Introduction
Central serous chorioretinopathy (CSC) is characterized by localized serous retinal detachment (SRD) in the macula, often accompanied by pigment epithelial detachment (PED) and changes in the retinal pigment epithelium (RPE)1,2. In classic CSC, fluorescein angiography (FA) can reveal single or multiple focal leakage points, gradually expanding in the subretinal space, at the level of the RPE1,3,4. Choroidal vascular abnormalities, such as delays in choroidal vascular filling, vascular dilation, vascular hyperpermeability, and punctate hyperfluorescence spots, can also be detected using indocyanine green angiography (ICGA)3,5, 6, 7, 8, 9, 10, 11–12. Recently, increased choroidal thickness, termed pachychoroid, has been reported in both CSC and unaffected fellow eyes using enhanced depth imaging (EDI) optical coherence tomography (OCT)13, 14–15. Based on these findings, numerous studies have documented RPE morphological abnormalities in CSC16, 17, 18, 19, 20, 21–22, describing not only changes in choroidal thickness23, 24, 25–26, but also a notable relationship between the dilation of large choroidal blood vessels, known as pachyvessels, and increased choroidal thickness23, 24–25,27, 28, 29–30. These angiographic and OCT findings suggest that the principal pathophysiologic mechanism of CSC may involve choroidal vascular disturbances, such as hyperpermeability of the choriocapillaris and increased hydrostatic pressure within the choroid31, 32, 33–34.
While pachyvessels are commonly observed in CSC, not all appear to share identical characteristics, and only a subset contributes to vascular leakage. This raises the question of whether there are discernible morphological variations among pachyvessels themselves. Accordingly, this study aims to explore the potential differences in pachyvessel morphology and their relative prevalence across eyes with CSC, unaffected fellow eyes, and healthy controls, utilizing comprehensive analysis of EDI-OCT raster scan images.
Methods
This study was approved by the institutional review board (IRB) of the Samsung Medical Center and adhered to the tenets of the Declaration of Helsinki.
Subjects
The records of consecutive patients diagnosed with CSC between December 2011 and February 2013 at Samsung Medical Center, Seoul, Korea, were reviewed. Patients were included if they had a diagnosis of CSC and had undergone FA and SD OCT, including EDI OCT raster scans. Exclusion criteria included: systemic or ophthalmologic conditions affecting the choroid (e.g., diabetes mellitus, hypertension, uveitis, and glaucoma); macular diseases other than CSC (e.g., age-related macular degeneration, polypoidal choroidal vasculopathy, choroidal neovascularization, and epiretinal membrane); history of intraocular surgery, including cataract surgery; history of treatment for CSC (e.g., laser photocoagulation and photodynamic therapy); evidence of steroid-induced or pregnancy-related CSC; refractive error exceeding ± 6 diopters; and incomplete examinations (e.g., absence of OCT and FA data necessary for the diagnosis of CSC).
From the database of 550 subjects enrolled in the Korean Twin Study at Samsung Medical Center (an IRB-approved prospective study conducted from April 2012 to November 2012)35,36 healthy subjects matched for number, age, and gender with CSC patients were selected by one researcher (Y.M.S.) who was blinded to the clinical history of the CSC patients. Data from these healthy subjects were used as normal controls. Exclusion criteria for healthy subjects included a medical history of diabetes mellitus, hypertension, glaucoma, chorioretinal disease, ocular surgeries (including cataract and refractive surgery), and refractive error exceeding ± 6 diopters. To avoid genetic duplication effects, only one twin from each pair was included in the study.
All patients and healthy subjects underwent a comprehensive ophthalmologic evaluation, including slit lamp examination, best corrected visual acuity (BCVA) assessment, intraocular pressure measurements, EDI OCT raster scan, and color fundus photography using a fundus camera (TRC 50 IX or DX, Topcon, Paramus, New Jersey, USA; nonmyd 7, Kowa, Tokyo, Japan). FA was performed using Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany), TRC 50 IX or DX, or Optomap 200 TX (Optos, Dunfermline, UK). Some patients also underwent ICGA with Spectralis HRA + OCT.
