MD Research News – Issue 426 – 21 June 2019
Drug treatment
Photodiagnosis Photodyn Ther. 2019 Jun 10. pii: S1572-1000(19)30169-3.
Prognostic factors for combined ranibizumab and prompt verteporfin photodynamic therapy for polypoidal choroidal vasculopathy.
Hsia Y, Chan LW, Yang CH, Yang CM, Hsieh YT.
Purpose: To investigate the prognostic factors for the combined therapy of ranibizumab and prompt verteporfin photodynamic therapy (vPDT) for eyes with polypoidal choroidal vasculopathy (PCV).
Methods: Sixty-two PCV eyes of 62 patients that received the initial treatment of intravitreal ranibizumab followed by vPDT within 1 week plus a 2nd intravitreal ranibizumab 1 month later in one single medical center were retrospectively enrolled. Best-corrected visual acuity (BCVA) and parameters obtained from optical coherence tomography at baseline, 3 months, 6 months and 1 year were measured and compared. Factors associated with polyp regression, recurrent hemorrhage and visual improvement were analyzed.
Results: After the loading treatment, complete and partial polyp regression was achieved in 53.6% and 39.3% of cases, respectively at Month 3. The mean logarithm of the minimum angle of resolution of BCVA improved from 0.64 ± 0.38 to 0.55 ± 0.46 (P = 0.008) at Month 12. Recurrent hemorrhage (P = 0.001) and previous anti-vascular endothelial growth factor (VEGF) treatment (P = 0.017) were associated with poorer visual improvement at Month 12. Incomplete polyp regression (P = 0.038) and previous anti-VEGF treatment (P = 0.005) were associated with a higher risk of recurrent hemorrhage.
Conclusions: Recurrent hemorrhage was associated with poor visual improvement after combined ranibizumab and vPDT for PCV. Complete polyp eradication was associated with a lower risk of recurrent hemorrhage. Patients who had previously received anti-VEGF were associated with recurrent hemorrhage and poor visual improvement; more frequent follow-ups and more aggressive subsequent treatments may be needed for these cases.
PMID: 31195145 DOI: 10.1016/j.pdpdt.2019.06.004
Retina. 2019 Jun 4.
Difference between pachychoroid and nonpachychoroid polypoidal choroidal vasculopathy and their response to anti-vascular endothelial growth factor therapy.
Chang YC, Cheng CK.
Purpose: Recent investigations have found a biphasic pattern of choroidal thickness within polypoidal choroidal vasculopathy (PCV) patients. This study aims to investigate the relationship between choroidal thickness and the clinical features of PCV eyes.
Method: We investigated the correlation between various clinical features including subfoveal choroidal thickness (SFCT) and the response to 3-monthly anti-vascular endothelial growth factor (VEGF) treatments in 62 consecutive, treatment-naive PCV patients (66 eyes). After finding out SFCT as the only factor that was correlated with anti-VEGF treatment, we then set up to determine a best cutoff line for SFCT that could be used as a parameter to differentiate PCV patients into pachychoroid and nonpachychoroid groups using the Youden index for best combined specificity and sensitivity. We then compared the demographic features, clinical characteristics, and the response to anti-VEGF between both groups, to determine whether there is a difference between these two groups.
Results: Subfoveal choroidal thickness was the only significant factor for the treatment effect. The SFCT of 267.5 µm is the best cutoff line. The pachychoroid group showed significant younger ages (64.1 ± 9.6 vs. 72.0 ± 8.2, P = 0.004), fewer age-related macular degeneration-like features (50.0 vs. 81.3%, P = 0.027), more central serous chorioretinopathy-like features (typical retinal pigment epithelial mottling [61.1 vs. 16.7%, P = 0.0014] and choroidal vascular hyperpermeability [88.9 vs. 37.5%, P = 0.0002]), and less response to 3-monthly anti-VEGF treatments (27.8 vs. 83.3%, P < 0.0001) as compared to the nonpachychoroid group.
