Optical coherence tomography angiography of myopic choroidal neovascularization treated by anti-VEGF therapy

Background: To analyze the efficiency of anti-vascular endothelial growth factor (anti-VEGF) therapy for myopic choroidal (CNV) by optical and to determine the reduction ratio of CNV lesions after anti-VEGF therapy. Methods: A total of 41 patients (41 eyes) with myopic CNV who were treated with anti-VEGF were included in the study. The best corrected visual acuity (BCVA), superficial vessel density, deep vessel density, the area of foveal avascular zone (FAZ), central macular thickness (CMT) and the area and the flow area of CNV lesion at baseline and at the follow-up after 1, 2, 3 and 6 months were measured. Results: After treatment, BCVA improved (F=6.848, P<0.05), while the CMT (F=2.489, P<0.05), the area (F=3.125, P<0.05) and the flow area (F=3.558, P<0.05) of CNV lesion reduced. On the other hand, superficial vessel density, deep vessel density and the area of FAZ had no change. The mean reduction ratio of lesions was 50.32% (7.07% to 100%). Only in two cases, 100% lesion regression was observed (4.88%). There was a negative correlation between the CNV lesion area and reduction ratio (r=–0.380 P=0.042) and the flow lesion area and reduction ratio (r=–0.402, P=0.030). Conclusions: Anti-VEGF therapy is efficient for myopic CNV without affecting superficial vessel density and deep vessel density of retina, but it is unable to completely eliminate CNV lesions in most cases. The mean reduction ratio is 50.32%, and the bigger myopic CNV lesions have a lower reduction ratio.

There was a negative correlation between the CNV lesion area and reduction ratio (r=-0.380 P=0.042) and the flow lesion area and reduction ratio (r=-0.402, P=0.030). Conclusions: Anti-VEGF therapy is efficient for myopic CNV without affecting superficial vessel density and deep vessel density of retina, but it is unable to completely eliminate CNV lesions in most cases. The mean reduction ratio is 50.32%, and the bigger myopic CNV lesions have a lower reduction ratio.

Background
Myopic choroidal neovascularization (CNV) is defined as CNV secondary to pathologic myopia (refractive error −6D or axial length 26 mm, associated with complications of the posterior segment secondary to excessive elongation of axial length), which has great impairment in vision and may cause legal blindness. Individuals (5.2%-11.3%) with pathologic myopia may develop myopic CNV, and approximately 15% of patients have bilateral CNV lesions.
Fundus fluorescein angiography is the standard examination and is most commonly used to evaluate myopic CNV; however, it's an invasive and time-consuming examination that has some risks for patients, such as anaphylactic shock. Optical coherence tomography angiography (OCTA) performs scans of areas of retinal tissue and constructs microvascular flow maps to evaluate the flow in various layers of the retina free of an injected dye. Various studies compared OCTA and fluorescein fundus angiography (FFA) and reported the potential of OCTA to diagnose and evaluate CNV. ,, Anti-vascular endothelial growth factor (Anti-VEGF) therapy is an efficient therapy for myopic CNV. As a noninvasive and fast technique, OCTA is more commonly applied during the follow-up after anti-VEGF therapy. Several studies assessed the anti-VEGF therapy for myopic CNV by OCTA. Cheng, Y. et al. demonstrated that the size of the CNV area and flow area decreased after the intravitreal administration of Ranibizumab for 1week and 1 month in 13 eyes. Gilda, C. et al. followed up 20 eyes and found that the neovascular area but not the vessel density by OCTA was decreased after Ranibizumab therapy for 6 months. Cai, M. et al. compared the changes at 1, 3 and 6 months after treatment and revealed a progressively smaller vascular lesion and reduction in capillary density of lesion. All these studies proved the reduction in the area of CNV lesion after treatment. However, there are only a few studies on the reduction ratio of CNV lesions and whether they will completely disappear after anti-VEGF therapy. Our study is designed to follow-up before and until 1, 2, 3 and 6 months after anti-VEGF treatment to know the variation tendency of CNV lesions better.
We aim to measure the vessel density and the area of myopic CNV lesion by OCTA, analyze the reduction ratio of CNV lesions and the relationship between visual acuity and determine the reduction ratio of CNV lesions to investigate the efficiency of anti-VEGF treatment for myopic CNV after Statistical analyses were performed using SPSS version 19.0 (SPSS 19.0, Inc., Chicago, IL). All data were expressed as mean ± standard deviation. Serial changes in LogMAR BCVA, superficial vessel density, deep vessel density, CMT, the area of FAZ, the area and the flow area of CNV lesion and CMT were compared using one-way ANOVA. The relationship between different parameters was evaluated using Pearson's correlation. Comparison of two groups (CNV area before treatment 0.5mm²and ≤0.5mm²) was used independent t-test. A P-value of less than 0.05 was considered statistically significant.   (Fig. 4). The difference between the area (F=3.125 P<0.05) and flow area (F=3.558 P<0.05) of the CNV lesion at baseline and at each follow-up was statistically significant. However, there was no difference between 1, 2, 3 and 6 months follow-up. Although the area of the CNV lesion reduced after injection, in most patients (95.12%), it didn't disappear even when its activity had been controlled. The mean reduction ratio of lesions was 50.32% (7.07% to 100%). In only two cases, 100% lesion regression was observed (4.88%).

