Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Volumetric fluid analysis of fixed monthly anti-VEGF treatment in patients with neovascular age-related macular degeneration

·AIM:To evaluate visual outcomes and changes in fluid after administering monthly anti-vascular endothelial growth factor(VEGF)injections to treat neovascular agerelated macular degeneration(n AMD)with subretinal fluid(SRF)and pigment epithelial detachment(PED).·METHODS:This prospective study included eyes with n AMD previously treated with as-needed anti-VEGF injections.The patients were treated with six monthly intravitreal injections of ranibizumab.Quantitative volumetric segmentation analyses of the SRF and PED were performed.The main outcome measures included best-corrected visual acuity(BCVA),and SRF and PED volumes.·RESULTS:Twenty eyes of 20 patients were included in this study.At the 6-month follow-up,BCVA and PED volume did not change significantly(P=0.110 and 0.999,respectively)but the mean SRF volume decreased from 0.53±0.82 mm3 at baseline to 0.08±0.23 mm3(P=0.002).The absorption rate of the SRF volume was negatively correlated with the duration of previous antiVEGF treatment(P=0.029).Seven of the 20 eyes(35%)showed a fluid-free macula and significant improvement in BCVA(P=0.036)by month 6.·CONCLUSION:Quantifying the SRF can precisely determine the patient’s responsiveness to anti-VEGF treatment of n AMD.

Circular RNA expression and the competitive endogenous RNA network in pathological,age-related macular degeneration events:A cross-platform normalization study

Age-related macular degeneration(AMD)causes irreversible blindness in people aged over 50 worldwide.The dysfunction of the retinal pigment epithelium is the primary cause of atrophic AMD.In the current study,we used the ComBat and Training Distribution Matching method to integrate data obtained from the Gene Expression Omnibus database.We analyzed the integrated sequencing data by the Gene Set Enrichment Analysis.Peroxisome and tumor necrosis factor-α(TNF-α)signaling and nuclear factor kappa B(NF-κB)were among the top 10 pathways,and thus we selected them to construct AMD cell models to identify differentially expressed circular RNAs(circRNAs).We then constructed a competing endogenous RNA network,which is related to differentially expressed circRNAs.This network included seven circRNAs,15 microRNAs,and 82 mRNAs.The Kyoto Encyclopedia of Genes and Genomes analysis of mRNAs in this network showed that the hypoxia-inducible factor-1(HIF-1)signaling pathway was a common downstream event.The results of the current study may provide insights into the pathological processes of atrophic AMD.

Image enhancement of color fundus photographs for age-related macular degeneration:the Shanghai Changfeng Study

AIM:To develop and evaluate a new fundus image optimization software based on red,green,blue channels(RGB) for the evaluation of age-related macular degeneration(AMD) in the Chinese population.METHODS:Fundus images that were diagnosed as AMD from the Shanghai Changfeng Study database were analyzed to develop a standardized optimization procedure.Image brightness,contrast,and color balance were measured.Differences between central lesion area and normal retinal area under different image brightness,contrast,and color balance were observed.The optimal optimization parameters were determined based on the visual system to avoid image distortion.A paired-sample diagnostic test was used to evaluate the enhancement software.Fundus optical coherence tomography(OCT) was used as the gold standard.Diagnostic performances were compared between original images and optimized images using Mc Nemar’s test.RESULTS:A fundus image optimization procedure was developed using 86 fundus images of 74 subjects diagnosed with AMD.By observing gray-scale images,choroid can be best displayed in red channel and retina in green channel was found.There was limited information in blue channel.Totally 104 participants were included in the paired sample diagnostic test to assess the performance of the optimization software.After the image enhancement,sensitivity increased from 74% to 88%(P=0.008),specificity decreased slightly from 88% to 84%(P=0.500),and Youden index increased by 0.11.CONCLUSION:The standardized image optimization software increases diagnostic sensitivity and may help ophthalmologists in AMD diagnosis and screening.

