features after treatment, associated clinical variables, and genetic mutations.

    RESULTS: The age of patients at the first IVR ranged from 0.2 to 36 months. An average of 1.3 IVR injections per eye were given. Familial exudative vitreoretinopathy regressed in 16 (57%) eyes and progressed in 12 eyes (43%) after IVR. Laser and/or vitrectomy was performed on 13 eyes. The retina was reattached in 22 eyes (78%) after 24 to 58 months follow-up. Clinical variables associated with progression after IVR were preexisting fibrovascular proliferation over one quadrant and persistent vascular activity after the initial injection (P < 0.05). Familial exudative vitreoretinopathy-causative genetic mutations in 11 patients were related to variable response to IVR treatment.

    CONCLUSION: Intravitreal ranibizumab treatment may effectively regress advanced familial exudative vitreoretinopathy with high vascular activity in selected cases. Different treatment outcomes may be relevant to variable presentation and genetic heterogeneity of familial exudative vitreoretinopathy.

    DOI: 10.1097/IAE.0000000000003122


    Correlation Between Localized Choriocapillaris Perfusion and Macular Function in Eyes with Geographic Atrophy: Choriocapillaris Flow Relates to Macular Function in AMD with GA.

    Am J Ophthalmol. 2021 Aug 23:S0002-9394(21)00420-7.

    Rinella NT, Zhou H, Wong J, Zhang Q, Nattagh K, Porco TC, Wang RK, Schwartz DM, Duncan JL.

    PURPOSE: To test the hypothesis that choriocapillaris perfusion correlates with visual function in geographic atrophy (GA).

    DESIGN: Cross-sectional, single-center study

    METHODS: We imaged choriocapillaris flow using 6mm x 6mm swept-source optical coherence tomography angiography (OCTA) scans and measured retinal sensitivity using fundus-guided microperimetry in the central 20° in 18 eyes of 12 subjects with GA and 7 eyes of 4 normal subjects. OCTA scans were divided into a grid and microperimetry results were superimposed using retinal vascular landmarks. The main outcome measure correlated choriocapillaris flow deficit with retinal sensitivity at each localized region. Robust linear mixed effects regression compared flow deficit or sensitivity with distance from the fovea. The Pearson ρ correlation described the relationship between flow deficit or retinal sensitivity and distance from the GA border.

    RESULTS: Choriocapillaris flow deficit was significantly greater in GA than normal (mean ± standard deviation 24.2 ± 7.9% vs 7.9 ± 2.3%, P = 0.0015), while retinal sensitivity was significantly lower in GA than normal (mean difference -17.0 ± 1.2 dB, P<0.001). In GA, choriocapillaris flow deficit decreased (ρ= -0.40, 95% CI: -0.54 to -0.27), while retinal sensitivity increased (ρ= + 0.63, 95% CI: 0.30 to 0.81) with distance from the GA margin. Choriocapillaris flow deficits inversely correlated with retinal sensitivity (ρ = -0.61, 95% CI: -0.75 to -0.42).

    CONCLUSION: Choriocapillaris flow and retinal sensitivity improved with distance from the GA margin. Choriocapillaris flow deficit was inversely correlated with sensitivity, supporting the hypothesis that choriocapillaris perfusion correlated with macular function.

    DOI: 10.1016/j.ajo.2021.08.007

    Manual Versus Semi-Automated Measurement of Geographic Atrophy Area in Eyes With Age-Related Macular Degeneration.

    Transl Vis Sci Technol. 2021 Aug 2;10(9):33.

    Mahmoudzadeh R, Salabati M, Khan MA, Garg SJ, Hsu J.

    PURPOSE: To investigate the agreement between and correlation of manual and semi-automated area measurements of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD) using Heidelberg Eye Explorer and ImageJ software.

    METHODS: Fundus autofluorescence (FAF) images of eyes with GA secondary to AMD were analyzed. Two graders measured the atrophic area using Heidelberg Eye Explorer manual and semi-automated (RegionFinder) software, as well as ImageJ manual and semi-automated (Color Threshold) software.