T-test
We divided the patients into two groups according to the CNV area before treatment ( 0.5mm²and ≤0.5mm²). The reduction ratio in the two groups was compared using independent t-test (t=2.136, P=0.042). The reduction ratio in the group with preoperative CNV area 0.5 mm² was smaller than the other group.

Correlation analysis
The Pearson correlation analysis showed the negative correlation between the area of the CNV lesion and the reduction ratio r=-0.380 P=0.042) and between the flow lesion area and the reduction ratio (r=-0.402, P=0.030). It means the bigger the CNV lesion is, the lower is the reduction ratio. There is no significant difference between the reduction ratio and other factors, such as age, LogMAR BCVA and CMT before treatment and the improvement of BCVA. Case 1. In a 33-year-old female with myopia CNV in the right eye, the refraction of myopia was -7.0 D and the LogMAR BCVA was 0.1. The lesion disappeared completely after one intravitreal Ranibizumab injection, and the LogMAR BCVA was improved to 0 (Fig. 5).
Case 2. In a 58-year-old female with myopia CNV in the right eye, the refraction of myopia was -9.5 D and the LogMAR BCVA was 0.7. The lesion just became smaller but still existed after three times intravitreal Conbercept injection, and the LogMAR BCVA was improved to 0.15 (Fig. 6).

Discussion
Our study found that anti-VEGF therapy could not eliminate the myopic CNV lesions completely in most cases (95.12%) at 6 months after treatment. The mean reduction ratio of lesions of 41 patients was 50.32% (varying from 7.07% to 100%). CNV is affected by various factors, such as interleukin 8 IL8 ; monocyte colonization protein MCP , etc. Simple anti-VEGF probably can't block all the factors that induce CNV. New treatments, such as anti-VEGF associated with other factors antagonists, are needed to be studied in the future.
There were two cases (4.88%) who reached complete disagreement of CNV lesions at 6-month followup. In both cases, the CNV lesions at baseline were relatively small (0.076 and 0.222 mm²) and the patients were young (26 and 33 years old). We speculate that the size of lesions and the age of patients may be the factors related to the complete regression of the lesions. According to the Pearson correlation analysis, we found that the smaller lesions would regress more r=-0.380 P=0.042). According to independent t-test, the reduction ratio in the group with preoperative CNV area 0.5 mm² was smaller than the other group.
Previous research studies on the treatment for CNV secondary to AMD by OCTA found that anti-VEGF therapy only prunes subtle small newly growing vessels and does not achieve vascular normalization. ,, Cheng, Y. et al. researched myopic CNV and found attenuation in capillaries and small caliber feeder vessels but not in large caliber feeder vessels treated by intravitreal Ranibizumab. 8 We guess the reasons for larger lesions leading to a lower reduction ratio are as follows: (1) larger lesions more likely have bigger feeder vessels that are more difficult to clear up; (2) larger lesions are more likely to be old lesion whose feeder vessels have been formed that are difficult to regress. There is no correlation between the lesion area and age. Maybe those two young persons had a better consciousness of visiting clinic leading to earlier treatment and better prognosis. Besides, we didn't find other factors that are related to the regression rate; thus further studies are needed.
In this study, the VA of patients improved after treatment, which proved the positive effect of anti -VEGF on myopic CNV. The change of VA had no relationship with the reduction ratio. We suspected that the VA was affected by various factors, such as age, axial, former fundus condition, duration of myopic CNV, etc. We didn't perfectly control these variables of the patients enrolled in our study. It is not enough to prove that visual acuity and reduction ratio are irrelevant. We also analyzed the other parameters measured by OCTA to investigate the efficiency of anti-VEGF. The CNV lesion area, the flow area of CNV lesion and CMT reduced mostly at the first month after injection and was stable in the following 5 months, which indicates that the anti-VEGF therapy is mainly effective during the first month. The FAZ, superficial vessel density and deep vessel density didn't change before and after treatment.
There are some limitations to this study. The number of patients enrolled was relatively small. The type of anti-VEGF therapy used was not identical for all the patients, the efficiency of Ranibizumab and Conbercept might be different. Thus, further studies may expand the number of samples and carry out control studies of Ranibizumab group and Conbercept group.

Conclusion
Anti-VEGF therapy is efficient for myopic CNV without affecting superficial vessel density and deep vessel density of retina but unable to eliminate CNV lesions completely in most cases, the the mean reduction ratio is 50.32%, the bigger myopic CNV lesions have lower reduction ratio. Further studies are needed to find new treatments to cure myopic CNV.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.   Figure 1 The tendency of LogMAR BCVA. The error bars represent the standard error of the mean value.

Figure 3
The tendency of the area of CNV lesion. The error bars represent the standard error of the mean value.

Figure 4
The tendency of the flow area of CNV lesion. The error bars represent the standard error of the mean value.