Choroidal Vein Alterations in Pachychoroid Disease With Choroidal Vascular Hyperpermeability: Evaluated by Wide-Field Indocyanine Green Angiography

Abstract

Purpose: The purpose of this study was to investigate choroidal vein (ChV) morphological features in pachychoroid disease (PCD) with choroidal vascular hyperpermeability (CVH).

Methods: This retrospective study assessed subfoveal choroidal thickness (SFCT) and CVH area numbers and locations of recruited patients with PCD using multimodal images. ChV alteration patterns, including fusiform, bulbosity, sausaging, confluence, and anastomoses, as well as asymmetric ChVs, dominant ChVs, and non-dominant ChVs, were evaluated using wide-field indocyanine green angiograms.

Results: Of 68 PCD eyes from 35 patients (mean age: 46.16 ± 6.28 years, 71.4% men), 2.9% had uncomplicated pachychoroid, 32.4% had pachychoroid pigment epitheliopathy (PPE), 55.9% central serous chorioretinopathy (CSC), and 8.8% pachychoroid neovasculopathy (PNV). Mean SFCT was 468.65 ± 131.40 µm. Among 419 CVH areas, ChV fusiform, ChV bulbosity, and ChV sausaging accounted for 35.8%, 35.1%, and 29.1%, respectively; 21.2% had ChV confluence and 11.9% had ChV anastomoses. At CVH areas, 13.1% had retinal pigment epithelium (RPE) leakage. ChV fusiform is steadily declining (37.4%, 36.8%, and 22.9%, respectively), and ChV sausaging, ChV anastomoses, and ChV confluence are increased gradually in the PPE, CSC, and PNV groups (21.4%, 30.0%, and 37.1%; 11.4%, 11.1%, and 20.0%; and 19.8%, 20.9%, and 28.6%, respectively). Dominant ChVs had higher CVH area numbers than non-dominant ChVs in the PPE and CSC groups (P = 0.010, P = 0.001).

Conclusions: Different patterns of ChV alterations, including the newly identified ChV confluence, are commonly present at CVH areas in PCD. The CVH areas in PCD eyes are primarily located within the dominant ChVs. These findings provide crucial evidence for advancing our understanding of the underlying mechanisms of PCD pathogenesis.

Pachychoroid disease (PCD)/pachychoroid spectrum disease are characterized by common morphological alterations in the choroidal structure, including choroidal thickening, dilation of choroidal vessels in Haller's layer, attenuation of the inner choroid, and choroidal vascular hyperpermeability (CVH) on indocyanine green angiography (ICGA).^1–3 The term “pachychoroid” refers to choroidal thickening, associated with dilatation of outer choroidal vessels (pachyvessels).^1,4 Current studies suggest that PCD encompasses central serous chorioretinopathy (CSC), pachychoroid pigment epitheliopathy (PPE), pachychoroid neovasculopathy (PNV), polypoidal choroidal vasculopathy (PCV)/aneurysmal type 1 neovascularization, and uncomplicated pachychoroid (UCP).^4,5 Prior studies have shown that CVH, characterized by the hyperfluorescence patchy areas of ICGA at the middle stage, is a common feature of PCD that is persistent even after subretinal fluid resorption.⁶ Additionally, new retinal pigment epithelium (RPE) leakage sites are often found in these CVH areas when the disease recurs. 

The vortex vein system, which is responsible for draining the choroidal circulation, plays a crucial role in efficiently draining the exceptionally high blood flow of the choroidal circulation. The vortex vein system can be anatomically divided into choroidal veins (ChVs), pre-ampulla, ampulla, post-ampulla, scleral entrance, intra-scleral channel, scleral exit, and extra-scleral vortex veins.⁷ With the increasing use of multimodal imaging, especially wide-field ICGA (WF-ICGA), emerging image-based evidence highlights choroidal vascular abnormalities in PCD.^8,9 In recent work, Spaide et al. observed caliber variations of the ChV in CSC, including sausaging and bulbosity, suggesting that PCD has choroidal vascular morphological alterations.¹⁰ Several studies have reported dilatation of asymmetric ChV and ChV anastomosis in PCD eyes, providing strong evidence for ChV remodeling. 