Conclusion: Polypoidal choroidal vasculopathy patients could be subclassified into pachychoroid and nonpachychoroid groups. The pachychoroid subtype of PCV has significantly younger ages, fewer age-related macular degeneration-like features, more central serous chorioretinopathy-like features, and less response to anti-VEGF treatment.
PMID: 31181038 DOI: 10.1097/IAE.0000000000002583
BMJ Open Ophthalmol. 2019 Apr 30;4(1):e000226.
Patient-reported outcomes in the RELIGHT clinical trial of ranibizumab in diabetic macular oedema.
Chakravarthy U, Pearce I, Banerjee S, Burton BJL, Downey L, Gale R, Patel J, Patra S, Sivaprasad S, Stevenson M, Lupton S.
Background/Aims: The RELIGHT clinical trial used an individualised treatment regimen of ranibizumab to treat diabetic macular oedema (DMO). We report findings from two patient-reported outcome instruments.
Methods: The National Eye Institute Visual Function Questionnaire (NEI-VFQ) was administered before starting treatment (M0) and at M6, 12 and 18. The Macular Disease Society Treatment Satisfaction Questionnaire (MacTSQ) was administered 1 month after treatment start (M1) and at M6, 12 and 18. Relationships between best-corrected visual acuity (BCVA) in the study eye (SE) and the status of the eye at baseline (as better or worse eye by BCVA) and the two instrument measures were investigated.
Results: BCVA in the SE correlated strongly with the NEI-VFQ composite scores and the majority of the subscales but not with the MacTSQ subscales. Statistically significant improvements were observed in the majority of the subscales of the NEI-VFQ at M6, 12 and 18. For the MacTSQ, improvements between baseline M6, 12 and 18 were seen for subscale 1 but only reached statistical significance at M12. In subscale 2, the changes in mean scores were statistically significant at all timepoints.
Conclusions: Although ranibizumab treatment in DMO over an 18-month period resulted in improvements in visual functioning and patient satisfaction, no correlation was found between the instruments used to measure these outcomes. Our finding of a lack of correlation between BCVA and the MacTSQ suggests the presence of psychophysical factors not measured by traditional means.
PMID: 31179389 PMCID: PMC6528749 DOI: 10.1136/bmjophth-2018-000226
Medicine (Baltimore). 2019 May;98(22):e15798.
Comparison of dexamethasone intravitreal implant with intravitreal anti-VEGF injections for the treatment of macular edema secondary to branch retinal vein occlusion: A meta-analysis.
Ji K, Zhang Q, Tian M, Xing Y.
Background: This meta-analysis compared the efficacy and safety of dexamethasone intravitreal implant (DEX) and anti-vascular endothelial growth factor (anti-VEGF) in the treatment of macular edema (ME) secondary to branch retinal vein occlusion (BRVO).
Methods: The PubMed, Embase, Cochrane Library, and Web of Science databases were comprehensively searched for published studies comparing DEX with anti-VEGF for the treatment of ME caused by BRVO. Outcomes of the selected studies included best-corrected visual acuity (BCVA), central macular thickness (CMT), and adverse events. Review Manager (RevMan) 5.3 was used to analyze the data.
Results: Six trials comparing the efficacy and safety of DEX with anti-VEGF were included in this meta-analysis. At 1 month, DEX achieved a mean BCVA superior to that achieved by anti-VEGF (MD = -0.11, P < .0001), in addition to a superior mean BCVA change (MD = -0.35, P < .00001). At 3 months, the mean BCVA showed a significant difference (MD = -0.06, P = .03) between DEX and anti-VEGF treatment, while the mean BCVA change was similar to that with anti-VEGF treatment (MD = -0.06, P = .11). However, neither mean BCVA nor mean BCVA change showed a significant difference between DEX and anti-VEGF treatment at 6 months (MD = 0.08, P = .06; MD = 0.06, P = .43, respectively). Mean CMT and mean CMT change were significantly lower in the DEX group than in the anti-VEGF group at 1 month (MD = -53.63 μm, P < .00001; MD = -60.1 μm, P = .005, respectively). However, at 3 months, mean CMT and mean CMT change were similar between DEX and anti-VEGF treatment (MD = 17.4 μ, P = .74; MD = 18.01 μm, P = .72, respectively). Although mean CMT in the anti-VEGF group was not significantly lower than that in the DEX group at 6 months (MD = 55.53, P = .07), the mean CMT change from baseline achieved by the anti-VEGF treatment was significantly superior to that obtained with DEX (MD = 75.53, P = .0002). Concerning adverse events, no statistically significant differences were observed in the incidence of cataract (OR = 4.25, P = .07), but the use of DEX led to a higher risk of intraocular pressure elevation compared with anti-VEGF treatment (OR = 12.04, P = .006).
