The Neovascular Signal of Myopic Choroidal Neovascularization from Perforating Scleral Vessel Prone to Recur after Anti-VEGF therapy

doi:10.21203/rs.3.rs-2010260/v1

Download PDF

Article

The Neovascular Signal of Myopic Choroidal Neovascularization from Perforating Scleral Vessel Prone to Recur after Anti-VEGF therapy

https://doi.org/10.21203/rs.3.rs-2010260/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objectives: To analyzed the recurrence of myopic choroidal neovascularization (mCNV) based on the neovascular signal from perforating scleral vessel (PSV) by optical coherence tomography angiography (OCTA) after anti-vascular endothelial growth factor (anti-VEGF) therapy.

Methods:A consecutive series of naïve patients with mCNV accepted anti-VEGF therapy with a minimum 12-month follow-up period. The location of PSV with CNV were classified into PSV adjacent to CNV or not by B scan and the flow signal of CNV was classified into the neovascular signal of CNV from PSV or not by OCTA. The recurrence of mCNV in various PSV with CNV types were compared. K-M survival and Cox proportional hazard model analysis were used to identify risk factors associated with recurrence of mCNV.

Results: PSVs were found in 59 of 63 eyes (93.7%) with mCNV in the macular region. The eyes with presence of neovascular signal of CNV from PSV were detected 25 eyes (39.7%). The overall mCNV recurrence rate was 46.0% (29/63) during the follow-up period. According to K-M analysis, the presence of neovascularization with mCNV from PSV predicted a higher recurrence of 60% and a shorter recurrent duration (χ2 =4.486, P=0.034). The Cox proportional hazard model demonstrated that the presence of neovascularization with mCNV from PSV was an independent risk factor for recurrence (HR: 2.19, 95%Cl 1.04-4.62).

Conclusions:PSV was mainly detected with mCNV. When the neovascularization of the mCNV comes from PSV, it has a greater recurrence rate with a shorter recurrence duration.

Perforating scleral vessel

Choroidal neovascularization

pathological myopia

Anti-VEGF therapy

Optical coherence tomography

Myopic choroidal neovascularization (mCNV) is one of the complications of pathologic myopia (PM), commonly resulting in severe visual impairment[1]. The natural course of long-term visual outcomes in patients with mCNV is unfavorable. Most patients with mCNV experience a decline in visual acuity (VA) to 20/200 or below in five to ten years following the onset with the development of CNV-related macular atrophy[2]. Currently, intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection is the first-line treatment for mCNV [3]. Recent clinical trials have shown that anti-VEGF therapy is safe and can considerably increase visual acuity in patients with mCNV [1, 4]. Rebleeding of mCNV was reported in 15–20% patients at the follow up of 10 years without treatment. However, even after treatment, 29.4%-46.1% patients with mCNV frequently recur [5–7]. The thinner choroid thickness and larger CNV size were considered as the factors for recurrence after anti-VEGF treatment[8, 9].

The latest study proposed that mCNV was closely related to perforating scleral vessels. PSVs was detected in 80% of mCNV[10]. Ohno-Matsui’s study reported that CNV in pathological myopia had a connection with short posterior ciliary arteries[11]. Querques et al speculated that the scleral dilatation at the location of the perforating vessels may play a role in the formation of lacquer crack, and lacquer crack is a risk factor for CNV [12]. Further study was reported that patients with mCNV and PSV need more injections and a higher recurrence rate than mCNV without PSVs[13]. The role of PSVs in mCNV was not clear.

In our earlier study, we found that when PSVs adjacent to mCNV, the VA outcome was poor. It was unclear whether the location and flow signal of PSVs with mCNV were related to recurrence. Therefore, in this study, we analyzed the location of PSVs with CNV in B-scan and analyzed the neovascular signal of mCNV is from PSV or not by OCTA and tried to find their clinical significance with recurrence of mCNV after therapy.

This retrospective study was performed at the Eye Hospital of Wenzhou Medical University in China. The study was approved by the Ethics Committee of Eye Hospital of Wenzhou Medical University, Zhejiang Province, China, and followed the tenets of the Declaration of Helsinki. The medical records of patients who visited Eye Hospital of Wenzhou Medical University between January 2017 and December 2021 were reviewed. All patients were informed the details of the research and agreed to sign a written general consent to participate in observational studies.