However, the relationship between CVH and choroidal vascular alterations, one of the most important clinical characteristics of PCD, still remains unclear, and the anatomical structure of the choroidal vasculature deserves further investigation. This study aims to describe the clinical features of ChV alterations using WF-ICGA and evaluate the relationship between choroidal venous remodeling and asymmetric ChV at the CVH areas in PCD. 

Methods

Patients

This retrospective study recruited patients examined at the Zhongshan Ophthalmic Center from January 2022 to September 2022. The study received approval from the Institutional Review Board of the Zhongshan Ophthalmic Center (2023KYPJ114). All research and data collection methods adhered to the tenets of the Declaration of Helsinki. 

We reviewed the data of consecutive patients with a history of PCD who had undergone WF-ICGA. The exclusion criteria were as follows: (1) absence of the early WF-ICGA images; (2) PCV eyes were excluded due to hemorrhagic obscuration affecting the assessment of the choroidal vasculature; (3) other concomitant diseases, such as inflammatory chorioretinal disease, choroidal tumors, glaucoma, or trauma; and (4) poor fixation or any media opacity resulting in poor imaging quality. 

PCD was defined as choroidal thickening (subfoveal choroidal thickness [SFCT] ≥300 µm), dilation of choroidal vessels in Haller's layer, attenuation of the inner choroid, and CVH on ICGA. CSC was characterized by neuroretinal detachment with or without RPE detachment, increased choroidal thickness, and dilated choroidal vessels in optical coherence tomography (OCT) images, and CVH in ICGA images. PNV was defined as type 1 neovascularization occurring over the focal areas of choroidal thickening.¹¹ PPE was defined as RPE abnormalities occurring over the focal areas of choroidal thickening but with no history of subretinal fluid.¹² UCP was defined as choroidal thickening and/or dilated choroidal vessels without RPE alterations.⁴ 

Image Acquisition

All the included patients underwent comprehensive clinical examinations, including best-corrected visual acuity (BCVA) analysis, slit-lamp examination, and multimodal imaging examinations, such as fundus color photography (FF450; Carl Zeiss, Germany or aTRC-50X, Topcon, Japan), fundus fluorescein angiography (FFA), WF-ICGA, ICGA, OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany), and OCT angiography (OCTA; RTVue 100; Optovue, Fremont, CA, USA). OCT scans were performed on single high-definition vertical and horizontal lines across the center of the fovea with a 30-degree area using the enhanced depth imaging technique. The SFCT was measured using the tool provided by the inbuilt software. OCTA scans were captured in high-definition 6 × 6 mm sections centered on the fovea. The presence or absence of neovascularization was specifically detected on the outer retinal slab and/or the choriocapillaris slab. WF-ICGA images for all included eyes were acquired centered on the fovea with a 102-degree area during the early and middle phases, and the duration of ICGA in this study was at least 30 minutes. The main affected eye's session was videotaped during 10 seconds after ChVs developed, and WF-ICGA images were acquired centered on the fovea both eyes during 1 minute, followed by other 8 fixation points (superior, superotemporal [ST], temporal, inferotemporal [IT], inferior, inferonasal [IN], nasal, and superonasal [SN]) to observe the full extent of the ChVs. FFA was used to assess the presence of RPE leakage. 

Choroidal Vascular Hyperpermeability, Choroidal Vein Alterations, and Distribution Analysis

CVH was defined as patches of hyperfluorescence with blurred contours during the middle phase (8-15 minutes) of ICGA after indocyanine green injection.¹³ In this study, the number of CVH areas was recorded using the middle phase of ICGA. The location of each CVH area was documented to correspond with the anatomic position identified through early-phase WF-ICGA imaging. This included the quadrant of the ChV involved and whether it occurred in the dominant or non-dominant ChV. Additionally, the study evaluated the correlation between different patterns of ChV alterations and the distribution of CVH areas. Furthermore, the number of RPE leaks at the CVH areas was recorded using both ICGA and FFA imaging techniques to ensure comprehensive assessment. 

