Int J Pharm. 2019 Jun 24:118458.
Transscleral sustained ranibizumab delivery using an episcleral implantable device: Suppression of laser-induced choroidal neovascularization in rats.
Nagai N, Nezhad ZK, Daigaku R, Saijo S, Song Y, Terata K, Hoshi A, Nishizawa M, Nakazawa T, Kaji H, Abe T.
Abstract: Successful treatment of age-related macular diseases requires an effective controlled drug release system with less invasive route of administration in the eye to reduce the burden of frequent intravitreal injections for patients. In this study, we developed an episcleral implantable device for sustained release of ranibizumab, and evaluated its efficacy on suppression of laser-induced choroidal neovascularization (CNV) in rats. We tested both biodegradable and non-biodegradable sheet-type devices consisting of crosslinked gelatin/chitosan (Gel/CS) and photopolymerized poly(ethyleneglycol) dimethacrylate that incorporated collagen microparticles (PEGDM/COL). In vitro release studies of FITC-labeled albumin showed a constant release from PEGDM/COL sheets compared to Gel/CS sheets. The Gel/CS sheets gradually biodegraded in the sclera during the 24-week implantation; however, the PEGDM/COL sheets did not degrade. FITC-albumin was detected in the retina during 18 weeks implantation in the PEGDM/COL sheet-treated group, and was detected in the Gel/CS sheet-treated group during 6 weeks implantation. CNV was suppressed 18 weeks after application of ranibizumab-loaded PEGDM/COL sheets compared to a placebo PEGDM/COL sheet-treated group, and to the intravitreal ranibizumab-injected group. In conclusion, the PEGDM/COL sheet device suppressed CNV via a transscleral administration route for 18 weeks, indicating that prolonged sustained ranibizumab release could reduce the burden of repeated intravitreal injections.
PMID: 31247277 DOI: 10.1016/j.ijpharm.2019.118458
JAMA Ophthalmol. 2019 Jun 27.
Association between change in visual acuity and change in central subfield thickness during treatment of diabetic macular edema in participants randomized to aflibercept, bevacizumab, or ranibizumab: A post hoc analysis of the Protocol T Randomized Clinical Trial.
Bressler NM, Odia I, Maguire M, Glassman AR, Jampol LM, MacCumber MW, Shah C, Rosberger D, Sun JK9,; DRCR Retina Network.
Importance: The determination of optical coherence tomography (OCT) central subfield thickness (CST) is an objective measure, and visual acuity (VA) is a subjective measure. Therefore, using OCT CST changes as a surrogate for VA changes in diabetic macular edema seems reasonable. However, studies suggest that change in OCT CST following anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema is correlated with changes in VA but varies substantially among individuals, and so may not be a good surrogate for changes in VA.
Objective: To determine associations between changes in VA and changes in OCT CST across 3 anti-VEGF agents (aflibercept, bevacizumab, or ranibizumab) used in a randomized clinical trial for diabetic macular edema.
Design, Setting and Participants: Post hoc analyses were conducted of DRCR Retina Network Protocol T among 652 of 660 participants (98.8%) meeting inclusion criteria for this investigation. The study was conducted between August 22, 2012, and September 23, 2015. The post hoc data collection and analysis were performed from May 29 to July 11, 2018.
Interventions: Six monthly intravitreous anti-VEGF injections (unless success was achieved after 3-5 months) were administered; subsequent injections or focal/grid laser photocoagulation treatments were given as needed per protocol to achieve stability.
Main Outcomes and Measures: Association between changes in VA letter score with changes in CST at 12, 52, and 104 weeks after randomization to aflibercept, bevacizumab, or ranibizumab.