Diagnosis and classification of CSC
CSC was diagnosed based on the presence of localized serous retinal detachment in the macular area, with or without PED, and leakage at the level of the RPE on FA. Eyes with CSC were classified into four categories - acute, chronic, recurrent, and resolved - based on the history, past medical records, and ocular findings on the day of the EDI OCT examination in line with previous literature37,38.
Acute CSC was defined by subjective symptoms within the past 3 months, such as decreased visual acuity, metamorphopsia, micropsia, and chromatopsia, with no evidence indicating chronic, recurrent, or resolved CSC. Chronic CSC was defined by the persistence of similar subjective symptoms, SRD lasting more than 3 months, or fundus lesions indicative of chronicity, including retinal or RPE atrophic changes, descending tract, and inferiorly located, bullous SRD, in the absence of any evidence suggesting recurrent or resolved CSC. Recurrent CSC was identified by a history of multiple CSC episodes documented in the past medical history or records, with no evidence suggesting resolved CSC. Resolved CSC was characterized by the absence of SRD, along with a documented history of CSC in the medical records, and no prior treatment, as confirmed through both medical chart review and patient-reported history. CSC eyes that underwent FA in conjunction with EDI OCT, or FA on the same day as the EDI OCT examination, were further subdivided based on FA findings indicating the presence or absence of active leakage. Active leakage was defined as one or more focal points of leakage from the RPE in the early phase of FA, gradually enlarging in the subretinal space. Eyes exhibiting focal hyperfluorescence in the early phase without enlargement in the late phase, or eyes showing no definite hyperfluorescence, were considered to exhibit no active leakage.
OCT scan and angiography
OCT images were acquired using the Spectralis HRA + OCT (version 1.7.0.0; Heidelberg Engineering, Heidelberg, Germany), which integrates the benefits of confocal scanning laser ophthalmoscopy (cSLO) and SD OCT to facilitate analysis through point-to-point registration. The raster scan for all study eyes was centered on the fovea, employing EDI protocols established by Spaide et al.39 The raster scan image comprised 31 B-scans, each containing 768 A-scans, 9.0 mm in length, and spaced 240 μm apart, covering a 30-degree by 25-degree area. Automatic real-time (ART) mode, utilizing the eye-tracker system, was activated, averaging a total of 25 frames per B-scan image. During the OCT examination, subjects were continuously instructed to maintain fixation on the internal fixation target. In addition to the raster scan, a horizontal EDI OCT cross-sectional scan at the fovea was performed for all eyes except for normal healthy subjects. Subfoveal choroidal thickness (SFCT) was manually measured at the foveal center using the software provided with the SD OCT device.
FA and ICGA were conducted, often concurrently with EDI OCT. For some CSC eyes, an EDI OCT raster scan with maximum density (11 μm distance between adjacent B-scans) and averaging (100 frames per B-scan image) was performed on hyperfluorescent lesions observed in early FA. When multiple hyperfluorescent lesions were present, only one lesion exhibiting focal leakage or located near the macular center was selected for scanning. The number of scan lines was generally limited and varied depending on the size of the hyperfluorescent lesion.
Morphological analysis of choroidal OCT images
OCT images scanned at points of active leakage identified on early FA in eyes with acute CSC were assessed for characteristic features of pachyvessels, focusing on size, location, and vascular wall intensities. The vascular diameter, length of the vessel wall, and distance from the RPE-Bruch’s membrane-choriocapillaris complex were manually measured using the proprietary software of the SD OCT device. Vascular wall reflectivity was quantified using Image J software (version 1.46; National Institutes of Health, Bethesda, MD). Pixel intensities along a vertical cross-sectional line within the selected area were calculated using the plot profile tool (Figs. 1, 2). In images with PED, the reflectivity profile displayed three consecutive hyperreflective bands corresponding to the RPE (P1), Bruch’s membrane (P2), and the vascular wall of the pachyvessel (P3). In images with RPE protrusion or normal RPE, only two peaks were observed, corresponding to the RPE-Bruch’s membrane complex (P1-2) and the vascular wall of the pachyvessel (P3). The relative reflectivity of the vascular wall (P3) was assessed in comparison with that of the RPE (P1) or the RPE-Bruch’s membrane complex (P1-2). The morphological sign representing the characteristic features of CSC was defined based on these measurements and findings.
