Correlation Between Macular Function And Characteristics Of Morphological And Microcirculation In Myopic Maculopathy

Myopic maculopathy(MM)with the degenerative changes of choroidal and retinal tissues,is the main cause of visual acuity impairment in pathological myopia(PM).In International Photographic Classification and Grading System,MM lesion was categorized into 5 categories:category 0(no myopic retinal degenerative lesion),category 1(tessellated fundus only),category 2(diffuse chorioretinal atrophy),category 3(patchy chorioretinal atrophy),and category 4(macular atrophy).Plus lesions inclued myopic choroidal neovascularization(mCNV),Lacquer cracks,and Fuchs spot.The classification of MM was based on the imaging manifestations.Understand the pathological changes of macular micro-structure and micro-circulation in different types of MM is helpful to understand the pathogenesis and monitor the progress of pathological condition.Retinal and choroidal tissue is nourished by the corresponding microcirculation,so microcirculation is susceptible to changes in nutritional needs caused by pathological structure.Macular is the main site of MM and the most sensitive area of visual acuity.Therefore,monitoring of macular disease is of great significance for visual acuity assessment.MCNV is a major visual acuity threatening complication of MM.Vascular endothelial growth factor(VEGF)was demonstrated to be important in the pathogenesis of choroidal neovascularization(CNV)and in the development of CNV through its angiogenic activitie.VEGF also displays other biologically relevant activities,such as the physiological effects to induce vascular relaxation and increase ocular blood flow.Apart from the benefit of anti-VEGF agents brought to mCNV,we have no idea whether it is associated with ischemia of retina and choroidal capillaries.Some studies focused on the influence of anti-VEGF agents on sub foveal choroidal thickness(SFCT)of mCNV eyes.However,the results were contradictory.Large studies of Lee have reported good initial efficacy of mCNV eyes for visual acuity improvement by application of intravitreal injection VEGF recently.However,Lee demonstrated that visual acuity decrease gradually,and return to that of before threatment due to CNV-related chorioretinal atrophy developing by long-term follow up.The other related factors affecting the development of CNV-related chorioretinal atrophy have not been reported.At present,the most serious problems we face are the low recognition of mCNV prognosis,and lack of effective measures to prevent macular damage and improve visual function.Optical coherence tomography angiography(OCTA)and multifocal electroretinography(mfERG),as objective assessment tools,has been recently used to characterize macular microvascular morphology and function,but have been rarely reported in previous studies on MM.In conclusion,analysis of macular morphological characteristics and microcirculation,and the correlation between each other and their effects on visual acuity in MM,can provide powerful insight into pathogenesis and disease progression,as well as data support for disease monitoring.In this study,we evaluate the potential adverse effects of anti-VEGF drugs on macular structure and microcirculation of mCNV,and determine whether morphological characteristics and macular function were correlated with prognoses to provide predictive indicators.Part1:Association between visual acuity and changes of macular structure and microcirculation in myopic maculopathy PurposeThe purpose of the present study was to compare macular morphological and microcirculatory parameters of MM to normal individuals.To assess the association between morphological parameters and microcirculatory parameters,and their correlation with AL and SE,and their effect on visual acuity.To compare macular retinal thickness of control group to normative database.MethodsThe present study included high myopia eyes(189 eyes,165 subjects)and healthy eyes(52eyes,52subjects)as control.The International Photographic Classification and Grading System for MM were adopted in the analysis of color fundus photos in high myopia eyes,which were divided into four groups according to category of MM:MO group(category 0,41 eyes),M1 group(category 1 without CNV,53 eyes),CSMM group(category 2 or greater without CNV,52 eyes),mCNV group(43 eyes).At baseline,all participants received ophthalmologic examinations including spherical equivalent(SE),axial length(AL)and best-corrected visual acuity(BCVA).Furthermore,all participants were tested by means of OCTA.A 3 × 3-mm scanned area centered on the fovea was used by Angio Retina 3.0 mm program.Superficial capillary plexus vessel density(SVD),deep capillary plexus vessel density(DVD),full retinal thickness(FRT),inner retinal thickness(IRT)and outer retinal thickness(ORT)in fovea,parafovea and four quadrants of parafovea were automatically generated by the instrument.The involved parameters of foveal avascular zone(FAZ)included FAZ area,the length of FAZ and fovea vessel density(FVD).The involved parameters of choroid included choroidal capillary vessel density(CVD)and SFCT.The