Conclusion: Our results show that visual acuity recovery and CMT were better in the DEX group than in the anti-VEGF group after 1 and 3 months, although the difference in CMT at 3 months was not significant. However, there were no significant differences in terms of visual acuity and CMT between the two groups after 6 months of follow-up. Therefore, DEX may be recommended as the first treatment option in ME associated with BRVO.
PMID: 31145307 DOI: 10.1097/MD.0000000000015798
Other treatment
Assay Drug Dev Technol. 2019 May/Jun;17(4):167-177.
Axitinib-loaded poly(Lactic-Co-Glycolic Acid) nanoparticles for age-related macular degeneration: formulation development and in vitro characterization.
Narvekar P, Bhatt P, Fnu G, Sutariya V.
Abstract: Despite all the research aiming to treat ocular diseases, age-related macular degeneration (AMD) remains one of the serious diseases worldwide, which needs to be treated. Neovascularization is a key factor in AMD and thus antiangiogenic therapy is beneficial in reducing the development of new abnormal blood vessels. Axitinib, multireceptor tyrosine kinase inhibitor, is a small molecule that works by blocking vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR) responsible for developing neovascularization. The goal of this study is to develop a sustained release formulation of axitinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles to minimize frequent administration of the drug by intravitreal injection. The nanoparticles were characterized for particle size and zeta potential, as well as using differential scanning calorimetry, transmission electrode microscope, and in vitro drug release profile. The cytotoxicity of the formulation was evaluated on human retinal pigmented epithelium ARPE19 cells by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide salt] assay. The cellular uptake, antimigration assay, and vascular endothelial growth factor (VEGF) expression levels were found out in vitro using cells. The optimized formulation was 131.33 ± 31.20 nm in size with -4.63 ± 0.76 mV zeta potential. Entrapment efficiency was found to be 87.9% ± 2.7%. The cytotoxicity of ARPE19 cells was <12% for nanoparticles suggesting the in vitro compatibility at 10 μM concentration of drug. Cellular uptake, antimigration assay, and VEGF expression levels for the nanoparticles suggested greater uptake, significant antiangiogenic potential, and inhibition of VEGF activity. The results showed successful development of axitinib-loaded PLGA nanoparticles as an alternative potential treatment for AMD.
PMID: 31184962 DOI: 10.1089/adt.2019.920
Imaging
Am J Ophthalmol Case Rep. 2019 Jun 1;15:100485.
Time course of swept-source optical coherence tomography angiography findings after photodynamic therapy and aflibercept in eyes with age-related macular degeneration.
Sayanagi K, Hara C, Fukushima Y, Sato S, Sakaguchi H, Nishida K.
Purpose: To report swept-source optical coherence tomography angiography (SS-OCTA) findings after full-fluence photodynamic therapy (PDT) and aflibercept intravitreal injection (IVA) for age-related macular degeneration (AMD).
Methods: Five eyes of five patients with AMD treated with PDT and IVA were include into the study. We retrospectively reviewed the data obtained from the five patients using SS-OCTA before and after treatment. Three eyes had type 1 choroidal neovascularization (CNV) and two eyes had polypoidal choroidal vasculopathy.
