Myopic choroidal neovascularization (mCNV) is theoretically originated in the choroid, despite its marked thinness in these patients and is the leading cause of vision loss in patients with high myopia (HM). It distorts overlying retina, causes hyperplasia and migration of retinal pigment epithelium cells, and is typically associated to the development of adjacent chorioretinal atrophy that further endangers visual acuity.1 Nevertheless, mCNV etiology has not been completely elucidated. Although lacquer cracks and increased levels of vascular endothelial growth factor seem to play a role in the disease, further studies will be necessary to fully understand the underlying mechanisms leading to mCNV appearance and conditioning its behavior.2,3
The continuous advancements on imaging technology,4–6 providing details of ever deeper structures of the posterior pole have led to publications that show the influence of different vascular conditions on mCNV activity.7,8 On the one hand, perforating scleral vessels (PSVs), believed to be short posterior ciliary arteries, underlying the neovascular complex, seem to make overlying mCNV more prone to reactivation, needing more injections to reach stability.9,10 Conversely, certain choroidal venous drainage alterations are also believed to play its role, being more common among HM eyes. Different variations of choroidal venous patterns have been reported in the literature, and dilated choroidal veins (DCVs) visible on indocyanine green angiography, for instance, have recently been reported to be associated with a more aggressive phenotype of CNV, calling for a tighter monitoring of our patients.11
The objective of this study was to analyze the potential influence of arterial and venous structures underlying mCNV complexes in disease activity in a series of eyes with pathologic myopia using optical coherence tomography (OCT) and OCT-angiography (OCTA).
Patients and Methods
This cross-sectional study included 681 eyes from 362 highly myopic patients who attended Puerta de Hierro Majadahonda University Hospital, a tertiary referral hospital for vitreoretinal pathology. It was performed in adhesion to the tenets of the Declaration of Helsinki for research involving humans, and its protocol was reviewed and approved by the Ethics Committee of the same institution. All included patients signed the appropriate informed consent.
Inclusion criteria were 1) presence of HM defined by an axial length (AL) ≥26; 2) presence of an active mCNV at baseline identified on structural OCT and OCTA and, when in doubt, fluorescein angiography was performed; 3) clear ocular media; 4) age 18 years or older; 5) minimum 1 year of follow-up; and 6) good imaging quality (>45 Image Quality Score of DRI Triton Swept Source (SS)-OCT software [Topcon Co.]). Patients suffering from any other ocular or systemic disease other than cataract or refractive surgery and/or eyes suffering from CNV secondary to other causes were excluded from this study. All patients were evaluated separately by two retina experts and, in cases of disagreement, those cases were excluded from the analysis.
Patients' clinical records were reviewed for demographical data and registers of number of intravitreal injections (IVIs) received, date of the first and last IVI, duration of follow-up, number of injections needed to obtain mCNV inactivation after the original diagnosis, and number of relapses (defined as the number of times the patient needs to resume treatment after reaching a lack of activity of the neovascular complex of at least 1 month). Patients were monitored monthly and were under a pro re nata treatment regimen.12,13
All patients underwent a complete ophthalmological examination at the date of their recruitment for the study that included best-corrected visual acuity (BCVA), refraction and optical biometry (IOL Master-500; Carl Zeiss Meditec AG, Jena, Germany) to obtain AL measurements, slit-lamp anterior segment examination, intraocular pressure (Goldmann applanation tonometry Haag Streit, Koenig, Switzerland), indirect fundus ophthalmoscopy, and a series of multimodal imaging examinations. All examinations were conducted in both eyes independently, as long as both met the study's criteria.
Optical Coherence Tomography Imaging
Fundus photography and swept source OCT examinations were conducted in all patients using a Topcon Triton platform (Topcon Co.). Structural OCT protocol consisted of 12-mm radial b-scans centered on the fovea and containing 1,024 axial scans each.
The software's automatic segmentation of the retina, from the inner limiting membrane to the retinal pigment epithelium, was visually checked and manually corrected, if necessary, in all eyes before data collection. Subfoveal choroidal thickness was manually measured under the fovea from the outer border of the retinal pigment epithelium to the choroid–scleral interface.