Results: Of the 652 participants, 304 were women (46.6%); median age was 61 years (interquartile range, 54-67 years). The correlation between CST and VA at the follow-up visits was 0.24 (95% CI, 0.16-0.31) in 616 patients at 12 weeks, 0.31 (95% CI, 0.24-0.38) in 609 patients at 52 weeks, and 0.23 (95% CI, 0.15-0.31) in 566 patients at 104 weeks. The correlation coefficients of change in VA vs change in OCT CST for these time intervals were 0.36 (95% CI, 0.29-0.43) at 12 weeks, 0.36 (95% CI, 0.29-0.43) at 52 weeks, and 0.33 (95% CI, 0.26-0.41) at 104 weeks.
Conclusions and Relevance: Changes in CST appear to account for only a small proportion of the total variation in changes in VA. These findings do not support using changes in OCT CST as a surrogate for changes in VA in phase 3 clinical trials evaluating anti-VEGF for diabetic macular edema or as a guide to inform the physician or patient about changes in VA after anti-VEGF treatment.
PMID: 31246237 DOI: 10.1001/jamaophthalmol.2019.1963
BMJ Open. 2019 Jun 21;9(6):e027441.
One and two-year visual outcomes from the Moorfields age-related macular degeneration database: a retrospective cohort study and an open science resource.
Fasler K, Moraes G, Wagner S, Kortuem KU, Chopra R, Faes L, Preston G, Pontikos N, Fu DJ, Patel P, Tufail A, Lee AY, Balaskas K, Keane PA.
Objectives: To analyse treatment outcomes and share clinical data from a large, single-centre, well-curated database (8174 eyes/6664 patients with 120 756 single entries) of patients with neovascular age-related macular degeneration (AMD) treated with anti-vascular endothelial growth factor (VEGF). By making our depersonalised raw data openly available, we aim to stimulate further research in AMD, as well as set a precedent for future work in this area.
Setting: Retrospective, comparative, non-randomised electronic medical record (EMR) database cohort study of the UK Moorfields AMD database with data extracted between 2008 and 2018.
Participants: Including one eye per patient, 3357 eyes/patients (61% female). Extraction criteria were ≥1 ranibizumab or aflibercept injection, entry of 'AMD' in the diagnosis field of the EMR and a minimum of 1 year of follow-up. Exclusion criteria were unknown date of first injection and treatment outside of routine clinical care at Moorfields before the first recorded injection in the database.
Main Outcome Measures: Primary outcome measure was change in VA at 1 and 2 years from baseline as measured in Early Treatment Diabetic Retinopathy Study letters. Secondary outcomes were the number of injections and predictive factors for VA gain.
Results: Mean VA gain at 1 year and 2 years were +5.5 (95% CI 5.0 to 6.0) and +4.9 (95% CI 4.2 to 5.6) letters, respectively. Fifty-four per cent of eyes gained ≥5 letters at 2 years, 63% had stable VA (±≤14 letters), 44% of eyes maintained good VA (≥70 letters). Patients received a mean of 7.7 (95% CI 7.6 to 7.8) injections during year 1 and 13.0 (95% CI 12.8 to 13.2) injections over 2 years. Younger age, lower baseline VA and more injections were associated with higher VA gain at 2 years.
Conclusion: This study benchmarks high quality EMR study results of real life AMD treatment and promotes open science in clinical AMD research by making the underlying data publicly available.
PMID: 31230012 DOI: 10.1136/bmjopen-2018-027441
PLoS One. 2019 Jun 25;14(6):e0218889.
Optical coherence tomography angiography characteristics of choroidal neovascularization requiring varied dosing frequencies in treat-and-extend management: An analysis of the AVATAR study.
Uchida A, Hu M, Babiuch A, Srivastava SK, Singh RP, Kaiser PK, Talcott K, Rachitskaya A, Ehlers JP.
Purpose: To evaluate optical coherence tomography angiography (OCTA) characteristics of choroidal neovascularization (CNV) in eyes requiring different treatment frequency of anti-vascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (NVAMD).
Design: Prospective observational case series.
Methods: Subjects who had undergone anti-VEGF treatment for NVAMD in the AVATAR study were subdivided into 3 groups depending on required anti-VEGF dosing: (i) treat-and-extend requiring every 4-6 weeks dosing (TEq4-6w), (ii) treat-and-extend requiring every 7-12 weeks dosing (TEq7-12w), (iii) eyes not requiring injection within last 12 months (PRN >12mo). OCTA images were evaluated for the morphological characteristics of CNV and the choriocapillaris flow void.