Results: Before treatment, the CNV signals detected in all cases, decreased in three eyes and were not detected completely in two eyes at 1 months after treatment. The areas indicating CNV increased over time, but they did not increase to the baseline level. No CNV signal was detected in one eye during follow-up. In all cases, the exudation unchanged or resolved without additional IVA; the exudation recurred in two cases. In one eye, the CNV signal and the exudation occurred simultaneously; however, there was no association in another eye. A feeder vessel, from which the CNV signal seemed to originate, was seen in one of the five eyes.
Conclusion and Importance: SS-OCTA is useful to monitor the morphology of CNV after PDT and IVA, indicating that the remodeling of the choroidal vasculature occurs gradually after treatment. The presence or absence of the CNV signal might indicate CNV activity.
PMID: 31198888 PMCID: PMC6556523 DOI: 10.1016/j.ajoc.2019.100485
Ophthalmologica. 2019 Jun 13:1-9.
The comparison of morphologic characteristics of type 1 and type 2 choroidal neovascularization in eyes with neovascular age-related macular degeneration using optical coherence tomography angiography.
Zhao Z, Yang F, Gong Y, Yu S, Liu H, Wang H, Wang F, Sun X.
Purpose: The purpose of this study was to use optical coherence tomography angiography (OCTA) to compare the morphology characteristics of type 1 and 2 choroidal neovascularization (CNV) in neovascular age-related macular degeneration (nAMD) patients.
Materials and Methods: This is a retrospective, observational study of 51 eyes with nAMD using OCTA from July 2016 through March 2017.
Results: In total, 51 eyes of 50 patients were included in the analysis. According to the anatomical classification based on OCT, 27 eyes (53%) were diagnosed with type 1 CNV, and 24 eyes (47%) were type 2 CNV. Type 2 CNV was characterized by smaller flow area, smaller greatest vascular caliber (GVC), smaller greatest linear dimension (GLD), and shorter duration of disease. The duration of disease only correlated with GVC (p = 0.026) in multivariate linear regression results. Meanwhile, GLD correlated with GVC and flow area whereas GVC was not associated with flow area.
Conclusion: This study demonstrated that type 2 CNV was characterized by shorter duration of disease, smaller GVC, smaller GLD, and smaller flow area compared with type 1 CNV. Additionally, we showed that the duration of the disease correlated with GVC of the CNV.
PMID: 31195396 DOI: 10.1159/000497491
Invest Ophthalmol Vis Sci. 2019 Jun 3;60(7):2503-2508.
Longitudinal association between drusen volume and retinal capillary perfusion in intermediate age-related macular degeneration.
Reiter GS, Told R, Schlanitz FG, Baumann L, Schmidt-Erfurth U, Sacu S.
Purpose: To evaluate vascular changes in the superficial and deep retinal capillary plexus (SCP, DCP) and their association with drusen volume changes in intermediate age-related macular degeneration (iAMD).
Methods: Patients with iAMD were examined at baseline and 12 months thereafter. Drusen volume was extracted from 20° × 20° OCT scans using a 3-mm ETDRS grid using a customized algorithm with manual correction. Vessel density (VD) and flow area (FA) were extracted from 3 × 3 mm SD-OCT-A scans after manual correction of the segmentation. Associations were investigated using multiple regression models.
Results: We used 31 eyes of 31 patients for evaluation. The mean age at baseline was 74.9 ± 5.4 years; 26 patients were female. Baseline visual acuity (VA) was 0.05 ± 0.08 logMAR (Snellen equivalent approximately 20/22). The initial mean 3-mm central drusen volume was 0.144 ± 0.136 mm3. A significant association with the signal strength index was consistently found, therefore all capillary measurements were corrected. VD in the same area was 49.88% ± 7.38% and 55.43% ± 9.31% for the SCP and DCP, respectively. The baseline FA resulted in 3.292 ± 0.218 mm2 and 3.433 ± 0.224 mm2 for the SCP and DCP, respectively. No association was found between changes in drusen volume and FA or VD after 12 months (all P > 0.05). VA worsened (P = 0.013) and the foveal FA of the SCP increased significantly (P = 0.014).
Conclusions: No significant association was found between the increase in drusen volume in iAMD and capillary retinal perfusion over a 12-month follow-up. Although VA decreased statistically over this time period, the foveal FA of the SCP increased.