Fig. 1 [Images not available. See PDF.]
Flow chart showing the exclusion and inclusion process of patients with central serous chorioretinopathy (CSC). FA = Fluorescein angiography.
Fig. 2 [Images not available. See PDF.]
Images of a 43-year-old woman with acute central serous chorioretinopathy. (A), Fluorescein angiography (FA) showed a focal leaking point at the nasal side of fovea. (B), The enhanced depth imaging (EDI) optical coherence tomography (OCT) image corresponding to the white horizontal arrow in (A) showed a pachyvessel (outlined by white arrowheads) abutting the retinal pigment epithelium (RPE)-Bruch’s membrane-choriocapillaris complex with hyperreflectivity of vascular wall (active sign). Protrusions (white arrow) of RPE were identified at the area corresponding to active sign. (C), The 1:1 micron image converted from the 1:1 pixel image of (B), showing a real morphology of a pachyvessel (outlined by white arrowheads). (D), Infrared photograph with raster scan lines of EDI OCT. (E), Sixteenth B-scan image showing a pachyvessel abutting the RPE-Bruch’s membrane-choriocapillaris complex with a hyperreflective vascular wall (active sign). Protrusions of RPE (white arrow) were identified at the area corresponding to the active sign. (F,G,H), Indocyanine green angiography showed a filling delay in early phase (F) (outlined by black arrowheads), a dilated large choroidal vessel (black arrowheads in G), and choroidal vascular hyperpermeability (black arrowheads in H).
The prevalence of the defined morphological sign was examined using the EDI OCT raster scan centered at the fovea to determine if this sign could differentiate eyes with CSC from unaffected fellow or healthy eyes, and acute CSC eyes from non-acute CSC eyes. An eye was considered to exhibit the defined sign if one or more of the 31 B-scan images showed this sign. If none of the B-scan images displayed the defined sign, the eye was deemed not to have the sign. The occurrence of abnormal RPE lesions, including PED and RPE protrusion, was also investigated. PED was defined as a localized, dome-shaped elevation of the RPE, while RPE protrusion was defined as multiple bulges of the RPE with no hyporeflective space beneath it.
Two independent graders (M.K. and S.Y.P.), who were blinded to clinical data, reviewed all EDI OCT images. If there was a discrepancy between the two graders, the image in question was reviewed by a senior grader (D.I.H.), and a final assessment was made following discussion.
Statistical analyses
Fisher’s exact test was employed to compare the frequency of the morphological sign between eyes of CSC patients and normal healthy eyes, as well as to compare the frequency of the characteristic sign among different CSC eyes. SFCT in eyes with CSC and unaffected fellow eyes was compared using paired’s t-test. The Mann-Whitney U test was used to compare clinical features among CSC eyes with different morphological signs. A p-value of less than 0.05 was considered statistically significant. All statistical analyses were conducted using SPSS version 23.0 software.
