| Retinopathy of prematurity(ROP)is a proliferative disease of retinal vascular tissues in premature and low birth weight infants.It is the leading cause of childhood blindness worldwide.At present,most of the prevention and control efforts are done based on indirect ophthalmoscopy or wide-angle digital retinal imaging system.However,they are insufficient to judge the retinal vascularization during the occurrence,development,and regression of ROP,and the severity of the disease and the changes during follow-up determined by the basic-level medical units is not accurate enough.Fundus fluorescein angiography(FFA)under general anesthesia designed for pediatric patients can provide more useful information regarding retinal and choroidal vasculature in ROP.FFA has been shown to be critical in ROP diagnosis,treatment guidance,efficacy evaluation,and follow-up.Therefore,it is necessary to systematically study the application of FFA in ROP,establish an acute ROP grading system based on FFA,and clarify the criteria for the evaluation of regression of ROP and treatment efficacy evaluation with the help of FFA,to have a deeper understanding the changes of ROP,to provide a basis for the development of scientific and efficient diagnosis,treatment,and follow-up strategies for ROP,and improve the efficacy of ROP prevention and treatment.PartⅠ.Development and validation of a diagnostic classification model for acute-phase retinopathy of prematurity based on fundus fluorescein angiographyObjective:To observe the characteristics of FFA in acute-phase ROP,analyze the diagnostic indicators related to the need for treatment of acute ROP,and to develop and validate the diagnostic classification model.Methods:A total of 227 eyes of 114 infants with acute ROP who underwent FFA from April 2018 to January 2022 in the Department of Ophthalmology of Xijing Hospital,were retrospectively included.Retinal vessel morphology of the posterior pole and FFA characteristics of the junction between vascular-avascular retina,within the vascularized retina,and in the macular area,were summarized.The location of the lesion was determined by the ratio between the distance of the center of the disc to the border of the lesion closest to the posterior pole(DB)and distance from the center of the disc to the fovea(DF).The children were randomly divided into the training set(160 eyes of 80infants)and the validation set(67 eyes of 34 infants)at a ratio of 7:3.Univariate and multivariate logistic regression analyses were performed to analyze the independent risk factors for treatment-requiring ROP in the training set,the diagnostic classification model and the nomogram was further developed.The receiver operating characteristic curve and area under the curve(AUC)was used to evaluate the model discrimination in the training and validation set.Results:Among the 227 eyes with acute ROP who underwent FFA under general anesthesia,the FFA characteristics are as follows:(1)without obvious dilation and tortuosity,mild dilation and tortuosity,and dilation and tortuosity in the posterior retinal area were detected in 132 eyes(58.15%),57 eyes(25.11%),and 41 eyes(18.06%).(2)At the junction between vascular-avascular retina,dilation and tortuosity of the posterior ridge vessels was present in 84 eyes(37.00%).Mild,moderate,and severe dye leakage were observed in 106 eyes(46.70%),90 eyes(39.65%),and 31 eyes(13.66%).The"popcorn"lesions,abnormal branching of vessels,and circumferential vessels were present in 40 eyes(17.62%),189 eyes(83.26%),and 96 eyes(42.29%).(3)It was noted that capillary bed loss in the peripheral retina shown in 134 eyes(59.03%),and areas of hypofluorescence appeared in 21 eyes(9.25%)within the vascularized retina.