Neovascular lesions were defined as active when elevations of retinal pigment epithelium were accompanied by intraretinal or subretinal fluid, blurred margins, and/or impossibility to identify the external limiting membrane. CNV lesions were subclassified depending on distance from foveal center as subfoveal (0–750 μm), parafoveal (750–1,250 μm), and perifoveal (1,250–1,500 μm). The localization of the CNV was measured from the nearest edge of the CNV to the foveal center based among the 12-mm radial OCT b-scan.
The presence of PSV was defined using the methods previously described by Giuffrè, Ohno-Matsui, and Ruiz-Medrano10,14,15 as a hyporeflective image crossing the sclera underneath the macular area seen in the OCT b-scan.
The presence of a DCV within the macular area was established using both manual segmentation of en face images provided by the OCTA examination and structural OCT b-scans. DCVs were defined as large choroidal veins showing a 2-fold width when compared with adjacent veins as reported by Xie et al11 using en face OCTA images. This was analyzed as well by two masked independent retina experts (Figure 1). Both the presence of PSV and DCV were assessed on the initial presentation for each patient.
;)
Fig. 1.: Presence of an artery–vein complex underlying a myopic mCNV in two different highly myopic patients (A and D). Manual segmentation of en face images provided by the OCTA examination showing a DCV (dashed arrow) of 2-fold width compared with adjacent veins (B and E). Structural OCT shows a hyporeflective structure across the sclera corresponding to a PSV (arrow) at the level of the DCV and under the mCNV (C and F).
The presence of an artery–vein complex (AVC) was defined by the identification of both PSV and DCV underneath the mCNV in the same case.
Statistical Analysis
All analyses were performed using IBM-SPSS statistical software analysis program (v. 28.0.1.0, Chicago, IL). The results were expressed in P value, and a two-tailed P < 0.05 was considered as statistically significant. Descriptive statistics were provided using the mean and SD for quantitative normally distributed variables, median and interquartile range for nonnormally distributed variables, and n (%) for categorical variables. To assess the normality or nonnormality of the variables, the Kolmogorov–Smirnov test was performed.
Categorical variables were compared using chi-square test for normally distributed and Fisher exact test for nonparametric categorical variables. To compare quantitative continuous distributed variables, independent Student t-test was used for normally distributed variables and Mann–Whitney U test for nonparametric variables. The Kruskal–Wallis test was used to compare ordinal variables between groups.
Results
A total of 681 highly myopic eyes from 362 patients were reviewed. Among them, there was an incidence of mCNV of 21.4%. Only patients with mCNV and good quality OCTA images were selected for our study, leaving a total of 74 eyes. Among them, 24 further cases were excluded for reasons including incomplete records of IVI at our center, suspicion of choroiditis-related CNV, focal choroidal excavation coincident with the mCNV lesion, and extensive macular hemorrhage.
Finally, 50 eyes of 49 highly myopic patients with mCNV were analyzed. Of the total, 75% were female (n = 37/49), mean age was 64.7 years old (range from 39 to 89), mean AL was 30.04 mm (range from 26.16 to 36.70), and mean BCVA was 0.4 LogMAR (range from 1.0 to 0.0).
The most frequent mCNV localization was subfoveal showed in 84% of the eyes (n = 42/50), followed by parafoveal location in 14.0% (n = 7/50). Exceptionally, one eye presented two separate mCNV lesions located in the subfoveal and parafoveal areas (the subfoveal lesion was the one used for the analyses).
The mean follow-up of patients was 6.47 years (range from 1 to 13.42). The median number of IVI/year during the follow-up was 0.71 (interquartile range: 0.40–2.22). Throughout the follow-up, 74% of eyes (n = 37/50) had at least one relapse being the mean time to first relapse 0.92 years (range from 0 to 6.33).
All eyes included showed PSVs in the macular region, and in addition, there was a PSV found under or in contact with the mCNV in 78% of the eyes (n = 39/50). Only these were taken into consideration for the statistical analyses. Within this subgroup, 51.28% (n = 20/39) of the eyes showed as well DCV under or in contact with the CNV, constituting an artery–vein complex—formed from the presence of both PSV and DCV. Moreover, there were no eyes with DCV if there were no PSV under or in contact with the mCNV (Table 1). Eyes where graders did not agree on the definition of vascular structures were excluded (n = 4, interrater agreement 0.92).