Results: Study consisted 40 eyes of 31 patients with a mean age of 79.9 ± 6.2 years. CNV morphology analysis on OCTA was feasible in 29 (73%) eyes. Ninety percent of CNVs in TEq7-12w group were irregular in shape involving foveal center, while 67% of CNVs in PRN>12mo group were circular in shape sparing foveal center. Among three groups, statistical difference was found in CNV shape (P = .012) and CNV location (P = .003), while no statistical difference was found in the CNV area (P = .14), vessel density (P = .19), presence of core vessels (P = .23), the presence of small margin loops (P = .20), large margin loops (P = .14), CNV maturity (P = .40), or the mean percentage of choriocapillaris area with flow void (P = .66).
Conclusion: The combination of CNV sparing the foveal center with higher circularity may suggest a clinically inactive CNV following initial anti-VEGF therapy. We found minimal distinguishing OCTA characteristics between those eyes that required ongoing therapy with the treat-and-extend regimen. More research is needed to identify specific CNV characteristics on OCTA that may become a useful tool for the management of NVAMD and timing of treatment.
PMID: 31237929 DOI: 10.1371/journal.pone.0218889
Am J Ophthalmol. 2019 Jun 20. pii: S0002-9394(19)30285-5.
Two-year risk of exudation in eyes with non-exudative AMD and subclinical neovascularization detected with swept source OCT angiography.
Yang J, Zhang Q, Motulsky EH, Thulliez M, Shi Y, Lyu C, de Sisternes L, Durbin MK, Feuer W, Wang RK, Gregori G, Rosenfeld PJ.
Purpose: Swept source optical coherence tomography angiography (SS-OCTA) was used to study the prevalence, incidence, and natural history of subclinical macular neovascularization (MNV) in eyes with unilateral non-exudative age-related macular degeneration (AMD).
Design: Prospective cohort study.
Methods: Patients were imaged using 3x3 mm and 6x6 mm SS-OCTA scan patterns. MNV was detected using the outer retina to choriocapillaris en face slab. Prevalence and incidence of subclinical MNV, Kaplan-Meier cumulative estimates for the overall risk of exudation, and the association between neovascular lesion size and the risk of exudation were assessed through 2 years.
Results: From August 2014 through March 2018, 227 patients (154 intermediate and 73 late AMD eyes) underwent SS-OCTA imaging. Thirty eyes (13.2%) had subclinical MNV at first imaging and 12 eyes (8.9%) developed subclinical MNV during follow-up. Of the 191 eyes with more than one visit, 19 developed exudation. Fourteen of these eyes had pre-existing subclinical MNV. The incidence of exudation from the time of first detection of any subclinical MNV was 34.5%. The relative risk of exudation after detection of subclinical MNV was 13.6 times greater (95% confidence interval, 4.9-37.7) than in the absence of subclinical MNV (P<0.001). There was no significant risk of exudation based on lesion size alone (P=0.91).
Conclusions: By 24 months, the risk of exudation was 13.6-times greater for eyes with subclinical MNV detected by SS-OCTA compared with eyes without subclinical MNV. For eyes with subclinical MNV in the absence of symptomatic exudation, we recommend close follow-up without treatment.
PMID: 31229464 DOI: 10.1016/j.ajo.2019.06.017
Ophthalmol Retina. 2019 May 7. pii: S2468-6530(18)30554-2.
OCT angiography biomarkers for predicting visual outcomes after ranibizumab treatment for diabetic macular edema.
Hsieh YT, Alam MN, Le D, Hsiao CC, Yang CH, Chao DL, Yao X.
Purpose: To correlate quantitative OCT angiography (OCTA) biomarkers with clinical features and to predict the extent of visual improvement after ranibizumab treatment for diabetic macular edema (DME) with OCTA biomarkers.