The inclusion criteria were followed: (1) Meet the criteria of pathological myopia: The refractive error (spherical equivalent) is less than − 6.00 Diopter or the axial length is more than 26.00 mm, with typical sclera, choroid and retina degeneration; (2) Existence of active CNV: comprehensive interpretation of fundus photography, optical coherence tomography (OCT), optical coherence tomography angiography (OCTA) and fluorescein angiography (FA); (3) The first anti-VEGF therapy was performed in this hospital. (4) Follow-up time ≥ 12 months. The exclusion criteria were followed: (1) At the first diagnosis, CNV was in the stage of scar or atrophy; (2) CNV was secondary to other diseases, such as punctate internal choroid disease, multifocal choroiditis, age-related macular degeneration; (3) During the follow-up period, the eyes that underwent internal eye surgery in addition to anti-VEGF therapy; (4) Combining with severe posterior segment complications, such as retinal detachment or macular hole; ( 5) Previous history of anti-VEGF therapy in other institutions; (6) CNV outside a 3×3 mm² on OCTA image, or CNV too large to fit within the 3×3 mm² area.

The age, sex, best-corrected VA (BCVA) and refractive error were collected from the medical records of the initial examination. The dilated fundus examination that included indirect ophthalmoscopy, color fundus photography (TRC-50DX, Topcon Corporation, Tokyo, Japan) or confocal scanning laser ophthalmoscopy (cSLO; Optos Daytona, Optos, England), structural SD-OCT (Spectralis SD-OCT; Heidelberg Engineering, Germany), and OCTA (Angio OCT; Optovue, Fremont, America) were performed. BCVA, OCTA and OCT were recorded before treatment, 6 months after treatment,12 months after therapy and the last visit. Central macular thickness (CMT), subfoveal choroidal thickness and subfoveal sclera thickness were measured before therapy.

The Classification Of Psv Based On B-scan And Octa

The location of PSV and the neovascular signal relationship between PSV and CNV were mainly analyzed through images of 512 consecutive horizontal and vertical B-scans on the 3×3 mm² by OCTA (Angio OCT; Optovue, Fremont, America), which incorporateed split-spectrum amplitude-decorrelation angiography (SSADA) software. Projection artifact removal technology by Optovue was used to analyze OCTA flow images for eliminating the interference of other vascular signals[14].

PSV was defined as (1) hyporeflective appearance presenting as linear or wavy morphology extension from the sclera through the choroid toward the retina in OCT B-scan images and (2) the corresponding projection on en face OCTA presented as a black low-reflection lumen-like structure [15].

In OCTA B-scan, based on whether the PSV was adjacent to CNV, the location of PSVs with mCNV was summarized to two groups: (1) PSV adjacent to mCNV, which presented as the linear hyporeflective structure was adjacent to the CNV through a defect of Bruch’s membrane) Fig. 1B, S-Video1; (2) No PSV adjacent to CNV, which was presented in three cases. (a)PSV penetrated into the choroidal vessels under mCNV, where it manifested as the linear hyporeflective structure extending into the choroidal compartment and branching out to an enclosed and hyporeflective area Fig. 1E, (b) PSV had not significant correlation with the position of mCNV Fig. 1I and (c) no PSVs were found in macular region.

The neovascular signal of mCNV was evaluated through the outer retinal layer (from the Bruch's membrane to the outer plexiform layer) by projection-resolved (PR)-OCTA. (1) Presence of neovascular signal from PSV, was defined as PSV (the linear hyporeflective structure) had flow signal passing RPE complex towards to CNV on OCTA cross section corresponding to the CNV lesion on en face OCTA (Fig. 1A-B); (2) Absence of neovascular signal from PSV, in which CNV flow signal with a connection to PSV is not detectable (Fig. 1C).

The Morphology Of Mcnv Analyzed By Octa

The morphology of mCNV was analyzed by en face OCTA according to previous research. CNV patterns were classified, including “Medusa” pattern, “Seafan” pattern, “indistinct network” pattern and “pruned vascular tree” pattern, based on the presence of thin branches, circular peripheral anastomosis, feeder vessel, filamentous flow and dark halo[16].

The area of mCNV were measured on en face OCTA images between Bruch's membrane and the outer plexiform layer which was automatically segmented by AngioVue software. Two independent retina specialists independently measured the area of each CNV using ImageJ (National Institutes of Health, Bethesda, MD). A second set of measurements was used to settle readings of the CNV area that conflicted by more than 10%[17].

Therapy Plan With Anti-vegf Treatment

All patients were naïve without any treatment before. A 1 + pro-re-nata (PRN) regimen was used to conduct the study using 0.5 mg of Ranibizumab or Conbercept. When the mCNV activity was completely quiet at the next check-up, no further injections were given unless a recurrence was observed. If the mCNV activity remained, further injections were given monthly until the mCNV stabilized.