Results
Of the 101 patients diagnosed with CSC, 58 ultimately met the study criteria (Fig. 1). A total of 232 eyes from 116 subjects were evaluated, including 116 eyes from 58 patients with CSC and 116 eyes from 58 age- and gender-matched normal healthy subjects. The average age of the subjects was 48.0 ± 7.7 years (range, 31–68 years), and the male-to-female ratio among CSC patients was 5.4 (49 males and 9 females). Bilateral involvement was observed in 8 CSC patients, resulting in 66 eyes with CSC and 50 unaffected eyes. In cases of bilateral CSC, both eyes were included, but this applied to only 8 eyes out of the total sample. To account for potential intra-subject correlation, analyses were conducted at the eye level and limitations of this approach are acknowledged. The average duration of subjective symptoms in eyes with CSC was 13.63 ± 16.37 months (range, 0.18–72.00 months). The average SFCT in eyes with CSC was 458.3 ± 130.8 μm (range, 232–862 μm), while in unaffected fellow eyes it was 415.8 ± 102.7 μm (range, 251–658 μm) (P = 0.052, paireds t-test). Clinical characteristics of the study eyes are summarized in Table 1.
Table 1. Clinical characteristics of study eyes.
CSC eyes | Unaffected fellow eyes | Healthy eyes | |
---|---|---|---|
Number of eyes | 66 | 50 | 116 |
Sex (male/female) | 56/10 | 42/8 | 98/18 |
Age (years) | 48.2 ± 7.3 | 48.1 ± 7.9 | 48.1 ± 7.7 |
Refractive errors (diopters) | −0.44 ± 1.38 | −0.54 ± 1.34 | −0.46 ± 1.32 |
Visual acuity (log MAR) | 0.19 ± 0.27 | 0.03 ± 0.13 | 0.03 ± 0.07 |
Subfoveal choroidal thickness | 458.3 ± 130.8 | 415.8 ± 102.7 | - * |
CSC = central serous chorioretinopathy.
*: not measured.
Eyes with CSC were further classified into four subgroups: acute, chronic, recurrent, and resolved CSC. The distribution was as follows: 18 eyes (27.3%) were classified as acute, 19 eyes (28.8%) as chronic, 12 eyes (18.1%) as recurrent, and 17 eyes (25.8%) as resolved. Of the 66 eyes with CSC, 55 (83.3%) underwent FA and EDI OCT on the same day. Among these, 30 eyes (54.5%) showed active leakage on FA: 17 in acute CSC eyes, 5 in chronic CSC eyes, and 8 in recurrent CSC eyes. Hyperfluorescent lesions without active leakage on FA were observed in 25 eyes (45.5%).
Characteristic morphology of pachyvessels in CSC
A total of the 55 eyes that underwent FA and EDI-OCT on the same day, 51 eyes were imaged with systems allowing spatial linkage between the two modalities. Images of 17 acute CSC eyes from a total of 51 CSC eyes that underwent FA-linked EDI OCT were analyzed to identify common morphological features of pachyvessels at points of active leakage on FA. The focus was on dilated pachyvessels that abut the RPE-Bruch’s membrane-choriocapillaris complex and are closely associated with abnormal RPE lesions. These pachyvessels were observed to be round, oval, or tube-like in shape, often with a slightly flattened top in 1:1 pixel images, and appeared more horizontally oval or tube-like in 1:1 micron images (Fig. 2A, B, C). The analysis revealed that characteristic morphological features of pachyvessels included: (1) a vertical diameter exceeding 200 μm, and (2) a horizontal length of the segment of the vascular wall located within 10 μm of the RPE-Bruch’s membrane-choriocapillaris complex exceeding 200 μm40,41. Additionally, some eyes exhibited hyperreflectivity in the part of the vascular wall along the RPE-Bruch’s membrane-choriocapillaris complex (Table 2). Hyperreflectivity of the vascular wall was defined as the reflectivity intensities of the vascular wall (P3) exceeding 80% of those of the RPE (P1) or the RPE-Bruch’s membrane complex (P1-2) in the plot profile (Fig. 3). The 80% reflectivity threshold used to define active HD signs was empirically determined based on clinical experience, and not derived from ROC analysis. This limitation should be addressed in future studies aiming to establish an optimal diagnostic cutoff.
Table 2. Morphological features of pachyvessels at the angiographic leakage point in 17 acute Csc eyes.