Different patterns of choroidal vein alterations were observed at the CVH areas within 1 minute after dye injection. During the early stage of ICGA, three patterns of ChV alterations at the CVH areas, including ChV fusiform, ChV bulbosity, and ChV sausaging, were found and distinguished based on the morphological characteristics in our study. ChV fusiform was defined as choroidal vessel dilation that is less than twice the diameter of the host vessel. ChV bulbosity was defined as a choroidal vessel dilation that is twice and more than twice the diameter of the host vessel.¹⁰ ChV sausaging was defined as a segment along a choroidal vessel in which 3 or more contiguous fusiform dilations differ by at least 50% in diameter from the narrowest to the largest.¹⁰ Additionally, two patterns of ChV alterations at the CVH areas, ChV anastomoses, and ChV confluence, were differentiated according to different structural characteristics. ChV anastomoses were defined as two anastomotic vessels connecting two separate vortex vein systems.¹⁴ ChV confluence was defined as the point of connection between the main vessel and its branches in our study (Figs. 1, 2). 

Figure 1.

 

Diagrams of different choroidal vein alterations patterns in the CVH areas of PCD eyes.

Figure 2.

 

ICGA characteristics of different choroidal vein alterations patterns in the CVH areas of two CSC eyes. (A) Early-phase ICGA in a CSC eye. (B) Mid-phase ICGA, displaying hyperfluorescent patches, CVH, in the same eye as in A. (C) Different patterns represented by different colors: yellow circle = ChV fusiform; green circle = ChV bulbosity; red circle = ChV sausaging; and yellow arrow = ChV confluence. (D) Magnified images of C. (E). Early phase ICGA in another CSC eye. (F) Mid-phase ICGA, displaying hyperfluorescent patches, CVH, in the same eye as in E. (G) Different patterns represented by different colors: red circle = ChV sausaging; yellow arrow = ChV confluence; and blue arrow = ChV anastomose. (H) Magnified images of G.

The dominant ChV was defined as the terminal of the lateral temporal ChV across the fovea of the macula, and the terminal of the lateral nasal ChV across the center of the disc in our study (Fig. 3). The non-dominant ChV was defined as the other ChV of the remaining quadrants. 

Figure 3.

 

Illustrations of choroidal vasculature in a normal eye and eyes with dominant ChVs in PCD eyes. (A, E) Symmetric ChVs in the normal eye: superior and inferior ChVs are symmetrical at the horizontal watershed zone. (B, F) Dominant ChV in the temporal side of the PCD eye: the terminal of the lateral temporal ChV (yellow arrowheads) crosses the macular fovea. (C, G). Dominant ChV in the nasal side of the PCD eye: the terminal of the lateral nasal ChV (orange arrowheads) crosses the disc center. (D, H) Two dominant ChVs in the temporal and nasal sides of the PCD eye: the terminal of the lateral temporal ChV (yellow arrowheads) crosses the macular fovea and the terminal of the lateral nasal ChV (orange arrowheads) crosses the disc center.

The number of vortex vein ampulla was recorded. The vortex vein ampulla was defined by the presence of numerous choroidal veins converging into an enlarged vestibular area before entering the sclera.⁷ 

Two trained investigators (authors G.H. and X.Z.) independently evaluated all multimodal images, and disagreements were resolved by a third retinal specialist (author F.W.) for final determination. 

Statistical Analysis

Statistical analysis was performed using SPSS (version 26.0; SPSS, Inc., Chicago, IL, USA). Descriptive statistics were reported as mean ± standard deviation (SD), median (interquartile range [IQR]), or as numbers (n) with percentages (%). One-way ANOVA was applied to compare continuous variables, such as age and SFCT, among the three subgroups of PCD eyes, assuming a normal distribution. Fisher's exact test was used to compare the categorical variable, gender, among the three subgroups. For nonparametric data, such as duration of symptoms, numbers of RPE leakage, different choroidal vein alterations patterns, etc., the Mann-Whitney U test was used to compare these continuous variables among the three subgroups of eyes with PCD. Additionally, the Wilcoxon signed-rank test was utilized to compare these continuous variables between the dominant and non-dominant ChVs of PCD eyes. Statistical significance was defined as P values < 0.05. Multiple comparisons were made using the Kruskal-Wallis test, and Bonferroni correction was applied. A significance level of P values < 0.0167 was used to account for multiple comparisons. Agreement between two masked investigators was gauged using the Kappa coefficient. 