Design: Retrospective longitudinal study in Taiwan.
Participants: Fifty eyes of 50 patients with DME and 22 eyes of 22 healthy persons, with the exception of cataract and refractive error, from 1 hospital.
Methods: Each eye underwent OCT angiography (RTVue XR Avanti System with AngioVue software version 2017.1; Optovue, Fremont, CA), and 3×3-mm2 en face OCTA images of the superficial layer and the deep layer were obtained at baseline and after 3 monthly injections of ranibizumab in the study group. OCT angiography images also were acquired from the control group.
Main Outcome Measures: Five OCTA biomarkers, including foveal avascular zone (FAZ) area (FAZ-A), FAZ contour irregularity (FAZ-CI), average vessel caliber (AVC), vessel tortuosity (VT), and vessel density (VD), were analyzed comprehensively. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) also were obtained. Student t tests were used to compare the OCTA biomarkers between the study group and the control group. Linear regression models were used to evaluate the correlations between the baseline OCTA biomarkers and the changes of BCVA and CRT after treatment.
Results: Eyes with DME had larger AVC, VT, FAZ-A, and FAZ-CI and lower VD than those in the control group (P < 0.001 for all). After the loading ranibizumab treatment, these OCTA biomarkers improved but did not return to normal levels. Among all biomarkers, higher inner parafoveal VD in the superficial layer at baseline correlated most significantly with visual gain after treatment in the multiple regression model with adjustment for CRT and ellipsoid zone disruption (P < 0.001). To predict visual improvement, outer parafoveal VD in the superficial layer at the baseline showed the largest area under the receiver operating characteristic curve (0.787; P = 0.004). No baseline OCTA biomarkers showed any significant correlation specifically with anatomic improvement.
Conclusions: For eyes with DME, parafoveal VD in the superficial layer at baseline was an independent predictor for visual improvement after the loading ranibizumab treatment.
PMID: 31227330 DOI: 10.1016/j.oret.2019.04.027
Transl Vis Sci Technol. 2019 Jun 19;8(3):43.
Subretinal transplantation of human central nervous system stem cells stimulates controlled proliferation of endogenous retinal pigment epithelium.
McGill TJ, Osborne L, Lu B, Stoddard J, Huhn S, Tsukamoto A, Capela A.
Purpose: The loss of retinal pigment epithelial (RPE) cells is a feature common to age-related macular degeneration (AMD) and retinitis pigmentosa (RP) and multiple early phase clinical trials are underway testing the safety of RPE cell replacement for these diseases. We examined whether transplantation of human neural stem cells into the subretinal space could enhance the endogenous proliferative capacity of the host RPE cell to regenerate.
Methods: Human central nervous system stem cells (HuCNS-SC) were isolated from enzymatically treated brain tissue using flow cytometry. Pigmented dystrophic Royal College of Surgeons (RCS) and S334ter-4 rats treated with oral bromodeoxyuridine (BrdU) received a unilateral subretinal injection of 1.0 × 105 HuCNS-SC cells at either postnatal day 21 or 60. Animals were sacrificed at 90, 120, and 150 days of age. Eyes were fixed processed for cryostat sectioning. Sections were immunostained with Stem101, Ku80, RPE65, OTX1/2, BrdU, and CRALBP antibodies and analyzed via confocal microscopy.
Results: RCS rats that received transplantation of HuCNS-SC had significantly more (approximately 3-fold) Ki67-positive or BrdU-labelled host RPE cells adjacent to the HuCNS-SC graft than controls. Significantly increased host RPE cell proliferation as a result of HuCNS-SC transplantation also was confirmed in S334ter-line 4 transgenic rats with higher proliferation observed in animals with longer posttransplantation periods.
Conclusions: These results suggest that controlled proliferation of endogenous RPE by HuCNS-SC may provide another mechanism by which RPE cell diseases could be treated.
Translational Relevance: Engaging the capacity for endogenous RPE cell regeneration in atrophic diseases may be a novel therapeutic strategy for degenerative diseases of the RPE and retina.