    RESULTS: Fifty-four FAF images were analyzed. The mean (SD) areas were 10.55 (11.4) mm2 and 9.6 (9.8) mm2 using the Heidelberg manual and semi-automated tools, respectively. The mean (SD) areas were 11.04 (12.25) mm2 and 9.75 (10.3) mm2 using ImageJ manual and semi-automated tools, respectively. Compared with the semi-automated Heidelberg RegionFinder (gold standard) area measurements, Bland-Altman plots showed mean differences of 0.96 mm2, 1.4 mm2, and 0.16 mm2 with manual Heidelberg, manual ImageJ, and semi-automated ImageJ measurements, respectively. Homogeneous GA lesions showed less disparity in area measurements across modalities compared with non-homogeneous lesions.

    CONCLUSIONS: ImageJ appears to be a reliable tool for GA area measurements when proprietary OCT software is unavailable. Manual measurements with Heidelberg Eye Explorer and ImageJ were comparable, as were semi-automated measurements with Heidelberg RegionFinder and ImageJ Color Threshold.

    TRANSLATIONAL RELEVANCE: Novel GA measurement techniques using open-source software appear to be comparable to established techniques using proprietary platform-specific software, which may permit more widespread analysis of GA progression from multiple platforms and databases.

    DOI: 10.1167/tvst.10.9.33

    MacuFix® versus Amsler grid for metamorphopsia categorization for macular diseases.

    Int Ophthalmol. 2021 Aug 22:1-10.

    Claessens D, Ichhpujani P, Singh RB.

    PURPOSE: Macular diseases often lead to metamorphopsia, which is traditionally tested using the Amsler grid. This study evaluates a novel method for assessing metamorphopsia, based on the software AMD-A Metamorphopsia Detector, application MacuFix®.

    METHODS: In this observational study, the usability of a new smartphone-based testing method to assess metamorphopsia was evaluated in 45 patients experiencing metamorphopsia in at least one eye using the questionnaire “System Usability Score (SUS).” Additionally, the diagnostic adherence of self-monitoring with the Amsler grid was compared to self-monitoring with the novel software MacuFix®.

    RESULTS: The average score of the SUS questionnaire in this study was 76.7 ± 15.5, corresponding to the “good” score on the grading scale. The average interval between two home administered tests was significantly shorter (6 days) when the application was used as compared to using the Amsler grid (19 days). The odds ratio of the frequency of patients using the application to the patients using the home test was 4.

    CONCLUSION: MacuFix® application can help in effective home monitoring of macular function as high user satisfaction and increased testing frequency was observed in its use in patients with macular diseases.

    DOI: 10.1007/s10792-021-02017-3

    Clinical course after the onset of choroidal neovascularization in eyes with central serous chorioretinopathy.

    Medicine (Baltimore). 2021 Aug 27;100(34):e26980.

    Kim RY, Ma GJ, Park WK, Kim M, Park YG, Park YH.

    Chronic central serous chorioretinopathy (CSC) can be complicated with choroidal neovascularization (CNV); however, the timing of its occurrence and its clinical significance are not well understood. This study aimed to observe the time of choroidal neovascularization detection after CSC diagnosis and determine whether clinical features and prognosis differed in patients with chronic CSC or age-related retinal degeneration. In this retrospective study, medical records of CSC patients complicated with CNV who visited Seoul St. Mary’s hospital of Korea between October 2009 and December 2020 were reviewed. The presence of CNV was determined using fluorescein, indocyanine green, or optical coherent tomography angiography (OCTA). Based on the patients’ medical records, we observed the change of clinical pattern, best-corrected visual acuity (BCVA) and central macular thickness (CMT) at CNV detection and at 6 months, 1 year, 3 years, and 5 years following CNV detection. Thirty eyes of 30 patients (male: female ratio of 13:17) were enrolled. Mean age at diagnosis of CSC was 54.0 ± 8.5 years (mean ± standard deviation). On average, CNV was detected 1.65 ± 2.30 years after the diagnosis of CSC. The mean CMT was significantly decreased at 6 months, 1 year, and 3 years after choroidal neovascularization detection (P < .001, P < .001, P = .001 respectively). BCVA tend to improve after CNV detection, but there was no statistical significance at 6 months, 1 year, 3 years, and 5 years (all with P > .05). There were no clinical findings suggesting age-related macular degeneration such as intraretinal, subretinal hemorrhage or drusen in any of the case during follow-up. None of the subjects had severe visual acuity loss of 1.0 logarithm of the minimum angle of resolution (logMAR) (20/200 Snellen equivalent) or greater. Among the subjects, 6 patients (20%) did not require any treatment during observation, while 24 other patients required anti-vascular endothelial growth factor (anti-VEGF) or photodynamic therapy. At the last visit, 22 patients (73.3%) remained stable for more than 6 months, without subretinal fluid recurrence. Choroidal neovascularization was detected earlier than previously reported. There was no rapid deterioration of visual acuity or clinical features even after CNV detection.