Bevacizumab vs ranibizumab for neovascular age-related macular degeneration in Chinese patients

AIM: To compare the clinical efficacy of intravitreal injections of bevacizumab and ranibizumab for treating Chinese patients with neovascular age-related macular degeneration (AMD).METHODS: Among 60 Chinese patients with exudative AMD (60 eyes), 28 received intravitreal bevacizumab injections (1.25mg) and 32 received intravitreal ranibizumab injections (0.5mg), once a month for 3 months and were followed for a total of 6 months. Monthly optical coherence tomography (OCT) was used to determine whether the patients received additional treatments during the follow-up. We compared the baseline and 6 -month follow-up values of mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in both groups of patients. We also compared the occurrence of adverse events.RESULTS: At the 6-month follow-up, the mean BCVA (logMAR) of the bevacizumab and ranibizumab treatment groups improved from the baseline measurements of 0.72 ±0.23 and 0.73 ±0.22 to 0.47 ±0.14 and 0.45 ±0.20, respectively (P 【0.05 for both groups). However, the change was not significantly different between the two groups. As evaluated by OCT, CRT decreased from 366.71 ±34.72μm and 352 ±36.9μm at baseline to 250.86 ± 41.51μm and 243.22 ±41.38μm in the bevacizumab and ranibizumab groups, respectively (P 【0.05 for both groups). However, the change was not significantly different between the two groups. There were no severe local adverse reactions or systemic adverse events.CONCLUSION:Intravitreal bevacizumab and ranibizumab have equivalent effects on BCVA and CRT and appeare safe over the short-term.

Comparison of visual acuity outcomes between ranibizumab and bevacizumab treatment in neovascular age-related macular degeneration

AIM: To compare visual acuity (VA) outcomes between intravitreal injection of bevacizumab and ranibizumab in the treatment of neovascular age-related macular degeneration (AMD). METHODS: We conducted a consecutive, retrospective case series study in patients with newly diagnosed all type choroidal neovascularization (CNV) secondary to AMD who received an intravitreal injection of bevacizumab (1.25mg) or ranibizumab (0.3mg) at Lions Eye Institute, Western Australia from Mar. 2006 to May 2008. All patients received injection at baseline with additional monthly injections given at the discretion of the treating physician. Main outcome measures were changes in VA. RESULTS: There were 371 consecutive patients received injection at least in one eye with at least 6 months of follow up (median of 12.0 months). Bevacizumab treatment prevented 221 out of 278 (79.5%) patient from losing < 15 letters in VA compared with 79 out of 93 (84.9%) of ranibizumab treated patients (P=0.25). While 68 (24.5%) of bevacizumab treated patients gained 15 letters of VA compared with 24 (25.8%) of ranibizumab treated patients (P=0.79). 75.3% and 66.2% patients benefited from ranibizumab and bevacizumab respectively with final VA better than 6/60 (P=0.10). Multivariate analysis showed that pre-treatment VA was negatively associated with benefit outcome. Assignment of injection was not associated with VA outcome of benefit after adjusting the covariate (P=0.857). CONCLUSION: There are no difference in treatment efficacy in terms of VA between bevacizumab and ranibizumab in routine clinical condition.

Comparison of two different treatment regimens’ efficacy in neovascular age-related macular degeneration in Turkish population—based on real life data-Bosphorus RWE Study Group