PMID: 31185089 DOI: 10.1167/iovs.18-26237
J Cataract Refract Surg. 2019 Jun 4. pii: S0886-3350(19)30046-X.
Prevalence of macular abnormalities identified only by optical coherence tomography in Brazilian patients with cataract.
Pinto WP, Rabello LP, Ventura MC, Rocha CS, Ventura BV.
Purpose: To assess the prevalence of macular abnormalities not suspected by the biomicroscopic fundus examination and identified only by macular optical coherence tomography (OCT) in the preoperative evaluation for cataract surgery in a large series of Brazilian patients.
Setting: Private practice, Recife, Brazil.
Design: Retrospective case series.
Methods: All eyes that had cataract surgery by the same physician between August 2014 and July 2016 were eligible. Excluded were eyes with a previous diagnosis of macular abnormalities, with a suspicious biomicroscopic fundus examination, and without OCT results. Based on the preoperative macular OCT, patients were divided into the following 2 groups: those with a normal OCT and those with an abnormal OCT.
Results: Nine hundred fifty-two eyes (614 patients) were included in the study. Macular OCT identified abnormalities in 47 eyes (4.9%) of 44 patients (7.2%). Thirty-one eyes (3.3%) had epiretinal membrane, 7 (0.7%) had age-related macular degeneration, 4 (0.4%) had intraretinal cysts, 4 (0.4%) had a lamellar hole, and 1 (0.1%) had a macular hole. Patients with an abnormal OCT had a statistically significant higher mean age (P = .004).
Conclusion: In the preoperative evaluation for cataract surgery in Brazilian patients, 7.2% of those with a normal biomicroscopic fundus examination had macular abnormalities that were identified only by OCT.
PMID: 31174986 DOI: 10.1016/j.jcrs.2019.01.022
Ophthalmol Retina. 2019 Jun;3(6):500-509.
Retinal morphology in Sjögren-Larsson Syndrome on OCT: from metabolic crystalline maculopathy to early-onset macular degeneration.
Staps P, Cruysberg JRM, Roeleveld N, Willemsen MAAP, Theelen T.
Purpose: To study long-term macular changes by spectral-domain (SD) OCT in patients with Sjögren-Larsson syndrome (SLS).
Design: Retrospective cohort study.
Participants: Twenty-two patients with genetically proven SLS (12 female, 10 male; median age, 21 years; range, 3-47 years) were included in the study. One or more SD-OCT scans were available from the period 2008 to 2017.
Methods: Seventeen patients underwent SD-OCT imaging of the macula in 2017. Earlier scans were available of the other 5 patients. The latest available SD-OCT scans were qualitatively assessed for morphologic changes in 19 patients. In addition, retinal layer thickness could be measured in 15 patients. The latest scans were compared with previous scans to assess the course of the disease qualitatively (n = 15 patients) and quantitatively (n = 10 patients).
Main Outcome Measures: Macular morphology and retinal layer thickness on SD-OCT scans during the study period.
Results: In all patients, abnormal macular morphology was observed in both eyes, already from the youngest age. Intraretinal crystals, visible as hyperreflective dots, were visible in all eyes and located in the retinal nerve fiber layer, inner plexiform layer, and outer plexiform layer. Furthermore, the photoreceptor (PR) layer lacked the physiologic thickness amplification beneath the fovea. Pseudocysts with limited interruption of the underlying PR layer were observed in half of the patients, all younger than 30 years of age. Frank atrophy of the retinal pigment epithelium (RPE) and a neovascular complex were seen in 3 older patients and 1 older patient, respectively. The fovea was significantly thinner compared with healthy controls and decreased even further during the study period.
Conclusions: Macular dystrophy in SLS may initially comprise an arrest in foveal development. Because of the absence of macular pigment, phototoxic damage may then cause central retinal degeneration of the vulnerable macula, marked by the development of pseudocysts. Eventually, the young adult patients may proceed to an early-onset end-stage macular degeneration with frank atrophy of the RPE or neovascularization.