Case | Sex | Age | Eye | Onset | Characteristics of large choroidal vessels | ||
---|---|---|---|---|---|---|---|
Vertical diameter (µm) | Horizontal length of choroidal vessel wall abutting Bruch’s membrane (µm)* | Hyperreflectivity of vascular wall along the RPE | |||||
1 | M | 43 | Left | 2 weeks | 320 | 207 | + |
2 | M | 42 | Right | 5 days | 243 | 355 | + |
3 | M | 43 | Left | 1 week | 282 | 302 | + |
4 | M | 45 | Right | 2 weeks | 373 | 522 | + |
5 | F | 38 | Right | 3 weeks | 285 | 302 | - |
6 | M | 42 | Right | 3 weeks | 346 | 452 | + |
7 | M | 51 | Right | 2 weeks | 240 | 344 | + |
8 | M | 51 | Left | 2 weeks | 292 | 322 | + |
9 | M | 36 | Left | 5 weeks | 312 | 281 | + |
10 | M | 51 | Left | 2 weeks | 461 | 258 | + |
11 | M | 50 | Left | 4 weeks | 331 | 430 | + |
12 | M | 46 | Right | 3 weeks | 253 | 393 | + |
13 | M | 36 | Left | 5 weeks | 299 | 451 | + |
14 | M | 44 | Right | 4 weeks | 310 | 250 | + |
15 | M | 44 | Left | 4 weeks | 328 | 339 | + |
16 | M | 41 | Left | 10 weeks | 466 | 371 | + |
17 | M | 56 | Left | 10 weeks | 324 | 344 | + |
* Choroidal vessel wall was located within 10 μm from the RPE-Bruch’s membrane-choriocapillaris complex.
Fig. 3 [Images not available. See PDF.]
Analysis on the reflectivity of vascular wall of a pachyvessel. (A), Optical coherence tomography (OCT) image showing serous retinal detachment (SRD) and shallow pigment epithelial detachment (PED). A pachyvessel abutting the RPE-Bruch’s membrane-choriocapillaris complex was identified. (B), Enlarged image extracted from area corresponding to white rectangle in (A). There were three hyperreflective bands, and the reflectivity was calculated along the white vertical arrow of enlarged image. (C), The reflectivity profile showed three consecutive peaks corresponding to RPE (P1: 216 [intensity of pixels]), Bruch’s membrane (P2: 172), and vascular wall of a pachyvessel (P3: 221). (D), OCT image showing SRD and protrusions of RPE. A pachyvessel abutting the RPE-Bruch’s membrane-choriocapillaris complex was identified. (E), There were two hyperreflective bands. (F), The reflectivity profile showed only two consecutive peaks corresponding to RPE-Bruch’s membrane complex (P1-2: 250), and vascular wall of a pachyvessel (P3: 231).
Given that a dilated pachyvessel abutting the RPE-Bruch’s membrane-choriocapillaris complex resembles a water droplet hanging from a branch, we propose the term “hanging drop (HD) sign” to describe these characteristic features. We further suggest categorizing this sign into “active HD sign” and “inactive HD sign” based on the presence or absence of vascular wall hyperreflectivity, respectively (Fig. 4). For simplicity, the terms “active sign” and “inactive sign” will be used interchangeably with “active HD sign” and “inactive HD sign,” respectively, throughout this article.
Fig. 4 [Images not available. See PDF.]
Schematic diagram of 1:1 pixel optical coherence tomography images showing the hanging drop (HD) sign. The HD sign is defined as a pachyvessel with the vertical diameter larger than 200 μm, showing the part of vascular wall, which is located within 10 μm from the RPE-Bruch’s membrane-choriocapillaris complex and more than 200 μm in the horizontal length. The active and inactive sign were defined as the HD sign with or without vascular wall hyperreflectivity, respectively.