Definition Of Recurrence In Mcnv

CNV recurrence was defined as a new development of dye leakage observed by FA, or a new or increased subretinal exudation-like serous retinal detachment observed in OCT images at least 3 months after the original fluid was completely resolved. Reactivation, enlargement of the original CNV, and a new CNV that developed away from the original CNV were the three categories into which the recurrences were categorized [18]. While observing the recurrence, B scan and OCTA are used to determine whether CNV has PSV at the site of recurrence, including their location and neovascular signal relationship.

Statistical analysis

Statistical analysis was performed with a commercial program (SPSS for Windows; version 26.0.0; SPSS Inc., Chicago, IL). Snellen visual acuity was converted to the logarithm of the minimal angle of resolution (logMAR units) for statistical purposes. The Kolmogorov-Smirnov test was used to determine the normality of all continuous variables. If it belonged to normal distribution, it was expressed as mean ± standard deviation (x ̅±s); otherwise, it was expressed as the median (interquartile range) M(Q). The independent t test or Mann-Whitney test were used to compare continuous variables, and the Pearson’s χ² test was used to compare categorical variables.

The Cox proportional hazard model and Kaplan- Meier survival analysis were performed for the first recurrence. Repeated measurement analysis of variance (RM-ANOVA) was used to compare the BCVA at each time point. P < 0.05 was considered statistically significant.

Clinical data of the study

The medical records of 207 patients (216 eyes) with mCNV who received anti-VEGF therapy for the first time in the hospital were reviewed retrospectively. 153 of them were excluded: 72 had a follow-up period of less than 12 months, 63 had missing or incomplete critical follow-up data, 8 had image quality less than three leading to blurred angiography, 4 had other internal surgery, 3 had retinal detachment during the follow-up period and 3 had suspicious age-related macular degeneration. Further research was conducted on 63 eyes from 58 patients.

Table 1 displays the demographic information of the 63 eyes. The average age was 56.41 ± 13.30 years old, with a refractive error of -13.53 ± 4.96 D. The median baseline BCVA was 0.70(0.52–1.30) LogMAR, and the follow-up duration was 28(19.0–42.0) months. 54(85.7%) eyes had been diagnosed with subfoveal CNV while 9(14.3%) with parafoveal CNV. The percentage of Medusa, Seafan, indistinct network and pruned vascular tree were 38(60.3%), 8(12.7%), 13(20.6%), 4(15.4%) at baseline. The median size of the baseline CNV was 0.283(0.175–0.625) mm². 56(88.9%) eyes had posterior staphyloma and 16(25.4%) eyes had retinoschisis. The median central macular thickness was 276.0(211.9–370.0) µm, the median subfoveal choroidal thickness was 46.0(31.0–76.0) µm and the median subfoveal scleral thickness was 266.0(212.0-314.0) µm.

Table 1

Baseline Characteristics of Eyes with Myopic Choroidal Neovascularization
	Total eyes(n = 63)
Age (years)	56.41 ± 13.30
Gender (n, %)
Female	46(73.0%)
Male	17(27.0%)
Refractive error (D)	-13.53 ± 4.96
BCVA(LogMAR)	0.70(0.52–1.30)
Follow- up duration (months)	28(19.0–42.0)
CNV location (n, %) Subfoveal	54(85.7%)
Parafoveal	9(14.3%)
CNV size (mm²)	0.283(0.175–0.625)
CNV pattern (n, %) “Medusa”: “Seafan”: “indistinct network”: “pruned vascular tree”	38:8:13:4 (60.3%:12.7%:20.6%:15.4%)
Posterior staphyloma (n, %)	56(88.9%)
Retinoschisis (n, %)	16(25.4%)
Central macular thickness (µm)	276.0(211.9–370.0)
Subfoveal choroidal thickness (µm)	46.0(31.0–76.0)
Subfoveal scleral thickness (µm)	266.0(212.0-314.0)
CNV, choroidal neovascularization; PSV, perorating scleral vessels; BCVA, best corrected vision acuity;
P < 0.05 was considered as significant.

The Different Types Of Psv With Mcnv According To B-scan And Octa At Baseline

13 eyes (20.6%) were found that PSV adjacent to CNV, 50 eyes (79.4%) were not. Of these 50 eyes, 22 (44.0%) demonstrated PSV penetration into the choroidal vessels beneath mCNV, 24 (48.0%) demonstrated PSV separation from CNV, and 4 (8.0%) demonstrated the absence of PSV in the scan area. Therefore, PSVs were found in 59 of 63 eyes (93.7%) with mCNV in the macular region. There was no significant difference between two groups at baseline (Table 2).