AIM: To compare two different anti-vascular endothelial growth factor(anti-VEGF) treatment regimens'-a priori pro re nata(PRN) and PRN regimen following^(th)e loading phaseanatomical and functional results in neovascular agerelated macular degeneration(n AMD) patients. METHODS: Totally 544 n AMD patients followed and treated with aflibercept(n=135) and ranibizumab(n=409)at 9 different centers between 2013 and 2015 were enrolled into^(th)is retrospective multicenter study. Patients with initial best corrected visual acuity(BCVA) interval of 1.3-0.3(log MAR) and a minimum follow-up of 12 mo were included. Patients under two different regimens-a priori pro re nata(1+PRN) or 3 consecutive intravitreal injections followed by a PRN regimen(3+PRN)-were compared in BCVA at 3^(th), 6^(th) and 12^(th) months, and in central macular^(th)ickness(CMT) at 6^(th) and 12^(th) months. The total study group, intravitreal ranibizumab(IVR) and intravitreal aflibercept(IVA) groups were evaluated separately. RESULTS: The mean CMT decreased in^(th)e 1+PRN(n=101) regimen from 407 to 358 and 340 μm and in^(th)e 3+PRN(n=443) group from 398 to 318 and finally to 310 μm at months 6 and 12, respectively. Anatomically,^(th)e CMT reduction at 6^(th) month(48.5 vs 76.4;P<0.05) was statistically significant in favor of 3+PRN group. BCVA changed in 1+PRN group from 0.77 to 0.78, 0.75 and 0.75;in 3+PRN group from 0.81 to 0.69, 0.72, and 0.76 at months 3, 6, and 12, respectively. Visual gain was statistically better in 3+PRN group at 3^(th) month(-0.01 vs 0.12;P<0.001). In IVR group, CMT reduction was in greater in 3+PRN at 6^(th)(44 vs 72) and 12^(th) month(61 vs 84), but statistically insignificant. The 3+PRN group revealed statistically better visual results at 3^(th) month(-0.02 vs 0.11, P<0.05). In IVA group, although statistically insignificant, CMT reduction(61 vs 89, 6^(th) month;85 vs 97, 12^(th) month) and visual gain(0.02 vs 0.16;0.02 vs 0.14;0.05 vs 0.11) was found in favor of 3+PRN group at all visits.CONCLUSION: The loading dose of anti-VEGF treatments in n AMD leads to significantly better anatomical and functional results, regardless of the agent, specially in early follow-up interval.

Assessment of the long-term visual and anatomical outcomes of ranibizumab to treat neovascular age-related macular degeneration

AIM： To investigate the long-term visual and anatomical outcomes of patients who underwent intravitreal ranibizumab monotherapy to treat neovascular age-related macular degeneration（AMD） and followed-up for at least 2 y.METHODS： A total of 74 eyes of 74 patients who underwent ranibizumab monotherapy for neovascular AMD were included in this retrospective study.RESULTS： The average patient age was 72.1±6.5（range, 57-85）y, the average follow-up time 46.2±13.1（range, 24-75）mo, and the average number of visits 24.1±9.5（range, 8-48）. The mean number of injections in year 1 was 4.5, 1.6 in year 2, 0.9 in year 3, 0.4 on year 4, and 0.1 in the following years. Within the entire follow-up period, the mean number of injections was 7.6±4.4（range, 2-21）. The mean visual acuity was 48.1±15（range, 15-76） letters at baseline and 45.7±19（range, 7-75） at year 5. The mean central macular thickness was 303±78（range, 178-552） μm at baseline and 251±51（range, 138-359） μm at year 5. Scars developed in 47（63.5%） eyes at the end of the follow-up period, and atrophy was evident in 6（8.1%） eyes.CONCLUSION： Ranibizumab monotherapy can stabilize visual acuity for a mean period of 4 y in patients with neovascular AMD.

Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment response in neovascular age-related macular degeneration

Age related macular degeneration （AMD） is a complex progres- sive neurodegenerative disease causing blindness in 30-35 million people worldwide. It affects the macula region of the retina leading to severe vision loss and legal blindness in individuals 〉 50 years of age （Wong et al., 2014）. The precise aetiology of AMD is unknown but smoking, age and genetic factors are major risk factors for AMD predisposition （Ding et al., 2009）. The genetic basis of AMD is well described with a recent study from the International AMD gene consortium （IAMDGC） reporting 52 genetic variants across 34 loci associated with the risk of AMD pathogenesis and explaining more than 50% of the genetic heritabilitv of the disease （Fritsche et al., 2016）.

Choroidal structural changes determined by the binarization method after intravitreal aflibercept treatment in neovascular age-related macular degeneration

AIM:To assess the choroidal structural alterations after intravitreal injection of aflibercept in neovascular agerelated macular degeneration(n AMD).METHODS:Fifty eyes with treatment-naive n AMD were evaluated at baseline,3^(rd),and 12^(th) month.Fifty eyes of 50 healthy subjects were also included as controls.Choroidal thickness(CT)was measured in the subfoveal region.Total circumscribed choroidal area(CA),luminal area(LA),stromal area(SA),and choroidal vascularity index(CVI)was calculated using Image J.RESULTS:At baseline,subfoveal CT was increased in n AMD patients compared to controls(P=0.321).Eyes with n AMD had a significantly increased total circumscribed CA and SA(P=0.041,0.005,respectively).The CVI was decreased(P=0.038).In the 3^(rd) month,the subfoveal CT,LA,and CVI revealed a decrease(P=0.005,P=0.039,0.043,respectively).In the 12th month,subfoveal CT,LA,and CVI were decreased in comparison to baseline measures(P<0.001,0.006,0.010,respectively).CONCLUSION:Significant structural alterations are found after intravitreal aflibercept treatment during the 12-month follow-up,in particular at the third month,in eyes with n AMD.