PMID: 31174672 DOI: 10.1016/j.oret.2019.01.023
Stem cells
Semin Ophthalmol. 2019 Jun 12:1-6.
Current stem-cell approaches for the treatment of inherited retinal degenerations.
Terrell D, Comander J.
Abstract: Stem cells provide a promising new therapeutic approach for the treatment of multiple acquired and inherited retinal conditions. While to date, there have been numerous clinical trials examining the ability of stem cells to treat the geographic atrophy found in advanced non-neovascular age-related macular degeneration, fewer clinical trials have specifically examined stem-cell therapy for inherited retinal disease. Moreover, it remains to be seen if human stem cells will be able to regenerate the lost retinal cell populations that represent a final common pathway for most of the inherited retinal diseases, or if stem cells will secrete a neuroprotective paracrine factor that will delay progression of these diseases. Here, we will review a number of the current clinical trials, either completed or in process, that have been designed to specifically treat inherited retinal conditions. There was considerable initial concern that using human stem cells as therapeutic agents might have the potential to form benign tumors or trigger an immune response that would have deleterious effects on the patient's retina. Currently, the majority of the clinical trials reviewed share the conclusion that intraocular stem-cell approach is generally well tolerated and safe for patients. While there are some efficacy data that have been published for a few of the reviewed trials, none of the completed studies have been empowered to demonstrate statistically significant efficacy in humans.
PMID: 31188052 DOI: 10.1080/08820538.2019.1620808
Stem Cell Res. 2019 May 29;38:101473.
Generation of a human iPS cell line (CABi003-A) from a patient with age-related macular degeneration carrying the CFH Y402H polymorphism.
Garcia-Delgado AB, Calado SM, Valdes-Sanchez LM, Montero-Sanchez A, Ponte-Zuñiga B, de la Cerda B, Bhattacharya SS, Diaz-Corrales FJ.
Abstract: Age-related macular degeneration (AMD) is the leading cause of adult blindness in developed countries and is characterized by progressive degeneration of the macula, the central region of the retina. A human induced pluripotent stem cell (hiPSC) line was derived from peripheral blood mononuclear cells (PBMCs) from a patient with a clinical diagnosis of dry AMD carrying the CFH Y402H polymorphism. Sendai virus was using for reprogramming and the pluripotent and differentiation capacity of the cells were assessed by immunocytochemistry and RT-PCR.
PMID: 31176916 DOI: 10.1016/j.scr.2019.101473
Genetics
Dis Markers. 2019 May 2;2019:5631083.
RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) gene variants with predisposition to age-related macular degeneration.
Vilkeviciute A, Kriauciuniene L, Chaleckis R, Deltuva VP, Liutkeviciene R.
Background: Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of a central part of the neural retina (macula) and a leading cause of blindness in elderly people. While it is known that the AMD is a multifactorial disease, genetic factors involved in lipid metabolism, inflammation, and neovascularization are currently being widely studied in genome-wide association studies (GWAS). The aim of our study was to evaluate the impact of new single nucleotide polymorphisms (SNPs) in RAD51B, TRIB1, COL8A1, and COL10A1 genes on AMD development.
Methods: Case-control study involved 254 patients diagnosed with early AMD, 244 patients with exudative AMD, and 942 control subjects. The genotyping of RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) was carried out using TaqMan assays by a real-time polymerase chain reaction (RT-PCR) method.
Results: Statistically significant difference was found in genotype (TT, TC, and CC) distribution of COL8A1 rs13095226 between exudative AMD and control groups (60.2%, 33.6%, and 6.1% vs. 64.9%, 32.3%, and 2.9%, respectively, p = 0.036). Also, comparing with TT+TC, rs13095226 CC genotype was associated with 3.5-fold increased odds of exudative AMD development (OR = 3.540; 95% CI: 1.415-8.856; p = 0.007).
Conclusion: Our study revealed a strong association between a variant in COL8A1 (rs13095226) and exudative AMD development.
PMID: 31191752 PMCID: PMC6525907 DOI: 10.1155/2019/5631083