Table 2

Clinical Characteristics of Eyes with PSV based on B scan and OCTA
	PSV adjacent to CNV(n = 13)	No PSV adjacent to CNV(n = 50)	P value	Presence of Neovascular signal from PSV (n = 25)	Absence of Neovascular signal from PSV (n = 38)	P value
Age (years)	59.62 ± 13.70	55.58 ± 13.19	0.334^‡	58.04 ± 13.58	55 ± 13.18	0.435^‡
Gender (n, %)			0.157 *			0.565 *
Female	7(53.8%)	39(78.0%)		17(68.0%)	29(76.3%)
Male	6(46.2%)	11(22.0%)		8(32.0%)	9(23.7%)
Refractive error (D)	-12.11 ± 4.24	-13.67 ± 4.12	0.236^‡	-12.58 ± 3.81	-13.85 ± 4.36	0.240^‡
Baseline BCVA(LogMAR)	0.75(0.65–1.40)	0.70(0.40–1.30)	0.143^†	0.82(0.70–1.30)	0.52(0.40–0.85)	0.010^†
Follow- up duration (months)	21.5(13.0-38.75)	27.5(18.5–39.5)	0.060^†	30.0(19.0-41.5)	25.5(19.0-43.5)	0.880^†
CNV location (n, %) Subfoveal	13(100%)	41(82.0%)	0.184*	23(92.0%)	31(81.6%)	0.298*
Parafoveal	0(0%)	9(18.0%)		2(8.0%)	7(18.4%)
Baseline CNV size (mm²)	0.471(0.175–1.047)	0.270(0.175–0.553)	0.285^†	0.341(0.175–1.135)	0.265(0.175–0.483)	0.137^†
CNV pattern (n, %) “Medusa”: “Seafan”: “indistinct network”: “pruned vascular tree”	8:2:1:2 (61.5%:15.4%:7.7%:15.4%)	30:6:12:2 (60%:12.0%:24.0%:4.0%)	0.266*	14:5:2:4 (56.0%:20.0%:8.0%:16.0%)	24:3:11:0 (63.2%:7.9%:28.9%:0.0%)	0.008*
Posterior staphyloma (n, %)	11(84.6%)	45(90%)	0.672*	22(88.0%)	34(89.5%)	1.000*
Retinoschisis (n, %)	2(15.4%)	14(28.0%)	0.486*	8(32.0%)	8(21.1%)	0.383*
Central macular thickness (µm)	283.0(200.8-405.8)	301.0(222.0-389.3)	0.231^†	290.0(217.0-408.5)	262.0(205.0-357.0)	0.518^†
Subfoveal choroidal thickness (µm)	53.0(29.0-84.5)	45.0(31.5–72.0)	0.677^†	51.0(27.5–81.5)	45.5(32.0-70.5)	0.752^†
Subfoveal scleral thickness (µm)	279.0(216.3-320.3)	260.5(211.5-324.8)	0.194^†	282.0(201.5–321.0)	265.5(219.8–300.0)	0.720^†
CNV, choroidal neovascularization; PSV, perorating scleral vessels; BCVA, best corrected vision acuity, P < 0.05 was considered as significant.
*Pearson’s χ² test. †Mann-Whitney U test. ‡Student’s t-test.

Neovascular signal of CNV from PSV was detected in 25 eyes (39.7%), but not in 38 eyes (60.3%). The eyes with neovascular signal from PSV had worse baseline BCVA (P = 0.010), lower rate of “indistinct network” pattern and greater rate of “pruned vascular tree” (P = 0.008) than those without neovascular signal from PSV (Table 2).

Higher Rate Of Recurrence Occurred When Neovascular Signal Of Cnv Detected From Psv

29 of 63 eyes (46.0%) experienced at least one recurrence throughout the follow-up period. The average anti-VEGF injection times were 3.4 times (median: 3 times). Recurrence rate was 53.8% (7/13) in eyes with PSV adjacent to CNV and 44.0% (22/50) in eyes without PSV adjacent to CNV (P = 0.550). Furthermore, the recurrence rate in eyes with neovascular signal from PSV was 60.0% (15/25) against 36.8% (14/38) in eyes without neovascular signal from PSV (P = 0.120). Although there were no significant differences, the recurrence rates of PSV-related groups were greater.