(4)In the macular area,the decrease or absence of foveal avascular zone,hypoperfusion,and dye leakage in the macula was present in 65 eyes(28.63%),184 eyes(81.06%),and 62 eyes(27.31%).The mean DB/DF ratio of all 227 eyes on the temporal side was 3.65±0.42 and3.16±0.36 in the nasal.In the analysis of risk factors related to treatment-requiring ROP,the results of univariate and multivariate logistic regression analysis showed that:retinal vessel morphology of the posterior pole(mild vessel dilation and tortuosity,OR=8.545,95%CI:2.536-28.792,P=0.001;vessel dilation and tortuosity,OR=115.796,95%CI:10.248-1308.408,P<0.001),dilation and tortuosity of the posterior ridge vessels(OR=5.159,95%CI:1.801-14.777,P=0.002),dye leakage(moderate leakage,OR=2.327,95%CI:0.809-6.694,P=0.117;sever leakage,OR=43.79,95%CI:7.039-272.426,P<0.001),capillary bed loss(OR=4.98,95%CI:1.58-15.698,P=0.006),and the DB/DF ratio in the temporal(OR=0.166,95%CI:0.042-0.657,P=0.010)were independent risk factors for treatment-requiring ROP.The diagnostic classification model for acute-phase ROP was developed,and the nomogram was drawn based on the above risk factors.The AUC in the training and validation sets was 0.936(95%CI:0.900～0.972)and 0.950(95%CI:0.904～0.996),respectively.The calibration plots showed excellent calibration of the nomogram.The DCA revealed that the model provided a positive net benefit at nearly all threshold probabilities.Conclusion:A variety of FFA characteristics may exist in acute ROP,such as dilation and tortuosity of vessels,dye leakage,and capillary bed loss.It can provide a reference for the interpretation of FFA images of ROP.The diagnostic classification model for acute-phase ROP based on FFA exhibits good diagnostic performance and provides evidence for clinical decision-making.PartⅡ.Evaluation of retinal vascularization in retinopathy of prematurity based on fluorescein angiographyObjective:To investigate the fluorescein angiography(FFA)findings and analyze the extent of retinal vascularization in retinopathy of prematurity(ROP),recovered after anti-vascular endothelial growth factor(VEGF)monotherapy and those regressed spontaneously,and to evaluate the date distribution of the extent of retinal vascularization after regression of ROP.Methods:A total of 110 eyes of 55 infants receiving intravitreal injection of ranibizumab(IVR)treatment(IVR group)and 76 eyes of 38 infants that regressed spontaneously without treatment(untreated group)who underwent FFA in the Department of Ophthalmology of Xijing Hospital between January 2019 and November 2021 were retrospectively included.The common FFA characteristics of regression of ROP were systematically summarized.The extent of retinal vascularization was determined by the ratio between the distance of the center of the disc to the border of the vascularized zone(DB)and the center of the disc to the fovea distance(DF).The width of the persistent avascular retina(PAR)in the temporal retina was counted by disc diameter(DD).The DB/DF ratio and PAR were employed to measure the extent of retinal vascularization after the completion of regression.The initial location of the temporal lesion(from the center of the optic disc to the initial demarcation line or ridge through the fovea)was noted by DD on the fundus images before treatment or the onset of spontaneous regression,and the final vascular termini after completion of regression were recorded in the same way on FFA.The progression of retinal vascularization was measured by the difference between the two measurements.The differences between the two groups,the difference between the two groups in zoneⅡROP,the difference between zoneⅠand zoneⅡROP in the IVR group,and the difference between zoneⅡand zoneⅢROP in the untreated group were all compared.Results:1.The FFA characteristics and measurement of retinal vascularization of ROP following IVR.(1)FFA characteristics:(1)The linear choroidal pattern was present in 10eyes(18.18%);(2)In the posterior retinal:tortuosity of arteries without venous dilation was detected in 33 eyes(30.00%);(3)In areas from the initial ridge to vascular termini after retinal vascularization ceased:it was noted that dye leakage appeared in 32 eyes(29.09%),increased branching of vessels presented in 72 eyes(65.45%),straight shape of vessels shown in 56 eyes(50.90%),circumferential vessels arisen in 64 eyes(58.18%),arteriovenous(AV)shunt,appeared in 27 eyes(24.54%),and abnormal capillary bed shown in 56 eyes(50.91%);(4)In the macular area:macular abnormalities were observed in 34 eyes(39.09%).