Results

Characteristics of the Included Patients

Table 1 displays demographic and clinical characteristics of the included patients. Among the 68 eyes with PCD from 35 patients, the mean age was 46.16 ± 6.28 years, and 25 patients were men (71.4%). ChV alterations in the 2 eyes with UCP, 22 eyes with PPE, 38 eyes with CSC, and 6 eyes with PNV were compared. The mean SFCT was 468.65 ± 131.40 µm. 

Table 1.

 

Demographic and Clinical Characteristics of Patients With PCD Eyes

 

A total of 419 CVH areas were associated with 419 ChV alterations; of these, ChV confluence accounted for 21.2% of ChV alterations, whereas ChV anastomoses accounted for 11.9%. ChV fusiform and ChV bulbosity constituted nearly identical proportions of CVH venous alterations (35.8% and 35.1%, respectively), whereas ChV sausaging had the least proportion (29.1%). Additionally, 13.1% of the CVH areas had RPE leakage. Among the 55 RPE leakage points, different patterns of ChV alterations at the area of CVH were observed: ChV confluence contributed 29.1% (16/55) of ChV alterations, whereas ChV anastomoses contributed 16.4% (9/55). ChV alterations in the RPE leakage points showed a gradually decreasing proportion with 43.6% (24/55) for ChV sausaging, 32.7% (18/55) for ChV bulbosity, and 23.7% (13/55) for ChV fusiform. 

A total of 83.8% (57/68) of PCD eyes had dominant ChVs. In all CVH areas, 51.3% (215/419) of CVH areas were located at dominant ChVs. Among the 55 RPE leakage points, 69.1% (38/55) were located in the quadrants with dominant ChVs. 

Clinical and Demographic Characteristics of Choroidal Vein Alterations at the Areas of CVH in PPE, CSC, and PNV

Table 2 shows the clinical features of different patterns of ChV alterations at the area of CVH. Despite the CSC group (45.63 ± 6.12 years) being younger than the PPE (46.23 ± 7.11 years) and PNV (50.17 ± 3.66 years) groups, there was no statistical difference in age among the three groups (P = 0.270). Compared to the CSC and PPE groups, patients with PNV had symptoms for a longer duration on average (P = 0.001). Additionally, patients with PNV exhibited worse BCVA than the CSC and PPE groups (P < 0.001) and had more RPE leakage points (P < 0.001). The CSC group had the highest mean SFCT (497.55 ± 144.15 µm), followed by the PPE (444.36 ± 99.46 µm) and PNV (400.33 ± 129.95 µm) groups. Nevertheless, the variations in SFCT among these groups were not statistically significant (P = 0.125). Equally, there was no statistically significant difference in the presence of dominant ChVs among the three groups (all P > 0.050). 

Table 2.

 

Clinical and Demographic Characteristics of Choroidal Vein Alterations at the CVH Areas in PPE, CSC, and PNV

 

Table 3 highlights the gradual increase in the proportion of ChV confluence and ChV anastomoses in the PPE, CSC, and PNV groups (19.8%, 20.9%, and 28.6%, and 11.4%, 11.1%, and 20.0%, respectively). Furthermore, there was a steady decline in ChV fusiform and a continual growth of ChV sausaging in PPE, CSC, and PNV groups (37.4%, 36.8%, and 22.9%, 21.4%, 30.0%, and 37.1%, respectively). 

Table 3.

 

Different Patterns of Choroidal Vein Alterations at the CVH Areas in 68 PCD Eyes

 

Dominant ChVs and Non-Dominant ChVs at the CVH Areas in PPE, CSC, and PNV

Table 4 demonstrates the distribution of different patterns of ChV alterations in the CVH areas between dominant and non-dominant ChVs in PCD eyes. The median number of the CVH areas differed significantly higher in dominant than non-dominant ChVs in both temporal and nasal quadrants for PPE eyes (P = 0.010 and P = 0.020, respectively) and CSC eyes (P = 0.001 and P = 0.010, respectively). However, no significant differences were found between dominant and non-dominant ChVs in both temporal quadrants and nasal quadrants for PNV eyes (P = 0.240 and P = 0.180, respectively). In our study, the dominant ChVs in PPE (58.3%), CSC (54.0%), and PNV (60%) eyes were more commonly located in the temporal quadrants than in the nasal quadrant. 