The duration of the first recurrence of PSV with CNV was analyzed using Kaplan-Meier survival analysis. The mean interval for the PSV adjacent to CNV group was 24.7 months (median interval of 21.0 months, range 4–41 months), while the mean interval for the no PSV adjacent to CNV group was 37.5 months (median interval of 45.0 months, range 3–58 months). The recurrence time did not differ substantially between the two groups ((χ² = 1.627, P = 0.210). The mean interval for CNV with a neovascular signal from the PSV group was 28.4 months (median interval: 27.00 months, range: 3–51 months), while the mean interval for CNV without a neovascular signal from the PSV group was 40.8 months (median interval: 45.0 months, range: 9–58 months; Fig. 3). CNV with neovascular signal from PSV had a shorter recurring duration than eyes without (χ² = 4.486, P = 0.034). The existence of neovascular signal from PSV in CNV was found to be an independent risk factor for recurrence in the Cox proportional hazard model (HR: 2.19, 95%Cl 1.04–4.62). Age and the morphology of mCNV, on the other hand, were not significant risk factors.

Additional analysis revealed that in 29 recurrent eyes, 8(27.6%) eyes were reactivated by the original CNV, 11(37.9%) eyes had an enlargement of the original CNV and 10(34.5%) eyes developed a new CNV that developed away from the original CNV (Fig. 2). In 15 recurrent eyes with neovascular signal from PSV, 4 (26.7%) eyes were reactivated by the original CNV, 5(33.3%) eyes had an enlargement of the original CNV and 6(40.0%) eyes developed a new CNV that developed away from the original CNV (Table 3). In 14 recurrent eyes without neovascular signal from PSV, 4(28.6%) eyes were reactivated by the original CNV, 6(42.9%) eyes had an enlargement of the original CNV and 4(28.6%) eyes developed a new CNV that developed away from the original CNV. The distribution of recurrence types did not differ (Fig. 4A). When observed the neovascular signal of recurrent CNV, 11(73.3%) eyes were found PSV in the site of recurrence in the presence of neovascular signal from PSV group, while no eye (0%) in the absence of neovascular signal from PSV group was found PSV in the site of recurrence. When the neovascular signal of mCNV from PSV is presence at baseline, PSV was more frequently discovered at the recurrent site (P<0.001; Fig. 4B).

Table 3

Characteristics and Treatment Outcome of the Recurrence of CNV with Neovascular Signal from PSV after anti-VEGF treatment
Patient No./Sex/Age, y	Affect eye		CNV patterns	Drug	No. of initial injections
1/F/57	Left	20/40	“Medusa”	Ranibizumab	1	12/ Reactivation	NO	20/25
2/F/85	Left	20/100	“Pruned vascular tree”	Conbercept	1	4/ New CNV	YES	20/200
3/M/36	Left	FC/20cm	“Indistinct network”	Conbercept	3	11/ Reactivation	YES	20/25
4/M/36	Left	20/100	“Pruned vascular tree”	Conbercept	1	6/Enlargement	YES	20/100
5/M/72	Right	20/100	“Seafan”	Conbercept	2	15/ Enlargement	YES	20/100
6/F/64	Right	20/200	“Seafan”	Conbercept	1	5/ Enlargement	YES	20/40
7/M/75	Left	FC/10cm	“Seafan”	Ranibizumab	2	51/ New CNV	NO	20/166
8/F/40	Right	20/40	“Medusa”	Conbercept	3	3/ Enlargement	YES	20/30
9/M/48	Left	20/100	“Medusa”	Ranibizumab	2	22/ New CNV	NO	20/40
10/F/62	Right	20/125	“Medusa”	Conbercept	2	7/Reactivation	YES	20/50
11/F/71	Right	20/400	“Medusa”	Conbercept	2	28/New CNV	NO	20/200
12/F/54	Left	20/400	“Medusa”	Conbercept	3	21/New CNV	YES	20/2000
13/M/66	Left	20/67	“Medusa”	Ranibizumab	1	47/New CNV	YES	20/133
14/F/54	Right	20/2000	“Pruned vascular tree”	Ranibizumab	2	27/Reactivation	YES	20/66
15/F/73	Left	20/200	“Medusa”	Conbercept	2	34/Enlargement	YES	FC/20cm
CNV, choroidal neovascularization; PSV, perorating scleral vessels; BCVA, best corrected vision acuity; F, female; M, male.