Evaluating role of bone marrow-derived stem cells in dry age-related macular degeneration using multifocal electroretinogram and fundus autofluorescence imaging

AIM：To evaluate the role of bone marrow-derived stem cells in the treatment of advanced dry age-related macular degeneration（AMD）using multifocal electroretinogram（mf-ERG）and fundus autofluorescence imaging.METHODS：Thirty patients（60 eyes）with bilateral central geographic atrophy（GA）were recruited.Worse eye of each patient received autologous bone marrow-derived hematopoietic stem cells（BM-HSCs）（group 1）and the fellow eye with better visual acuity served as control（group2）.The effect of stem cell therapy was determined in terms of visual acuity,amplitude and implicit time in mf-ERG and size of GA on fundus autofluorescence imaging.These tests were performed at presentation and first,third and sixth month follow up.Adverse events（if any）were also monitored.RESULTS：At 6mo follow-up there was no statistically significant improvement in median log MAR best corrected visual acuity（BCVA）in either group.Mf-ERG revealed significant improvement in amplitude and implicit time in the intervention group.A significant decrease was also noted in greatest linear dimension（GLD）of GA in the eyes receiving stem cells[6.78±2.60 mm at baseline to 6.56±2.59 mm at 6mo（P=0.021）].However,no such improvement was noted in the control group.CONCLUSION：Electrophysiological and anatomical improvement in the intervention group sheds light on the therapeutic role of BM-HSCs.Further studies are required to determine the stage of disease at which the maximal benefit can be achieved and to standardize the dose andfrequency of stem cell injection.

6-weekly bevacizumab versus 4-weekly ranibizumab for neovascular age-related macular degeneration:a 2-year outcome

AIM： To compare visual acuity and central macular thickness（CMT） changes in neovascular age-related macular degeneration patients treated with either 6weekly bevacizumab regimen or 4 weekly ranibizumab on an as required basis.·METHODS： Patients made an informed choice between bevacizumab 1.25 mg or ranibizumab 0.5 mg. The selected treatment was administered in the first 3 visits.Bevacizumab patients were followed-up 6 weekly and ranibizumab 4 weekly. Retreatment criteria was based on the reduction of 〉5 letters in the best-corrected visual acuity（BCVA）, the presence of retinal fluid on optical coherence tomography（OCT） or new retinal haemorrhage.·RESULTS： Visual acuity at 2y bevacizumab patients gained 7. 0 letters and ranibizumab 9. 2（ P = 0. 31, 95 %CI-6.4 to 2.0）. At 2y 86% of bevacizumab and 94%ranibizumab patients had not lost 15 letters or more（P =0.13）. Mean CMT decreased at 2y bevacizumab by 146 μm,ranibizumab 160 μm（P =0.72）. Mean number of injections was at 2y bevacizumzb 11.9, ranibizumab 10.3（P =0.023）.· CONCLUSION： Bevacizumab 6 weekly on an as required basis was not demonstrably non-inferior to ranibizumab 4 weekly pro re nata（prn） in terms of BCVA and change in CMT. In the bevacizumab group, one more injection was required in the second year compared to the ranibizumab group.