Raster scan, FA and ICGA
The definition of the HD sign was applied to images obtained from the 31-line raster scan, as the relative reflectivity of the vascular wall in OCT images averaged over 25 frames was found to be acceptably similar to that in OCT images averaged over 100 frames (Fig. 2B, E, and Fig. 5B, D). Analysis of 7,192 raster scan images from 232 eyes revealed 76 b-scan images with the active sign and 148 images with the inactive sign, distributed as follows: 114 images from CSC eyes, 25 images from unaffected fellow eyes, and 9 images from healthy eyes. Each sign appeared in one or a few consecutive b-scan images. On average, a single eye exhibited 2.05 ± 1.18 (range, 1–6) b-scan images with the active sign and 1.37 ± 1.86 (range, 1–8) b-scan images with the inactive sign.
Fig. 5 [Images not available. See PDF.]
Images of a 42-year-old man with acute central serous chorioretinopathy. (A), Fluorescein angiography showed an ink-blot pattern of leakage. (B), The enhanced depth imaging optical coherence tomography (EDI OCT) scan corresponding to the white horizontal arrow in (A) showed a pachyvessel (outlined by white arrowheads) abutting the retinal pigment epithelium (RPE)-Bruch’s membrane-choriocapillaris complex with hyperreflective vascular wall (active sign), and flat pigment epithelial detachment (PED) (white arrow). (C), Infrared photograph with raster scan lines of EDI OCT. D, Eighteenth B-scan image also showed a pachyvessel with the active sign (outlined by white arrowheads), and flat pigment epithelial detachment (PED) (white arrow). (E,F), Thirty-first B-scan image of the same eye showed a pachyvessel (outlined by white arrowheads in (F) abutting the retinal pigment epithelium (RPE)-Bruch’s membrane-choriocapillaris complex without hyperreflective vascular wall (inactive sign). All OCT scans (B, D, and F) were acquired on the same day. B and D were obtained using different scan modes (cross-sectional and raster scan, respectively), and the selected images represent the most anatomically comparable locations available.
Among the eyes with CSC, 86.4% (57/66) displayed the HD sign, either active or inactive. Specifically, the active sign was observed in 56.1% (37/66) of CSC eyes, the inactive sign in 77.3% (51/66), and neither sign in 13.6% (9/66). Of the eyes with the active sign, 83.8% (31/37) also exhibited the inactive sign, while 60.8% (31/51) of eyes with the inactive sign also had the active sign (Fig. 5). Notably, 9.1% (6/66) of CSC eyes had only the active sign, and 30.3% (20/66) had only the inactive sign. The active sign was exclusively found in CSC eyes. However, the inactive sign was observed in 30.0% (15/50) of unaffected fellow eyes and 9.5% (11/116) of healthy eyes (Figs. 6 and 7). The prevalence of the inactive sign was significantly higher in CSC eyes compared to unaffected fellow eyes (P = 0.000, Fisher’s exact test) and healthy eyes (P = 0.000, Fisher’s exact test), and was also more common in unaffected fellow eyes than in healthy eyes (P = 0.002, Fisher’s exact test). Furthermore, the inactive sign without the active sign was more frequently observed in CSC eyes than in healthy eyes (P = 0.000, Fisher’s exact test) (Fig. 6).
Fig. 6 [Images not available. See PDF.]
Prevalence of characteristic signs in each study group. CSC = Centra serous chorioretinopathy; UAE = Unaffected fellow eyes.
Fig. 7 [Images not available. See PDF.]
Color photographs, infra-red images, and enhanced depth imaging optical coherence tomography (EDI OCT) raster scan images of unaffected fellow eyes and healthy eyes. (A), Images from an unaffected fellow eye of 55-year-old man who had chronic central serous chorioretinopathy in the right eye. The seventeenth B-scan image with EDI OCT raster scan showed a pachyvessel (outlined by white arrowheads) abutting the retinal pigment epithelium (RPE)-Bruch’s membrane-choriocapillaris complex without vascular wall hyperreflectivity (inactive sign). Color photograph showed a vertically crossing pachyvessel (black arrowheads) near the fovea, at the area corresponding to the inactive sign on EDI OCT. (B), Images from an unaffected fellow eye of 41-year-old man who had acute central serous chorioretinopathy in the right eye. The fifth B-scan image with EDI OCT raster scan showed the inactive sign (outlined by white arrowheads) with protrusions of RPE (white arrow). Color photograph showed a pachyvessel (black arrowheads) near the inferior vascular arcade, at the area corresponding to inactive sign on EDI OCT. (C), Images from 43-year-old healthy man. The twenty-fourth B-scan image with EDI OCT raster scan showed the inactive sign (outlined by white arrowheads) near the superior vascular arcade. (D), Images from 42-year-old healthy woman. The eighteenth B-scan image with EDI OCT raster scan showed the inactive sign (outlined by white arrowheads) near the fovea, and protrusions of RPE (white arrow) at the area corresponding to the inactive sign.