Table 4.

 

Distribution of Different Patterns of Choroidal Vein Alterations at the CVH Areas in the Dominant and Non-Dominant Choroidal Veins of PCD Eyes

 

Interestingly, the clinical characteristics of different ChV alterations patterns in the CVH areas between dominant and non-dominant ChVs in the temporal side of CSC eyes were statistically significant, including ChV fusiform, ChV bulbosity, ChV sausaging, and ChV confluence (P = 0.030, P = 0.010, P = 0.020, and P = 0.001, respectively), except for ChV anastomoses (P = 0.250). In contrast, this difference was only observed in ChV anastomoses (P = 0.050) in PNV eyes. 

Remarkably, the number of RPE leakage points had significantly greater median differences in dominant than non-dominant ChVs in the temporal quadrants of CSC eyes (P = 0.001) and PNV eyes (P = 0.030). 

Interobserver Agreement

Interobserver agreement for both morphological and structural patterns was quantified using the Kappa coefficient. The results showed a Kappa coefficient ± SE of 0.780 ± 0.026 (P < 0.001) for morphological patterns, and a Kappa coefficient ± SE of 0.663 ± 0.067 (P < 0.001) for structural patterns, indicating substantial agreement between the two masked investigators. Furthermore, for dominant ChVs, the interobserver agreement demonstrated a Kappa coefficient ± SE of 0.962 ± 0.019 (P < 0.001), reflecting almost perfect agreement between the investigators. 

Discussion

In this study, we described the clinical features of ChV alterations using wide-field ICGA at the CVH areas (419) of the pachychoroid spectrum disease. The patterns were classified according to their morphological alterations, including ChV fusiform, ChV bulbosity, and ChV sausaging, and structural alterations, including ChV confluence, and ChV anastomoses. To our knowledge, this is the first research to investigate choroidal vascular alterations in choroidal vascular hyperpermeability region, and we discovered that ChV confluence plays a vital role in the presence at the CVH areas. This study showed dominant ChVs are more likely to have RPE leakages and ChV alterations in the CVH of eyes with PCD, and in those eyes, dominant ChVs are more prone to locate in the temporal side than the nasal side. 

ChV confluence at the CVH areas of the PCD is a newly described phenomenon. In normal physiological states, blood flow is relatively slow at the venous confluence. This is because the increase in the cross-sectional area of the blood vessels as it passes through the venous confluence results in a decrease in blood flow velocity, according to the theory that blood flow velocity being inversely proportional to the total cross-sectional area of the blood vessels. Decreased blood flow velocity leads to reduced wall shear stress (WSS) to maintain normal vascular physiology. In pathological states, increasing venous pressure can increase blood flow, resulting in increased WSS¹⁵ at the venous confluence. Furthermore, alterations in blood flow velocity and WSS may simultaneously trigger the production of a series of signaling molecules by vascular endothelial cells, such as nitric oxide and endothelin, which can affect the contraction and relaxation of smooth muscle cells, leading to vasodilation.¹⁶ Therefore, under the theory of venous pressure overload, ChV confluence is also one of the characteristic alterations of PCD. In our study, venous confluence alterations in CVH were more prominent in dominant ChVs. 

In our study, we revealed growth trend in the number of ChV anastomoses in PPE, CSC, and PNV eyes. Simultaneously, other researchers regard ChV anastomosis as playing a significant role in PCD, especially in the development from normal to CSC to PNV to PCV eye.² Takahashi et al. reported that the scleral buckling surgery resulted in a new venous drainage pathway connecting the ChV in different drainage quadrants.¹⁷ The ChV exhibited obvious plasticity, and the drainage channel was remodeled with the obstruction of the vortex vein. However, we observed ChV anastomosis accounts for only 11.9% (50/419) of different ChV alterations in the CVH areas with PCD, significantly less than that in other studies.^14,18–21 The following should be considered when explaining these differences. First, ChV anastomosis identification requires careful identification based on ICGA's early dynamic images, avoiding misidentification of the overlapping venous endings of the ChVs in two quadrants as anastomotic connections. Second, in the previous literature, OCTA imaging with a small perspective was often used, leading to misinterpretation of the ChV beyond the fovea as ChV anastomosis. In fact, it was the dominant ChV described in this paper. Thus, correctly identifying ChV anastomosis is crucial for exploring the underlying pathogenesis of PCD. 