Table 1. -
Prevalence and Location of Perforating Scleral Vessels and Dilated Choroidal Veins
|
PSV under or in contact with mCNV |
|
| YES |
NO |
|
| DCV |
|
|
|
| Yes |
20 |
0 |
20 |
| No |
19 |
11 |
30 |
|
39 |
11 |
50 |
Eyes with AVC were statistically older than eyes without AVC (69.95 ± 13.53 vs. 60.83 ± 10.47 years old, P < 0.01), needed less IVI/year along follow-up period (0.80 ± 0.62 vs. 1.92 ± 0.17; P < 0.01), and showed less relapses/year (0.58 ± 0.75 vs. 0.46 ± 0.42; P < 0.05). Same results were obtained after adjusting for age. Moreover, eyes with AVC were less prone to relapse during the first year of mCNV activation (n = 5/14 vs. n = 14/16; P < 0.01). No significant differences were found between eyes with and without AVC regarding either AL (30.55 ± 2.31 vs. 29.65 ± 2.24, P > 0.05), BCVA (0.4 ± 0.5 vs. 0.4 ± 0.5, LogMAR P > 0.05), or subfoveal choroidal thickness between groups (43.42 ± 32.80 vs. 81.21 ± 90.48 > 0.05) (Table 2). mCNV localization did not have an influence on its activity (P > 0.05).
Table 2. -
Clinical Comparison Between Eyes With and Without ACV
|
PSV Under/in Contact with mCNV without DCV |
PSV Under/in Contact with mCNV + DCV (AVC) |
P
|
| No. of total = 39 (%) |
19 (48.72) |
20 (51.28) |
|
| Age (years old) |
61±11.04 |
70.5±13.64 |
<0.05* |
| Sex (women/men) |
15/4 |
14/6 |
>0.05 |
| AL (mm) |
29.38 ± 2.15 |
30.55 ± 2.32 |
>0.05 |
| BCVA (LogMAR) |
0.5 ± 0.5 |
0.4 ± 0.5 |
>0.05 |
| Relapses (yes/no) |
16/3 (84.2%) |
12/8 (60%) |
>0.05 |
| Relapses during the 1st year (yes/no) |
14/2 (87.5%) |
5/9 (35.7%) |
<0.01* |
| No. of IVI for dry the first time |
2.88 ± 3.05 |
2.45 ± 1.82 |
>0.05 |
| No. of IVI/year |
1.95 ± 1.75 |
0.78 ± 0.63 |
<0.01* |
| No. of relapses/year |
0.58 ± 0.75 |
0.46 ± 0.42 |
<0.05* |
*Statistically significant results.
BCVA, best-corrected visual acuity.
Discussion
Myopic CNV is the leading cause of visual acuity loss among patients suffering from myopic maculopathy, and yet, its pathogenesis is still not completely elucidated. The choroid has been shown to grow thinner the longer the AL,16 and there are extreme cases that are practically devoid of choroidal tissue, with the subsequent impairment of the choriocapillaris flow that would be theoretically necessary to feed a potential mCNV lesion.17 But despite all this, these lesions are believed to be originated in the choroid.
The continuous advancements in imaging technology and the development of high-penetrance OCT devices have led to a deeper knowledge of the vascular anatomy of the posterior pole, especially in HM eyes, where tissue thinness allows for a better visualization of the scleral tissue and the structures that go through it. These have helped identify new characters that could play a role as both feeders and drainers of the neovascular networks that emerge in the myopic macula.