Table 3 presents the clinical features associated with each characteristic sign of CSC. Eyes displaying the active sign (whether exclusively or in conjunction with the inactive sign) had a significantly shorter duration of subjective symptoms compared to other eyes (P = 0.001; comparison with eyes exhibiting only the inactive sign, P = 0.000; comparison with eyes showing no sign). Additionally, eyes with the inactive sign (whether solely or combined with the active sign) also demonstrated a significantly shorter duration of subjective symptoms compared to eyes without any sign (P = 0.003). However, there was no significant difference in the duration of subjective symptoms between eyes showing only the inactive sign and those with no sign. Both eyes with the active sign and those with the inactive sign exhibited increased SFCT compared to eyes without any sign (P = 0.000 for both comparisons).
Table 3. Clinical features of CSC eyes with the characteristic sign.
Eyes with CSC | P‡ | P§ | P║ | P¶ | ||||
---|---|---|---|---|---|---|---|---|
Active sign* | Inactive sign† | Inactive sign only | No sign | |||||
Number of eyes | 37 | 51 | 20 | 9 | ||||
Mean age (years) | 48.2 ± 7.2 | 47.4 ± 7.5 | 46.6 ± 9.1 | 50.7 ± 5.3 | 0.426 | 0.249 | 0.193 | 0.194 |
Male to female ratio (male/female) | 8.25 (33/4) | 5.38 (43/8) | 4.0 (16/4) | 3.5 (7/2) | N/A | N/A | N/A | N/A |
Visual acuity (Log MAR) | 0.20 ± 0.28 | 0.19 ± 0.29 | 0.21 ± 0.29 | 0.08 ± 0.17 | 0.918 | 0.137 | 0.108 | 0.131 |
SFCT (µm) | 486.0 ± 129.3 | 481.7 ± 130.1 | 470.4 ± 115.7 | 317.8 ± 76.7 | 0.744 | 0.000 | 0.002 | 0.000 |
Mean duration of subjective symptoms (months) | 6.1 ± 6.7 (range 0.18–26) | 11.5 ± 15.4 (range 0.18–72) | 20.8 ± 20.2 (range 0.75–72) | 28.6 ± 19.2 (range 6–64) | 0.001 | 0.000 | 0.219 | 0.003 |
CSC = central serous chorioretinopathy.
Log MAR = logarithm of minimum angle of resolution.
SFCT = subfoveal choroidal thickness.
Data are presented as mean ± standard deviation.
*Including eyes with active sign only and eyes with both active and inactive signs.
†Including eyes with inactive sign only and eyes with both active and inactive signs.
‡Comparison between active sign and inactive sign only by Mann-Whitney U test.
§Comparison between active sign and no sign by Mann-Whitney U test.
║Comparison between inactive sign only and no sign by Mann-Whitney U test.
¶Comparison between inactive sign and no sign by Mann-Whitney U test.
All eyes and B-scan images showing the active sign exhibited RPE abnormalities. Specifically, B-scan images revealed PED in 54.0% (41/76) and RPE protrusion in 67.1% (51/76) at the locations corresponding to the active sign (Fig. 2B, E, and Fig. 5B, D). In contrast, 62.7% (32/51) of CSC eyes and 67.5% (77/114) of B-scan images with the inactive sign exhibited RPE abnormalities. Among these, PED was observed in 36.8% (42/114) and RPE protrusion in 46.5% (53/114) at the regions corresponding to the inactive sign (Fig. 7).