Changes on optical coherence tomography angiography and fluorescein angiography in eyes with neovascular age-related macular degeneration

AIM:lo evaluate the changes on optical coherence tomography angiography(OCTA) and fluorescein angiography(FA) and their correlation in neovascular agerelated macular degeneration(nAMD) before and after intravitreal aflibercept injections(IAIs).METHODS:In 43 treatment-na?ve patients with nAMD,choroidal neovascularization(CNV) in OCTA were morphologically and quantitatively analyzed before and after IAIs to determine whether they are correlated with leakage on FA or not.By combining CNV in OCTA and leakage in FA,lesions were characterized as three types:L+C+(with both CNV and leakage),L-C+(with CNV but without leakage),or L+C-lesion(with leakage outside CNV).RESULTS:Before IAI,while 27 eyes had L+C+lesion only,16 eyes had both L+C+and L-C+lesions simultaneously.Tiny capillaries and anastomosis in CNV were more developed in L+C+lesion,at 86.0% and58.1%,respectively,relative to 9.3% and 9.3% in L-C+lesions(P<0.001).After IAIs in 33 eyes,tiny capillaries and anastomosis were decreased in the lesions with cessation of leakage on FA(P<0.001 and P=0.001,respectively).In quantitative analysis,neovascularization length and numbers of junctions and endpoints were also significantly decreased.CONCLUSION:Leakage on FA is associated with CNV morphology in OCTA and remained so after IAls.Therefore,by carefully assessing the morphological and quantitative changes of CNV in OCTA before and after treatment,activity of nAMD is expected even though CNV on OCTA is not completely matched with fluorescein leakage.

Bevacizumab versus ranibizumab for neovascular agerelated macular degeneration: a Meta-analysis

AIM: To systematically compare the efficacy and safety of off-label bevacizumab versus licensed ranibizumab intravitreal injections as well as monthly regimen versus pro re nata [PRN(as needed)] regimen in the treatment of neovascular age-related macular degeneration(n AMD).METHODS: Relevant publications were identified through automatically retrieve of database and manually retrieving. The methodological quality of studies included was assessed using the Jadad score and the risk-of-bias assessment. The efficacy estimates were measured by the weight mean difference(WMD) for the improvement of best-corrected visual acuity(BCVA) and central retinal thickness(CRT) reduction. The safety estimates were measured by odds ratios(OR) for adverse events rates. Statistical analysis was conducted by Revman 5.2.7.RESULTS: Seven studies were included in the Metaanalysis. There were no statistically significant differences between bevacizumab and ranibizumab in BCVA at 1 and 2y(P =0.37, P =0.18, respectively),However, both drugs has better BCVA given monthly than given as needed at 1 and 2y(P 【0.05). The results demonstrated the mean decrease in CRT was less in bevacizumab group than ranibizumab group at 1y(P 【0.05),while the difference was not significant at 2y(P =0.24).Treatment monthly gained much more decrease in CRT at 1 and 2y(P 【0.005).There were no differences between drugs in the rates of death, arterial thrombotic events and venous thrombotic events(P =0.41, P =0.55, P =0.10,respectively), while the rates of medical dictionary for regulatory activities(Med DAR) system organ class events and ≥1 systemic serious adverse events were higher in bevacizumab group than ranibizumab group(P 【0.05).But the incidences of death, arterial thrombotic events,venous thrombotic events, Med DAR system organ class events as well as ≥1 systemic serious adverse events were not statistically different between both treatment regimens of monthly and as needed(P =0.14, P =0.76,P =0.73, P =0.12, P =0.11, respectively).· CONCLUSION: Bevacizumab was equivalent to ranibizumab for BCVA, however bevacizumab tended to gain less decrease in CRT and had higher rates of serious adverse events. Compared with treatment as needed, treatment monthly showed superior efficacy in BCVA improvement and CRT reduction, while the rates of adverse events were similar in the two dosing regimens.

Predictors of visual outcome in eyes with choroidal neovascularization secondary to age related macular degeneration treated with intravitreal bevacizumab monotherapy

AIM:To evaluate the predictors of visual improvement in eyes with naive choroidal neovascularization secondary to age-related macular degeneration (CNV -AMD) treated with intravitreal bevacizumab (IVB) monotherapy. METHODS:Fifty eyes with naive CNV-AMD with pretreatment best-corrected visual acuity (BCVA) better than 20/200 and treated with IVB monotherapy were evaluated. Several variables including age, sex, pre-treatment BCVA, CNV type and lesion size on fluorescein angiogram as well as SD-OCT parameters including pre-treatment central macular thickness (CMT), inner-segment/outer-segment (IS/OS) junction integrity, and external limiting membrane (ELM) integrity were analyzed to predict visual outcome.RESULTS:On univariate regression, pretreatment ELM damage was associated with less visual improvement after treatment (P =0.0145). However, ELM damage predicted only 10% of the visual outcome. On multivariate regression, pretreatment BCVA, IS/OS junction, and ELM integrity on SD-OCT were the significant predictors for the treatment effect and together predicted 37% of visual improvement. CONCLUSION:Pretreatment BCVA, ELM and IS/OS junction integrity on SD-OCT are of significant value inpredicting the visual improvement in naive wet AMD patients treated with IVB monotherapy.