(2)Measurement of retinal vascularization:the mean DB/DF ratio on the temporal side was 4.48±0.36 and 3.73±0.22 in the nasal.The mean avascular area on the temporal retina and progression of retinal vascularization were(2.63±1.16)DD and(2.59±1.23)DD.The width of PAR>2.0 DD was detected in 63 eyes(57.27%).2.The FFA characteristics and measurement of retinal vascularization of ROP regressed spontaneously.(1)FFA characteristics:The linear choroidal pattern was present in 7 eyes(18.42%);tortuosity of arteries over the posterior pole was detected in 28 eyes(36.84%);Dye leakage,increased branching of vessels,straight shape of vessels,circumferential vessels,AV shunt,and abnormal capillary bed were noted in 23 eyes(30.26%),43 eyes(56.58%),27 eyes(35.53%),40 eyes(52.63%),16 eyes(21.05%),and 41 eyes(53.95%);Macular abnormalities were observed in 28 eyes(36.84%).(2)Measurement of retinal vascularization:the mean DB/DF ratio on the temporal side was 4.63±0.29 and 3.78±0.23in the nasal.The mean avascular area on the temporal retina and progression of retinal vascularization were(1.76±1.00)DD and(1.23±1.10)DD.The width of PAR>2.0 DD was detected in 25 eyes(32.89%).3.Comparison of FFA characteristics and measurement of retinal vascularization.The straight shape of vessels in the IVR group was more common than that in the untreated group,the difference was statistically significant(χ~2=4.304,P=0.038).Compared with the untreated group,the DB/DF ratio in the temporal retina was smaller(t=-3.061,P=0.003),the width PAR and progression of retinal vascularization were more significant(t=5.332,P<0.001;t=5.152,P<0.001)in the IVR group.The progression of retinal vascularization of zoneⅡROP in the IVR group was greater than that in the untreated group,with statistically significant difference(t=3.032,P=0.003).Compared with ROP in zone II,increased branching of vessels,the straight shape of vessels,and the width of PAR>2.0 DD were more common(χ~2=4.626,11.501,15.730;P=0.031,0.001,P<0.001),and the width of PAR and the progression of retinal vascularization were more significant(t=3.098,4.052;P=0.002,P<0.001)in zoneⅠROP of the IVR group.Compared with ROP in zoneⅢ,dye leakage,increased branching of vessels,abnormal capillary bed,and the width of PAR>2.0 DD were more common(χ~2=9.976,11.346,4.039,9.221,P=0.002,0.001,0.044,0.002;t=4.896,P<0.001),and the width of PAR was more significant(t=4.896,P<0.001)in zone II ROP of the untreated group.4.The DB/DF ratios of 95%of eyes in the IVR group were greater than 3.89 on the temporal retina and 3.37 in the nasal,while the DB/DF ratios of 95%of eyes in the untreated group were greater than 4.15 on the temporal side and 3.40 in the nasal.Conclusion:As well as a wide variety of extent of retinal vascularization,increased branching of vessels,circumferential vessels,straight shape of vessels,and abnormal capillary bed are the main FFA characteristics in ROP regressed after IVR or without treatment.The vascular abnormalities,the extent of retinal vascularization,and the residual PAR may be related to ROP itself,which are common results of ROP regression.Combined with the statistical results,clinical practice,and zone of ROP,the DB/DF ratio of 4.0 temporally and 3.3 nasally could be the preliminary indicators of the safe extent of retinal vascularization in ROP regression.SummaryIn the present study,the large sample clinical data of infants with ROP in the acute-phase,regressed spontaneously or treated with anti-VEGF agent,who underwent FFA were systematically reviewed.The characteristics of FFA in acute-phase ROP were summarised,and the diagnostic classification model for acute-phase ROP based on FA was established.The nomogram exhibits good diagnostic performance and has a certain application value in clinical.The manifestations of retinal vascularization in ROP following anti-VEGF monotherapy and those regressed spontaneously were further analyzed and compared.In addition,we provided the preliminary indicators of the safe extent of retinal vascularization in ROP regression.These findings may serve as a reference for developing follow-up plans. |
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