measurements of VD,vessel skeleton density(VSD)and vessel diameter index(VDI)in superficial capillary plexus(SCP)and deep capillary plexus(DCP)of macular(3 x 3-mm scanning area)were made on ImageJ.Fractal dimension(FD)was made on Fractalyse.Results1.Comparison of thickness and microcirculation of individual macular retinal layers in each groupCompared to control group,the present study revealed decreased foveal FRT andORT in M0,M1 and CSMM groups(P<0.0001,respectively),decreased foveal SVD and DVD in CSMM and mCNV groups(P<0.001,respectively),decreased FRT and ORT in parafovea and four quadrant of parafovea in M0,M1,CSMM and mCNV groups(P<0.0001,respectively),decreased IRT,SVD and DVD in parafovea and four quadrant of parafovea in CSMM and mCNV groups(P<0.0001,respectively),decreased VD,VSD and FD of superficial capillary plexus and deep capillary plexus in macular in CSMM and mCNV groups(P<0.0001,respectively),decreased FAZ area,the length of FAZ and FVD in mCNV group(P<0.01,respectively).2.Comparison of thickness and vessel density of individual retinal layers in fovea and parafoveaCompared to parafovea,the present study revealed significantly decreased foveal FRT,IRT,SVD and DVD in all groups(P<0.05,respectively),significantly thicker foveal ORT in mCNV group(P<0.05).3.Comparison of microcirculation in superficial capillary plexus and deep capillary plexusFoveal DVD was significantly increased compared to foveal SVD in all groups(P<0.001,respectively).Compared to superficial capillary plexus,the present study revealed increased VSD and decreased VDI of deep capillary plexus in macular in all groups(P<0.001 and P<0.05,respectively).Parafoveal DVD was significantly increased compared to parafoveal SVD in CSMM and mCNV groups(P<0.01,respectively).4.Comparison of SFCT and CVD in each groupCompared to control group,the present study revealed significantly decreased SFCT and CVD in choroidal capillary layer in M0,M1,CSMM and mCNV groups(P<0.0001,respectively).5.Correlation analysisIn control group:Foveal retinal vessel density showed significantly positive correlations with retinal thickness(P<0.001);CVD showed significantly positive correlations with SFCT(P<0.05);Parafoveal retinal thickness,foveal and parafoveal vessel density,FAZ parameters,CVD and SFCT showed significantly negative correlations with age(P<0.01,respectively).In myopic maculopathy without CNV:Vessel density in foveal retina and choroid showed significantly positive correlations with corresponding thickness(P<0.05,respectively);Vessel density and thinckness in parafoveal retina and choroid showed significantly negative correlations with AL,significantly positive correlations with SE(P<0.05,respectively);In multivariate regression analyses,BCVA significantly correlated with AL,parafoveal FRT,SFCT,and diffuse or patchy chorioretinal atrophy(P<0.05,respectively).In mCNV group:foveal SVD showed significantly positive correlations with foveal IRT(P<0.0001);Foveal DVD showed significantly negative correlations with foveal FRT and ORT(P<0.05,respectively),significantly positive correlations with foveal IRT(P<0.0001);CVD showed significantly positive correlations with SFCT(P<0.05);The same parafoveal correlation analysis was found in mCNV group and myopic maculopathy without CNV;In univariate regression analyses,BCVA significantly correlated with foveal FRT and ORT(P<0.01,respectively).6.Comparison of macular retinal thickness in control group and normative database(NDB)Compared to NDB,the present study revealed significantly decreased FRT in parafovea and four quadrants(P<0.0001,respectively).Both NDB and our study have documented males have thicker macular retinas than females.ConclusionMacular morphology and microcirculation characteristic in MM:1.Degenerative changes occured in macular retinal and choroid in MM with retinal morphological changes preceding microcirculation changes.Most of all,ORT changes precede IRT changes.2.Microvascular damage in MM was characterized by a decrease in vascular skeleton structure rather than a change in the diameter of vessel.FAZ parameters remained statistically unchanged in MM without CNV compared to control group.3.The distribution characteristics of vessel density were similar between MM and healthy subjects.Parafoveal vessel density significantly increased compared to foveal vessel density.Vessel density of DCP significantly increased compared to SCP.Compared to SCP,the present study revealed significantly increased VSD and significantly decreased VDI of DCP in macular.4.Vessel density in foveal retina and choroid showed significantly positive correlations with corresponding tissue thickness.With the extension of AL and the decreasing degree of SE,vessel density and tissue thickness in parafoveal retina and choroid siginificently decreased.5.In MM without CNV,BCVA significantly correlated with diffuse chorioretinal atrophy,foveal FRT,foveal SVD and AL.BCVA significantly correlated with foveal FRT and ORT in mCNV group.6.The application of OCTA provide a useful approach for monitoring macular thickness and perfusion,and caution must be exercised with regard to age-,sex-,and