Recent Developments in the Treatment of Wet Age-related Macular Degeneration

Age-related macular degeneration(AMD)is the most common cause of irreversible blindness and visual impairment in individuals over the age of 50 years in western societies.More than 25 million people currently suffer from this illness in the world,with an additional 500000 every year,approximately.It is a multifactorial ocular disease that affects the maculae due to a late-onset progressive neurodegeneration and dysfunction of photoreceptors and retinal pigment epithelium(RPE).There are many subtypes of AMD but basically two broad forms:the nonneovascular(dry,nonexudative)and neovascular(wet,exudative).Exudative AMD is the less common form(about 15%)but tends to progress more rapidly.At the moment,wet AMD is treated primarily on the basis of anti-vascular endothelial growth factor(VEGF)agents,which have led to massive improvement in the prognosis of the disease since they were first introduced.This article focuses on the latest treatment approaches to neovascular AMD.An extensive literature review was performed in order to illustrate the effectiveness of current and future anti-VEGF agents as well as the landmark clinical studies that have been carried out to establish these drugs as a gold standard in the therapy of wet AMD.

Evaluation of fundus autofluorescence patterns in age-related macular degeneration

AIM： To study the various morphological patterns of fundus autofluorescence （FAF） images in patients with age-related macular degeneration （AMD） in Indian population.METHODS： Totally 179 eyes of 104 patients with clinical diagnosis of AMD were recruited into the study. Autofluorescence images were captured using confocal scanning laser ophthalmoscope and the patterns of FAF were classified.RESULTS： Of 179 eyes, 27 （15.08%） were early AMD, 58 （32.41%） were intermediate AMD, 94 eyes （52.51%） were late AMD. Of 94 eyes with late AMD, 79 （84.04%） were neovascular AMD and 15 （15.96%） were central geographic atrophy. In eyes with early and intermediate AMD, 9 patterns of FAF were noted. Six patterns （normal, minimal change, focal increased, patchy increased, linear, reticular） were similar to that in the published classification. Two patterns （lacelike and speckled） described in the published classification were not found. Three new patterns （focal hypo-fluorescence, patchy hypo-fluorescence, mixed focal hypo-fluorescence and hyper-fluorescence） were detected. In eyes with neovascular AMD, 6 morphological patterns of FAF were noted. Two patterns （mixed hypo-fluorescence and hyper-fluorescence, central hypo-fluorescence with hyper-fluorescent rim） were similar to that in published classification. Two patterns （normal, near normal or normal background fluorescence in the centre of hypo-fluorescent area） described in the published classification were not found. Four new patterns （minimal change, hypo-fluorescent patch, central hypo-fluorescence with surrounding reticular, bull’s eye） were recognized. In eye with central geographic atrophy 5 morphological patterns were noted and these were similar to that in published classification.CONCLUSION： Phenotypic differences in the pattern of FAF exist in the study population compared to existing classification systems.

Matrix γ-carboxyglutamate protein and Fetuin-A, in wet type age-related macular degeneration