PMID: 31245172 PMCID: PMC6586077 DOI: 10.1167/tvst.8.3.43
Adv Ther. 2019 Jun 25.
Effects of Macuprev® supplementation in age-related macular degeneration: A double-blind randomized morpho-functional study along 6 months of follow-up.
Parravano M, Tedeschi M, Manca D, Costanzo E, Di Renzo A, Giorno P, Barbano L, Ziccardi L, Varano M, Parisi V.
Background: To evaluate the effects of Macuprev® supplementation on macular function and structure in intermediate age-related macular degeneration (AMD) along 6 months of follow-up.
Methods: In this double-blind, monocentric, randomized, and prospective study, 30 patients with intermediate AMD were enrolled and randomly divided into two age-similar groups: 15 patients (AMD-M group; mean age 68.50 ± 8.79 years) received 6-month oral daily supplementation with Macuprev® (Farmaplus Italia s.r.l., Italy, two tablets/day on an empty stomach, before meals; contained in total lutein 20 mg, zeaxanthin 4 mg, N-acetylcysteine 140 mg, bromelain 2500GDU 80 mg, vitamin D3 800 IU, vitamin B12 18 mg, alpha-lipoic acid 140 mg, rutin 157 mg, vitamin C 160 mg, zinc oxide 16 mg, Vaccinium myrtillus 36% anthocyanosides 90 mg, Ganoderma lucidum 600 mg) and 15 patients (AMD-P group; mean age 70.14 ± 9.87) received two tablets of placebo daily on an empty stomach, before meals. A total of 28 eyes, 14 from each AMD group, completed the study. Multifocal electroretinogram (mfERG) and spectral domain-optical coherence tomography (SD-OCT) were assessed at baseline and after 6 months.
Results: At 6-month follow-up, AMD-M eyes showed a significant increase of mfERG response amplitude density (RAD) recorded from the central macular areas (ring 1, 0-2.5°; ring 2, 2.5-5°), whereas non-significant changes of retinal and choroidal SD-OCT parameters were found when values were compared to baseline. Non-significant correlations between functional and structural changes were found. In AMD-P eyes, non-significant differences for each mfERG and SD-OCT parameters were observed at 6 months.
Conclusion: In intermediate AMD, Macuprev® supplementation increases the function of the macular pre-ganglionic elements, with no associated retinal and choroidal ultra-structural changes.
Trial Registration: ClinicalTrials.gov identifier, NCT03919019.
Funding: Research for this study was financially supported by the Italian Ministry of Health and Fondazione Roma. Article processing charges were funded by Farmaplus Italia s.r.l., Italy.
PMID: 31243641 DOI: 10.1007/s12325-019-01016-2
Ophthalmic Surg Lasers Imaging Retina. 2019 Jun 1;50(6):398-400.
Bilateral choroidal osteoma complicated by bilateral choroidal neovascularization.
Arrigo A, Pierro L, Sacconi R, Querques G, Bandello F.
Abstract: Choroidal osteoma is a rare, classically unilateral tumor. Less than half of the cases are complicated by the onset of choroidal neovascularization (CNV). The authors describe a case of bilateral choroidal osteoma in a 10-year-old female patient complicated by the onset of bilateral CNV. The diagnosis was made by multimodal imaging and ultrasonography. Best-corrected visual acuity (BCVA) was 20/63 for the right eye (OD) and 20/25 for the left eye (OS). Interestingly, CNV OD resulted exudative, whereas no signs of fluid were detected OS. OCT angiography (OCTA) clearly detected the presence of CNV in both eyes. The patient underwent a single 1.0 mg/0.025 mL aflibercept injection OD. At follow-up, BCVA improved to 20/32 OD after 1 month and to 20/25 after 3 months, with no exudation recurrence. Both BCVA and imaging findings were unremarkable OS, thus suggesting the possible "quiescent" nature of this CNV.
PMID: 31233159 DOI: 10.3928/23258160-20190605-10