SE-related variations.Part2:Effects of ranibizumab on macular microcirculation and structure of myopic choroidal neovascularization Purpose:To evaluate the therapeutic effect on choroidal neovascularization(CNV)and the changes of microcirculation and tissue thickness parameters of macular retina and choroid after anti-VEGF therapy on mCNV by using OCTA.Methods:This prospective study included 34 eyes of 30 consecutive patients with mCNV who visited Qilu Hospital of Shandong University between October 2016 and December 2018.All patients were treated with IVR and followed by pro-re-nata(1+PRN)injection.All patients had undergone follow-up examinations for 6 month.Every patient was examined by OCTA before treatment,1 month,3 months and 6 months after treatment.The involved parameters included the same parameters as the first part,CNV area,CNV flow area,and the greatest linear dimension(GLD)of CNV was measured in outer retina images.Continuous variables at baseline,one month,3 months and 6 months after treatment were compared with repeated measuresment.Results:The anti-VEGF treatment revealed improved BCVA(P<0.0001),decreased CNV area,flow area,GLD and CVD(P<0.0001,respectively)1 month,3 months and 6 months after treatment.Foveal FRT,ORT and SFCT revealed significant decrease(P<0.05,respectively)after treatment.No changes were presented on SVD and DVD in fovea and parafovea(P>0.05,respectively),VD,VSD,VDI and FD of SCP and DCP in macular(P>0.05,respectively),foveal IRT,parafoveal FRT,IRT and ORT,FAZ area,the length of FAZ and FVD after anti-VEGF treatment(P>0.05,respectively).Conclusion:1.Ranibizumab was found safe and effective in patients with mCNV,with significantly decreased foveal ORT.2.OCTA was sensitive and intuitive for evaluating and monitoring the therapeutic effect in mCNV with small lesions.3.No significant changes were presented on macular microcirculation,FAZ parameters and parafoveal retina thicknes after IVR.4.The anti-VEGF therapeutics revealed significantly decreased CVD and SFCT after ranibizumab treatment.Part3:Correlation between prognoses and macular function and morphological characteristics in myopic choroidal neovascularizationPurpose:To quantitatively evaluate the changes of macular function and morphological characteristics after intravitreal injection of ranibizumab(IVR)on mCNV by using mfERG and OCTA.Methods:This prospective study included 56 eyes of 53 consecutive patients with mCNV who visited Jinan Mingshui Eye Hospital between September 2014 and December 2018.All patients were treated with IVR followed by pro-re-nata(1+PRN)intravitreal injection of ranibizumab and had been follow-up for 24 months.At baseline,all participants received ophthalmologic examinations including slit-lamp biomicroscopy examinations,best-corrected visual acuity(BCVA),dilated fundus examination by pre-place-mirror,spectral-domain optical coherence tomography(SD-OCT),fundus fluorescein angiography(FFA),color fundus photography and mfERG.Every patient was examined by color fundus photography,SD-OCT,and mfERG before treatment,1 month,3 months,6 months,12 months and 24 months after treatment.Results:1.Changes of BCVA,mfERG and SD-OCT featuresThe anti-VEGF treatment revealed improved BCVA,N1 amplitude density and P1 amplitude density of 1-2 ring(P<0.0001,respectively),significantly decreased CMT,GLD and SFCT 1 month,3 months,6 months,12 months and 24 months after treatment(P<0.0001,respectively).No significant changes were presented on N1,P1 amplitude density of 4-6 ring,and N1,P1 latencies of 1-6 ring(P>0.05,respectively).2.Correlation between BCVA and mfERT,SD-OCT featuresBaseline N1 amplitude density of 1-2 ring showed significantly negative correlations with baseline GLD(P<0.0001).Baseline mfERG latency was not correlated with baseline SD-OCT features(P>0.05).Baseline BCVA showed significantly negative correlations with baseline N1 amplitude density of 1-2 ring(P<0.01),and baseline CMT(P<0.001).3.Factors associated with prognosesIn multivariate regression analyses:Final BCVA was associated with baseline BCVA,recurrence,baseline N1 amplitude density of 1-2 ring,and CNV-related chorioretinal atrophy(P<0.05,respectively);Final GLD was associated with baseline GLD and recurrence(P<0.01,respectively).In binary logistic regression analysis:Recurrence was associated with baseline GLD(P<0.05);The progress of CNV-related chorioretinal atrophy was associated with baseline GLD and recurrence(P<0.05,respectively).In regarding generalized linear model(GLM)analyses,number of injections was associated with recurrence(P<0.001).Conclusion:1.Ranibizumab was effective in treating patients with mCNV,with significantly improved macular function.2.Better BCVA and higher mfERG amplitude density at baseline,without recurrence and CNV-related chorioretinal atrophy progress may indicate better BCVA outcome after anti-VEGF treatment in eyes with myopic CNV.3.Larger baseline GLD and recurrence may indicate poor anatomic outcome after anti-VEGF treatment in eyes with myopic CNV.4.Larger baseline GLD and recurrence are the strongest predictors of CNV-related chorioretinal atrophy progress and poor BCVA outcome.