The first description of PSVs goes back to 2012, when Ohno-Matsui described a series of hyporeflective structures crossing the sclera, identified as short posterior ciliary arteries based on their indocyanine green angiography pattern.15 The presence of these vessels was corroborated by Pedinielli et al,8 in relation with marked variations of choroidal curvature in the posterior pole of HM eyes.19 Since then, several authors have described different rates of PSV prevalence in cases diagnosed of mCNV that ranges from 70 to more than 90%7,10,14 and offered different hypotheses regarding their potential role on the neovascular activity, from promoting the appearance of lacquer cracks to increasing the number of relapses and the need for antivascular endothelial growth factor injections as our group recently published.10
In addition, although PSVs, as the short posterior ciliary arteries they are believed to be, could feed the neovascular tissue, recent publications point at venous structures as a new factor that could influence the balance of these lesions and thus mCNV activity. The asymmetry of choroidal venous patterns was reported by Mori back in 2004,18 and a recent publication by Lu et al19 describes the presence of three different types of large choroidal veins that can be found even in the absence of mCNV. But different groups have reported the presence of dilated subfoveal venous structures under the term DCVs.20,21
Xie et al found DCVs in 29.3% of eyes with mCNV and very thin choroids, although they admit they could be as prevalent in eyes without neovascularization. In their series, 40% of them drain near the optic nerve and are considered posterior vortex veins while the remaining 60% drain into equatorial vortex veins.22 But what is more interesting, they suggest that the blood feeding the mCNV could drain into DCVs based on indocyanine green angiography video analyses. They discuss how chronic venous congestion could lead to the development of mCNV.22
The same group in a more recent work reports the presence of DCVs in 47 of 168 HM eyes with mCNV (28.0%) that were either under or adjacent to the lesion in 72.3% of cases.11 They found that the recurrence rate in eyes with DCVs was statistically higher in the first and second years of follow-up when compared with those without DCVs (0.44 vs. 0.21 recurrences/year during the first year, P = 0.005; 0.38 vs. 0.08 recurrences/year, P < 0.001, during the second year). They also reported the interval between mCNV and the first recurrence to be shorter in these patients. It must be noted that for our study, a relapse was defined as the number of times the patient needs to resume treatment after reaching a lack of activity of the neovascular complex of at least 1 month. Conversely, Xie's study used an interval of 2 months for this definition.
Our rate of DCV is greater than that of Xie et al11 (40% vs. 28%), but those figures are hardly comparable as the inclusion criteria and methods used to identify such vessels differ from one article to the other. They based their exploration on ICG while this study is focused on OCTA and en face imaging obtained from dense scans. In addition, as stated before, the definition of relapse is not the same. Xie et al hypothesize that a compression mechanism, similar to that of pachychoroid diseases takes place above the DCV, compromising the choriocapillaris, which together with a possibly increased retrograde pressure makes these CNV lesions more active.
However, the results of our study suggest the opposite. 39 of 50 eyes with mCNV showed a PSV under or in contact with the lesion, and 51.28% of these showed DCV too, resulting in an AVC. Eyes with mCNV in the presence of AVC needed less injections/year, showed less relapses/year, and were less prone to have a relapse during the first year of follow-up than patients without AVC. If Xie et al's hypothesis is indeed right and DCVs act as a natural drainage for mCNV lesions, their presence could alleviate the pressure inside the neovascular membrane as opposed to those patients who show a PSV alone, minimizing its effects on the outer retina leading to less active lesions (Figure 2). Eyes without a DCV would hypothetically have more difficulties draining the blood inside the CNV, which would leak into the subretinal or intraretinal space more easily. In addition, none of the eyes studied showed a DCV in absence of a PSV, which may lead to think they may develop as a consequence or adaptation to a higher flow induced by the PSV.
Fig. 2.: Image showing different mCNV lesions. Without PSVs or DCVs (left). Myopic CNV lesions with PSV only have been reported to be more aggressive and require more IVIs to achieve inactivity (center). The presence of an AVC could alleviate the pressure inside the neovascular membrane as opposed to those patients who show a PSV alone, potentially acting as a drain and minimizing its effects on the outer retina leading to less active lesions (right).
Back in 2015, Spaide described how high-flow states can lead to vascular dilation in a neovascular context. Although angiogenesis involves the formation of a new capillary network, the term arteriogenesis defines the arterial dilations that seem as a consequence of persistent high flows leading to vascular remodellation.23 These mature vessels referenced in this article and the potential drainage through dilated veins in an otherwise bare choroid is a similar concept that should be further explored.
This study has several limitations: It is a retrospective study that was conducted in a tertiary referral center so the study sample may not correctly represent the general myopic population. Indocyanine green angiography was not performed to corroborate the origin of PSV or DCV. However, en face OCTA was performed instead to identify these structures, and images were analyzed by two masked, independent, trained observers. Larger studies will be necessary to corroborate these results.
In conclusion, AVC complex has an influence over mCNV activity resulting in less aggressive neovascular lesions than those with PSV only.
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