Table 4

BCVA Changes of CNV Eyes During the Follow-up Period after anti-VEGF treatment
Group	BCVA
Group	Baseline	6 months	12 months	Final visit	F	P value
PSV Adjacent to CNV	0.80(0.70–1.3)	0.82(0.35–1.30)	1.00(0.35–1.30)	0.82(0.35–1.30)	6.43	0.008^a
No PSV Adjacent to CNV	0.70(0.40–1.3)	0.30(0.15–0.52)	0.35(0.15–0.70)	0.35(0.15–0.70)	10.91	0.002^b
Presence of Neovascular signal from PSV	0.82(0.70–1.3)	0.80(0.26-1.00)	0.70(0.35–1.20)	0.70(0.30 − 0.10)	15.62	<0.001^c
Absence of Neovascular signal from PSV	0.52(0.40–85)	0.30(0.15–0.43)	0.22(0.14–0.52)	0.30(0.14–0.54)	17.06	<0.001^d
BCVA, best corrected vision acuity; CNV, choroid neovascularization; PSV, perforating scleral vessel; P < 0.05 was considered as significant by Repeated Measures ANONA or GEE. P^a, P^c stands for BCVA changes with time by ANONA analysis, P^b, P^d stands for BCVA changes in different groups interacted with time by ANONA analysis. GEE, generalized estimating equation; ANONA, analysis of Variance. Before ANONA, LogMAR BVCA is processed by open square root and converted into normal distribution data for analyzing.

The Neovascular Signal Of Cnv From Psv Got A Worse Visual Outcome After Treatment

The BCVA changes were compared between groups based on whether PSV was adjacent to CNV or not and whether PSV had a neovascular signal or not. Initial, 6months, 12 months and final BCVA were significantly improved during time in all subgroups (P = 0.008, P < 0.001). Less BCVA improvement was seen in the PSV adjacent to CNV group (F = 10.91, P = 0.002) and the presence of neovascular signal from the PSV group compared to comparison groups (F = 17.06, P < 0.001; Fig. 5, Table 5).

We observed that PSV was mainly detected in patients with mCNV. Not only the location of PSV was discovered around mCNV, but also the neovascular signal of mCNV was closely related to PSV detected by OCTA. During the follow-up period, 46.0% (29/63) of the eyes with mCNV recurred. Additionally, when the neovascular signal of mCNV comes from PSV, it showed a worse VA result and a greater probability of recurrence with a shorter recurrence time.

PSV was detected to be adjacent to CNV through a defect of Bruch’s membrane in 13/63 of mCNV. Ishida et al reported the connection between PSV and CNV, 10/91 eyes were continuous with the CNV through a defect of Bruch’s membrane [11]. PSV was reported to be associated with lacquer cracks in myopic CNV. The reason was unclear [12]. PSV was considered to join in the process of mCNV by releasing scleral interruption by the gradual extension of the globe [19, 20]. The Bruch membrane of the eye is under more tension as a result of PSV's release from the scleral. Therefore, the disruption of scleral from PSV may become a risk factor for the development of CNV in diseased eyes when scleral and choroid get thinner.

In this study, a greater rate of recurrence and poor outcome were found in patients with mCVN when the neovascular signal of CNV comes from PSV. VEGF is a main reason for mCNV, it was effective after adopting anti-VEGF therapy for patients with mCNV [21]. However, after anti-VEGF therapy in the study, approximately half of the eyes with mCNV (60.0%) recurred. It implies that VEGF was not the main reason for mCNV. We observed a complex of CNV network made up of arteries and mCNV in our previous study. The arteries and vascular signal from PSV may contribute to the formation of a complex CNV network. PSV was considered to be intrascleral arteries which originated from the retrobulbar short posterior ciliary arteries by a combination of the swept-source OCT, OCTA, FA and ICGA[11].We speculate that this type of CNV may be composed of arterialized blood vessels. Angiogenesis is highly dependent on VEGF, while arteriogenesis is independent of VEGF[22]. Therefore, poorer outcome and higher recurrence were found after anti-VEGF therapy.

In this study, we performed a first assessment of the neovascular signal from PSV on OCTA and examined PSV's impact. The neovascular supply has a greater impact on the recurrence of mCNV than spatial relationship does. Furthermore, when the neovascular signal of mCNV comes from PSV at baseline, it showed higher recurrence (73.3%) than that (0%) in the absence of neovascular signal from PSV at baseline group. We conducted a more thorough analysis of the relationship between PSV and mCNV, even when PSV is not directly adjacent to CNV, PSV still supplies blood flow to CNV through small blood vessels in Fig. 2D&J, this blood supply may be from the arteries which endures anti-VEGF treatment. As Spaide et al advocated that arteriogenesis and angiogenesis occur in the eyes of the long-standing neovascular AMD[23].