    DOI: 10.1097/MD.0000000000026980


    Rapid formation of macular pucker following intravitreal ranibizumab injection for branch retinal vein occlusion.

    Am J Ophthalmol Case Rep. 2021 Aug 10;23:101192.

    Oshiro A, Imanaga N, Koizumi H.

    PURPOSE: To report a case of branch retinal vein occlusion (BRVO) in which rapid formation of macular pucker was observed after an intravitreal ranibizumab (IVR) injection.

    OBSERVATIONS: A 66-year-old patient was referred to our department for the treatment of macular edema (ME) secondary to BRVO in the left eye. On the initial visit, widespread retinal hemorrhage was observed around the superior temporal vascular arcade, and the decimal best-corrected visual acuity (BCVA) was 0.7 (Snellen equivalent 20/29) in the left eye. Optical coherence tomography demonstrated a thin epiretinal membrane (ERM) accompanied by diffuse retinal thickening. A 0.5 mg IVR injection was administered for the treatment of ME and prompt resolution of retinal hemorrhage. Fourteen days after IVR administration, the ERM had progressed remarkably into a macular pucker and had spread from the superior macula to the equator, accompanied by partial tractional retinal detachment. We performed pars plana vitrectomy combined with encircling scleral buckling. Three months after the surgery, the decimal BCVA was 0.4 (Snellen equivalent 20/50), the retina was attached, and no recurrence of ME or proliferation was observed.

    CONCLUSIONS AND IMPORTANCE: IVR for BRVO may cause rapid formation of macular pucker in the eye, especially in the presence of pre-existing ERM. Careful observation of patients with BRVO is essential after administration of anti-VEGF agents, especially in eyes with pre-existing ERM.

    DOI: 10.1016/j.ajoc.2021.101192


    Intravitreal Pharmacotherapies for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.

    Ophthalmology. 2021 Aug 23:S0161-6420(21)00520-0.

    Ehlers JP, Yeh S, Maguire MG, Smith JR, Mruthyunjaya P, Jain N, Kim LA, Weng CY, Flaxel CJ, Schoenberger SD, Kim SJ.

    PURPOSE: To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME).

    METHODS: Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist.

    RESULTS: Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2).

    CONCLUSIONS: Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.

    DOI: 10.1016/j.ophtha.2021.07.009

    Prevention of vision-threatening complications in diabetic retinopathy: two perspectives based on results from the DRCR Retina Network Protocol W and the Regeneron-sponsored PANORAMA.

    Curr Opin Ophthalmol. 2021 Aug 20.

    Nanegrungsunk O, Bressler NM.

    PURPOSE OF REVIEW: The use of intravitreous antivascular endothelial growth factor to prevent center-involved diabetic macular edema (CI-DME) with vision loss and proliferative diabetic retinopathy (PDR) has been investigated and recently reported in two randomized clinical trials. Although both trials showed substantial superiority of aflibercept at preventing the development of vision-threatening complications (VTCs) of CI-DME or PDR compared with sham at 1 or 2 years, without a concomitant benefit in visual acuity outcomes, the interpretation of the results and its application to clinical practice resulted in two disparate opinions. In this review, we discuss these two trials including their similarities and differences, other relevant studies, and considerations regarding the interpretation and the application of these results into clinical practice.