AIM: To evaluate the high sensitivity C-reactive protein(hs CRP), Fetuin-A and matrix γ-carboxyglutamate protein(MGP) as the main factors for vascular calcification and inflammation in serum of patients with advanced age-related macular degeneration(ARMD) in comparison to healthy controls. METHODS: The subjects were 40 patients with choroidal neovascularization(CNV) having a mean age of70.9 ±9.1y and a matched group of 49 apparently healthy control subjects. The ARMD was diagnosed using a slitlamp with superfield lens, fundus photography and fluorescein angiography. Measurement of hs CRP was done by nephelometry method. Levels of Fetuin-A and MGP were measured by enzyme-linked immunosorbent assay(ELISA) technique.RESULTS: hs CRP [0.45(0.07-2.63) mg/L vs 0.25(0.03-1.2) mg/L, P =0.02)] and Fetuin-A levels(50.27 ±5.04 vs44.99±10.28 ng/m L, P =0.009) were higher in the patients than in the control groups. We could not find significant difference in MGP level between two groups(P =0.08).There was not a significant correlation between MGP with Fetuin-A and hs CRP among the patients(P =0.7, P =0.9respectively). A significant negative correlation of hs CRP with Fetuin-A was observed in both case and control groups(P =0.004, r =-0.33 and P =0.001, r =-0.54,respectively).CONCLUSION: Although our study shows that serum hs CRP and Fetuin-A is increased in CNV patients as well as negatively correlated with both study groups, their direct role on pathogenesis of ARMD required future studies.

A narrative review on the role of abicipar in age-related macular degeneration

In developed countries,age-related macular degeneration(AMD)is the main cause of visual impairment in the elderly.Though the etiology of AMD is still unclear,it has been well understood that vascular endothelial growth factor(VEGF)is involved in the development of aberrant vasculature that represents the neovascular AMD(nAMD).Hence,VEGF inhibition is a more effective way to control nAMD.Pegaptanib,ranibizumab,and aflibercept are three drugs approved by the US Food and Drug Administration(FDA)to treat nAMD.Bevacizumab(an anti-VEGF medication comparable to ranibizumab)is already widely used off label.Existing anti-VEGF medicines are made up of antibodies or pieces of antibodies.Synthetic designed ankyrin repeat proteins(DARPins)imitate antibodies introduced recently by evolutions in bioengineering technology.These agents are designed to have high specificity and affinity to a specific target,smaller molecular size,and better tissue penetration,making them more stable and longer-acting at less concentration.Abicipar pegol(Allergan,Dublin,Ireland)is a DARPin that interlocks all VEGF-A isoforms.It has a greater affinity for VEGF and a longer intraocular half-life than ranibizumab,making it a feasible anti-VEGF agent.This review describes the properties and efficacy of abicipar,the new anti-VEGF agent,in clinical practice,which aims to improve outcomes,safety,and treatment burden of nAMD.

Prediction of the short-term efficacy of anti-VEGF therapy for neovascular age-related macular degeneration using optical coherence tomography angiography

Background To evaluate whether the specific choroidal neovascularization(CNV)characteristics measured using optical coherence tomography angiography(OCTA)can predict the 6-month prognosis of neovascular age-related macular degeneration(nAMD)after anti-vascular endothelial growth factor(anti-VEGF)therapy.Methods Patients with type 1,type 2,or mixed-type neovascularization(NV)were prospectively included.Participants underwent an initial loading phase of three consecutive monthly intravitreal injections of Conbercept(0.5 mg)and were switched to a pro re nata(PRN)treatment strategy.OCTA images were evaluated for eyes that underwent follow-up assessments for more than 6 months.CNV lesions were manually segmented,and the CNV area,vessel area,greatest vascular caliber(GVC),and greatest linear dimension(GLD)were compared between responders and non-responders.Two masked graders independently measured the above-mentioned parameters using OCTA,and consistency was assessed using the intraclass correlation coefficient(ICC)values.Multiple logistic regression analysis was performed to evaluate the effect of a 3-month change in the CNV area,GLD,and GVC on the 6-month response to anti-VEGF agents.Results Among the 60 eyes of 60 patients with nAMD,39 were responders and 21 were non-responders.The proportion of CNV types was significantly different between responders and non-responders(P=0.009).Patients with type 2 or mixed NV seemed more likely to respond to the treatment(28.2%vs.0.0%,and 30.8%vs.23.8%,respectively).The change in GVC showed a significant difference between responders(−4.98±17.17μm)and non-responders(11.01±14.10μm)after three monthly intravitreal anti-VEGF injections.Multiple logistic regression analysis showed that only the change in GVC remained significant after controlling for baseline GVC,injection number,and CNV type(adjusted OR=1.083;P=0.008).Conclusions Type 2 and mixed-type NV were significantly associated with a better response to anti-VEGF therapy.Changes in GVC after 3 months of treatment were significantly associated with a response to anti-VEGF therapy at 6 months.