In order to investigate the causes of mCNV with PSV. The previous study indicated that atrophy was larger in PSV groups[24]. Bruch's membrane was interrupted and destroyed around the PSV. We speculated that the type of mCNV adjacent to PSV was a later stage of mCNV. At early stage, the PSV was initially separated from CNV; when the choroid and scleral became atrophy and were destroyed, which causing PSV to become closer to the destroyed Bruch's membrane and CNV. Following the interruption, VEGF levels may rise, and mCNV may enlarge with larger atrophy regions. PSV may move closer to the regions and merge with neovascularization, resulting in a neovascular signal. Patients with mCNV adjacent to PSV experienced less improvement in visual acuity following anti-VEGF therapy. The baseline BCVA in the group with neovascular signal from PSV was considerably poorer. It indicated that the retinal structure may be destroyed at this stage, the improvement of BCVA and retinal structure were limited after therapy. This finding supported the conclusion that PSV adjacent to mCNV may be the final stage with mCNV composed of arteries and neovascularization. The role of VEGF is not the only reason for mCNV, which results in a poor visual prognosis[7].

The study has several limitations. First, the study is a retrospective study with a small sample size; to prove the hypothesis, a well-designed prospective study with a large sample size is required. Second, different anti-vascular endothelial growth factor drugs injected into the vitreous cavity may have an effect on the curative effect to some extent. Third, indocyanine green angiography was not performed in each patient to confirm the source of intrascleral vessels seen on structural OCT images. Further studies with larger samples will be necessary to corroborate our results.

Finally, we discovered that nearly half of the mCNV eyes had neovascular signal from PSV. Both the physical connection and neovascular supply of PSV with CNV had a worse visual outcome after anti-VEGF therapy. When the neovascularization of mCNV comes from PSV it showed a shorter recurrence time and a higher recurrence risk factor. The interesting study would better guide the clinical practice and deeply understand the pathology of mCNV.

Acknowledgements

Not applicable.

Conflict of Interest

The authors declare that they have no competing interests.

Funding

The project was supported by Zhejiang Provincial Natural Science Foundation of China (LQ20H120004); Basic Scientific Project of Wenzhou Science and Technology Commission(Y20190647). The National Natural Science Foundation of China (82101158).

Author Contributions

Study conception and design: XJS, WJY, ZL and GYH. Data collection and analysis:

WJY, GYH, JX, JWT and ZL. Drafting the manuscript: XJS, WJY and LJS. Critically revising the manuscript for intellectual content: SLW, JBM, CYQ, YZ and LJS. All authors have read and approved the final manuscript.