    RECENT FINDINGS: The Diabetic Retinopathy Clinical Research Retina Network Protocol W and the PANORAMA study demonstrated significantly lower probabilities of developing CI-DME or PDR at 2 years with intravitreous aflibercept compared with sham in eyes with moderate (Protocol W) or moderately severe (PANORAMA) to severe non-PDR (NPDR). However, visual acuity outcomes were not different.

    SUMMARY: Although intravitreous aflibercept injections reduce the risk of VTCs in eyes with moderate-to-severe NPDR, the absence of visual acuity benefits supports the need for four-year results.

    DOI: 10.1097/ICU.0000000000000799

    Biomarkers for Nonexudative Age-Related Macular Degeneration and Relevance for Clinical Trials: A Systematic Review.

    Mol Diagn Ther. 2021 Aug 25.

    Fang V, Gomez-Caraballo M, Lad EM.

    TOPIC: The purpose of the review was to identify structural, functional, blood-based, and other types of biomarkers for early, intermediate, and late nonexudative stages of age-related macular degeneration (AMD) and summarize the relevant data for proof-of-concept clinical trials.

    CLINICAL RELEVANCE: AMD is a leading cause of blindness in the aging population, yet no treatments exist for its most common nonexudative form. There are limited data on the diagnosis and progression of nonexudative AMD compared to neovascular AMD. Our objective was to provide a comprehensive, systematic review of recently published biomarkers (molecular, structural, and functional) for early AMD, intermediate AMD, and geographic atrophy and to evaluate the relevance of these biomarkers for use in future clinical trials.

    METHODS: A literature search of PubMed, ScienceDirect, EMBASE, and Web of Science from January 1, 1996 to November 30, 2020 and a patent search were conducted. Search terms included “early AMD,” “dry AMD,” “intermediate AMD,” “biomarkers for nonexudative AMD,” “fundus autofluorescence patterns,” “color fundus photography,” “dark adaptation,” and “microperimetry.” Articles were assessed for bias and quality with the Mixed-Methods Appraisal Tool. A total of 94 articles were included (61,842 individuals).

    RESULTS: Spectral-domain optical coherence tomography was superior at highlighting detailed structural changes in earlier stages of AMD. Fundus autofluorescence patterns were found to be most important in estimating progression of geographic atrophy. Delayed rod intercept time on dark adaptation was the most widely recommended surrogate functional endpoint for early AMD, while retinal sensitivity on microperimetry was most relevant for intermediate AMD. Combinational studies accounting for various patient characteristics and machine/deep-learning approaches were best suited for assessing individualized risk of AMD onset and progression.

    CONCLUSION: This systematic review supports the use of structural and functional biomarkers in early AMD and intermediate AMD, which are more reproducible and less invasive than the other classes of biomarkers described. The use of deep learning and combinational algorithms will gain increasing importance in future clinical trials of nonexudative AMD.

    DOI: 10.1007/s40291-021-00551-5


    Predicting risk of late age-related macular degeneration using deep learning.

    NPJ Digit Med. 2020 Aug 27;3(1):111.

    Peng Y, Keenan TD, Chen Q, Agrón E, Allot A, Wong WT, Chew EY, Lu Z.

    By 2040, age-related macular degeneration (AMD) will affect ~288 million people worldwide. Identifying individuals at high risk of progression to late AMD, the sight-threatening stage, is critical for clinical actions, including medical interventions and timely monitoring. Although deep learning has shown promise in diagnosing/screening AMD using color fundus photographs, it remains difficult to predict individuals’ risks of late AMD accurately. For both tasks, these initial deep learning attempts have remained largely unvalidated in independent cohorts. Here, we demonstrate how deep learning and survival analysis can predict the probability of progression to late AMD using 3298 participants (over 80,000 images) from the Age-Related Eye Disease Studies AREDS and AREDS2, the largest longitudinal clinical trials in AMD. When validated against an independent test data set of 601 participants, our model achieved high prognostic accuracy (5-year C-statistic 86.4 (95% confidence interval 86.2-86.6)) that substantially exceeded that of retinal specialists using two existing clinical standards (81.3 (81.1-81.5) and 82.0 (81.8-82.3), respectively). Interestingly, our approach offers additional strengths over the existing clinical standards in AMD prognosis (e.g., risk ascertainment above 50%) and is likely to be highly generalizable, given the breadth of training data from 82 US retinal specialty clinics. Indeed, during external validation through training on AREDS and testing on AREDS2 as an independent cohort, our model retained substantially higher prognostic accuracy than existing clinical standards. These results highlight the potential of deep learning systems to enhance clinical decision-making in AMD patients.