Our results highlight the importance of dominant ChVs in PCD eyes. Generally, the choroidal watershed zone crosses the optic disc and macula horizontally and passes the optic disc and macula vertically.^22–24 Mori et al. found that half (18 of 36 eyes) of normal individuals had asymmetric choroidal venous drainage.²⁵ Subsequently, successive studies have found PCD eyes have more asymmetric vortex veins than normal ones.^14,26–28 In our study, we clearly distinguish the asymmetric ChV as dominant ChV, crossing the macula horizontally or crossing the optic disc vertically, and non-dominant ChVs. We found that 83.8% (57/68) of the examined PCD eyes have dominant ChVs. And 69.1% RPE leakage was located at the quadrants with dominant ChVs. The number of RPE leakages and CVH in the dominant ChVs in PCD eyes was higher than that in the non-dominant ChVs. A recent study also reported that the quadrant where the vortex veins with large drainage areas are located shows a greater density at the CVH areas points.¹⁴ With an imbalanced choroidal venous drainage system, we hypothesize that the dominant ChVs had more blood drainage and were therefore more prone to choroidal vascular abnormalities when the vein is obstructed and overloaded,²⁹ and eyes with dominant ChVs crossing the macula horizontally were more susceptible to have CSC, resulting in RPE leakage that led to CSC occurrence. Therefore, we consider that people with dominant ChVs need to be alert to some predisposing factors,^30–32 including hormone use, smoking, staying up late, insomnia, anxiety, and so on, to avoid the occurrence of PCD. However, this observation has not been appreciated before, resulting in dominant ChVs appearance being misidentified as ChV anastomosis, such as in previous studies described,^19,33 especially in 6 × 6 mm OCTA images. 

We found bulbosity and sausaging changes of ChVs in the CVH region, referring to the previous study. Additionally, fusiform changes in those areas have also been found. Those vascular alterations were similar to those seen in varicose veins, with venous dilatation due to increased venous pressure, localized variable dilatation, and remodeling with irregularities up to several times the diameter of normal veins.^10,34 Long-term venous hypertension causes macromolecular leakage from the microcirculation and red blood cell extravasation due to altered vascular architecture.³⁵ Furthermore, significant endothelial heterogeneity in the vortex venous system provides additional evidence that it may be a preferred site affected by pathological alterations.⁷ Combined with the three morphological alterations we observed in the CVH region, we reasonably hypothesize that this site exhibits hyperpermeable features in ICGA due to chronic venous hypertension and impaired microcirculation. 

The present study has several limitations. First, due to the retrospective observational study, inherent reporting biases exist. Ophthalmologists tend to perform ICGA for PCD patients with more severe condition after comprehensive assessment, which may result in an increased proportion of the CVH areas and dominant ChVs in PCD eyes. Second, our sample size is relatively small. Third, morphological remodeling is a slow process, but this study lacked long-term follow-up. Future studies will need to further investigate the longitudinal connections between choroidal vessels alterations in the morphology and structure at the CVH areas in eyes with PCD. Fourth, the absence of comparative data from normal eyes or other disease entities is another limitation. Regardless of these limitations, the study has strengthened our understanding of the pathogenesis at the CVH areas, providing directions for the prevention and treatment of it. 

In conclusion, using WF-ICGA, this study found different patterns of ChV alterations, including the newly identified feature, ChV confluence, are common features at CVH areas in PCD, and our findings highlight dominant ChVs, as essential features in PCD with CVH. The different manifestations of ChV alterations at the CVH areas and the high frequency of dominant ChVs in PCD further complement the theory of choroidal vein remodeling and provide evidence for the exploration of the pathogenesis of PCD eyes. 

Acknowledgments

Disclosure: G. He, None; X. Zhang, None; Y. Gan, None; M. Li, None; X. Zhuang, None; Y. Zeng, None; Y. Su, None; X. Chen, None; F. Wen, None