Wolf S, Balciuniene VJ, Laganovska G, Menchini U, Ohno-Matsui K, Sharma T, et al. RADIANCE: A Randomized Controlled Study of Ranibizumab in Patients with Choroidal Neovascularization Secondary to Pathologic Myopia. Ophthalmology. 2014 Mar;121(3):682–692.e2.
Asakuma T, Yasuda M, Ninomiya T, Noda Y, Arakawa S, Hashimoto S, et al. Prevalence and Risk Factors for Myopic Retinopathy in a Japanese Population. Ophthalmology. 2012 Sep;119(9):1760–5.
Ohno-Matsui K. Diagnosis and treatment guideline for myopic choroidal neovascularization due to pathologic myopia. Progress in Retinal and Eye Research. 2018;15.
Ikuno Y, Ohno-Matsui K, Wong TY, Korobelnik JF, Vitti R, Li T, et al. Intravitreal Aflibercept Injection in Patients with Myopic Choroidal Neovascularization. Ophthalmology. 2015 Jun;122(6):1220–7.
Kang HM, Koh HJ. OCULAR RISK FACTORS FOR RECURRENCE OF MYOPIC CHOROIDAL NEOVASCULARIZATION: Long-Term Follow-Up Study. Retina. 2013 Sep;33(8):1613–22.
Takao-Okuma H, Terao R, Nagahara M, Azuma K, Inoue T, Uemura Y, et al. Distribution of recurrence time intervals after anti-vascular endothelial growth factor therapy for myopic choroidal neovascularization. Canadian Journal of Ophthalmology. 2021 Apr;56(2):137–8.
Wang HY. Baseline characteristics of myopic choroidal neovascularization in patients above 50 years old and prognostic factors after intravitreal conbercept treatment. Scientific Reports. 2021;9.
Ahn SJ, Woo SJ, Kim KE, Park KH. Association between choroidal morphology and anti-vascular endothelial growth factor treatment outcome in myopic choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013 Mar 1;54(3):2115–22.
Yang HS, Kim JG, Kim JT, Joe SG. Prognostic factors of eyes with naïve subfoveal myopic choroidal neovascularization after intravitreal bevacizumab. Am J Ophthalmol. 2013 Dec;156(6):1201–1210.e2.
Fan Y, Xu X. Morphologic Features of Myopic Choroidal Neovascularization in Pathologic Myopia on Swept-Source Optical Coherence Tomography. Frontiers in Medicine. 2020;7:10.
Ishida T, Watanabe T, Yokoi T, Shinohara K, Ohno-Matsui K. Possible connection of short posterior ciliary arteries to choroidal neovascularisations in eyes with pathologic myopia. Br J Ophthalmol. 2019 Apr;103(4):457–62.
Querques G, Corvi F, Balaratnasingam C, Casalino G, Parodi MB, Introini U, et al. Lacquer Cracks and Perforating Scleral Vessels in Pathologic Myopia: A Possible Causal Relationship. American Journal of Ophthalmology. 2015 Oct;160(4):759–766.e2.
Ruiz-Medrano J, Almazan-Alonso E, Flores-Moreno I, Puertas M, García-Zamora M, Ruiz-Moreno JM. RELATIONSHIP BETWEEN MYOPIC CHOROIDAL NEOVASCULARIZATION ACTIVITY AND PERFORATING SCLERAL VESSELS IN HIGH MYOPIA. Retina. 2022 Jan 1;42(1):204–9.
Zhang M, Hwang TS, Campbell JP, Bailey ST, Wilson DJ, Huang D, et al. Projection-resolved optical coherence tomographic angiography. Biomed Opt Express. 2016 Mar 1;7(3):816.
Giuffrè C, Querques L, Carnevali A, De Vitis LA, Bandello F, Querques G. Choroidal Neovascularization and Coincident Perforating Scleral Vessels in Pathologic Myopia. European Journal of Ophthalmology. 2017 Mar;27(2):e39–45.
Miere A, Butori P, Cohen SY, Semoun O, Capuano V, Jung C, et al. VASCULAR REMODELING OF CHOROIDAL NEOVASCULARIZATION AFTER ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY VISUALIZED ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina. 2019 Mar;39(3):548–57.
Muakkassa NW, Chin AT, de Carlo T, Klein KA, Baumal CR, Witkin AJ, et al. CHARACTERIZING THE EFFECT OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY ON TREATMENT-NAIVE CHOROIDAL NEOVASCULARIZATION USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina. 2015 Nov;35(11):2252–9.
Xie S, Du R, Fang Y, Onishi Y, Igarashi T, Takahashi H, et al. Dilated choroidal veins and their role in recurrences of myopic macular neovascularisations. Br J Ophthalmol. 2021 Apr 28;bjophthalmol-2021-318970.
Ohno-Matsui K. Patchy atrophy and lacquer cracks predispose to the development of choroidal neovascularisation in pathological myopia. British Journal of Ophthalmology. 2003 May 1;87(5):570–3.
Wong TY, Ohno-Matsui K, Leveziel N, Holz FG, Lai TY, Yu HG, et al. Myopic choroidal neovascularisation: current concepts and update on clinical management. Br J Ophthalmol. 2015 Mar;99(3):289–96.
Cheung CMG, Arnold JJ, Holz FG, Park KH, Lai TYY, Larsen M, et al. Myopic Choroidal Neovascularization: Review, Guidance, and Consensus Statement on Management. Ophthalmology. 2017 Nov;124(11):1690–711.
Schierling W, Troidl K, Troidl C, Schmitz-Rixen T, Schaper W, Eitenmüller IK. The Role of Angiogenic Growth Factors in Arteriogenesis. J Vasc Res. 2009;46(4):365–74.
Spaide RF. Optical Coherence Tomography Angiography Signs of Vascular Abnormalization With Antiangiogenic Therapy for Choroidal Neovascularization. American Journal of Ophthalmology. 2015 Jul;160(1):6–16.
Xie S, Fang Y, Du R, Yokoi T, Takahashi H, Uramoto K, et al. ABRUPTLY EMERGING VESSELS IN EYES WITH MYOPIC PATCHY CHORIORETINAL ATROPHY. 2019;00(00):9.

(Not answered)

SVideo1.mov
S-Video 1

Download PDF

Version 1

posted

You are reading this latest preprint version

The Neovascular Signal of Myopic Choroidal Neovascularization from Perforating Scleral Vessel Prone to Recur after Anti-VEGF therapy

Status:

Version 1

Abstract

Figures

Introduction

Methods

The Classification Of Psv Based On B-scan And Octa

The Morphology Of Mcnv Analyzed By Octa

Therapy Plan With Anti-vegf Treatment

Definition Of Recurrence In Mcnv

Statistical analysis

Result

Clinical data of the study

The Different Types Of Psv With Mcnv According To B-scan And Octa At Baseline

Higher Rate Of Recurrence Occurred When Neovascular Signal Of Cnv Detected From Psv

The Neovascular Signal Of Cnv From Psv Got A Worse Visual Outcome After Treatment

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1