    DOI: 10.1038/s41746-020-00317-z


    LRG1 Expression Is Elevated in the Eyes of Patients with Neovascular Age-Related Macular Degeneration.

    Int J Mol Sci. 2021 Aug 18;22(16):8879.

    Mundo L, Tosi GM, Lazzi S, Pertile G, Parolini B, Neri G, Posarelli M, De Benedetto E, Bacci T, Silvestri E, Siciliano MC, Barbera S, Orlandini M, Greenwood J, Moss SE, Galvagni F.

    Leucine-rich a-2-glycoprotein 1 (LRG1) is a candidate therapeutic target for treating the neovascular form of age-related macular degeneration (nvAMD). In this study we examined the expression of LRG1 in eyes of nvAMD patients. Choroidal neovascular membranes (CNVMs) from patients who underwent submacular surgery for retinal pigment epithelium-choroid graft transplantation were collected from 5 nvAMD patients without any prior intravitreal anti-VEGF injection, and from six patients who received intravitreal anti-VEGF injections before surgery. As controls free of nvAMD, retina sections were obtained from the eyes resected from a patient with lacrimal sac tumor and from a patient with neuroblastoma. CNVMs were immunostained for CD34, LRG1, and α-smooth muscle actin (α-SMA). Aqueous humor samples were collected from 58 untreated-naïve nvAMD patients prior to the intravitreal injection of anti-VEGF and 51 age-matched cataract control patients, and LRG1 concentration was measured by ELISA. The level of LRG1 immunostaining is frequently high in both the endothelial cells of the blood vessels, and myofibroblasts in the surrounding tissue of CNVMs of treatment-naïve nvAMD patients. Furthermore, the average concentration of LRG1 was significantly higher in the aqueous humor of nvAMD patients than in controls. These observations provide a strong experimental basis and scientific rationale for the progression of a therapeutic anti-LRG1 monoclonal antibody into clinical trials with patients with nvAMD.

    DOI: 10.3390/ijms22168879


    Subretinal Transplantation of Human Embryonic Stem Cell-Derived Retinal Tissue in a Feline Large Animal Model.

    J Vis Exp. 2021 Aug 5;(174).

    Occelli LM, Marinho F, Singh RK, Binette F, Nasonkin IO, Petersen-Jones SM.

    Retinal degenerative (RD) conditions associated with photoreceptor loss such as age-related macular degeneration (AMD), retinitis pigmentosa (RP) and Leber Congenital Amaurosis (LCA) cause progressive and debilitating vision loss. There is an unmet need for therapies that can restore vision once photoreceptors have been lost. Transplantation of human pluripotent stem cell (hPSC)-derived retinal tissue (organoids) into the subretinal space of an eye with advanced RD brings retinal tissue sheets with thousands of healthy mutation-free photoreceptors and has a potential to treat most/all blinding diseases associated with photoreceptor degeneration with one approved protocol. Transplantation of fetal retinal tissue into the subretinal space of animal models and people with advanced RD has been developed successfully but cannot be used as a routine therapy due to ethical concerns and limited tissue supply. Large eye inherited retinal degeneration (IRD) animal models are valuable for developing vision restoration therapies utilizing advanced surgical approaches to transplant retinal cells/tissue into the subretinal space. The similarities in globe size, and photoreceptor distribution (e.g., presence of macula-like region area centralis) and availability of IRD models closely recapitulating human IRD would facilitate rapid translation of a promising therapy to the clinic. Presented here is a surgical technique of transplanting hPSC-derived retinal tissue into the subretinal space of a large animal model allowing assessment of this promising approach in animal models.

    DOI: 10.3791/61683