A significantly higher frequency of the HD sign was found in eyes with serous retinal detachment (SRD) (98.0%, 48/49) compared to eyes without SRD (52.9%, 9/17) (P = 0.000, Fisher’s exact test). Specifically, the active sign was observed in 69.4% (34/49) of eyes with SRD versus 17.6% (3/17) of eyes without SRD, and the inactive sign was present in 87.8% (43/49) of eyes with SRD versus 47.1% (8/17) of eyes without SRD (P = 0.000 and P = 0.001, respectively, Fisher’s exact test).
Angiographic images were analyzed for 55 eyes from 47 patients with CSC who underwent FA and EDI OCT on the same day. Among these, 51 eyes had simultaneous FA and EDI OCT. Hyperfluorescent lesions on early FA were detected in all eyes (55/55), with active leakage points observed in 54.5% (30/55) of the eyes. The active sign and inactive sign were identified in 65.5% (36/55) and 27.3% (15/55) of the eyes, respectively. A total of 74 B-scan images demonstrated the active sign, while 108 images showed the inactive sign across the 55 CSC eyes. All active signs were located at hyperfluorescent lesions, whereas the inactive signs were found both at hyperfluorescent (65.7%, 71/108) and non-hyperfluorescent areas (34.3%, 37/108). In all eyes with active leakage on early FA, the HD sign was present in the area corresponding to or adjacent to the leakage point. Specifically, 10% (3/30) of these eyes exhibited only the active sign, 13.3% (4/30) displayed only the inactive sign, and 76.7% (23/30) showed both signs (Fig. 2D, E, and Fig. 5C, D). Additionally, all eyes with active leakage on early FA exhibited RPE abnormalities in the region corresponding to or near the leakage point. Of these, 6.7% (2/30) displayed only PED, 20.0% (6/30) showed only RPE protrusion, and 73.3% (22/30) exhibited both. The active sign was significantly more prevalent in eyes with active leakage (86.7%, 26/30) compared to those without active leakage (40.0%, 10/25; P = 0.000, Fisher’s exact test). However, no statistically significant difference in the frequency of the inactive sign was observed between eyes with active leakage and those without (90.0%, 27/30 vs. 72.0%, 18/25; P = 0.158, Fisher’s exact test). Angiographic images were also evaluated in 10 eyes from 8 patients who underwent ICGA and EDI OCT on the same day. All ten eyes that underwent ICGA exhibited either the active or inactive sign; 7 had the active sign, and 9 had the inactive sign. Dilated choroidal vessels were identified on ICGA in all areas corresponding to either the active or inactive sign (see Fig. 2G). Vascular hyperpermeability was observed on ICGA in regions corresponding to the active sign in 85.7% (6/7) and the inactive sign in 77.8% (7/9) of the cases (Fig. 2H). Among the 51 eyes with available FA images, 38 eyes (74.5%) showed spatial alignment between the HD sign and the leakage site. In the subset of 17 eyes that underwent ICGA, 13 eyes (76.5%) demonstrated choroidal hyperpermeability at the corresponding HD location.
Subgroup analysis in eyes with CSC
SFCT was measured across different categories of CSC and unaffected fellow eyes. The SFCT values were as follows: 479.7 ± 98.7 μm (ranging from 347 to 702 μm) in acute CSC eyes, 473.7 ± 161.0 μm (ranging from 273 to 862 μm) in chronic CSC eyes, 503.7 ± 101.0 μm (ranging from 369 to 678 μm) in recurrent CSC eyes, 386.5 ± 123.2 μm (ranging from 232 to 612 μm) in resolved CSC eyes, and 415.8 ± 102.7 μm (ranging from 251 to 658 μm) in unaffected fellow eyes. Statistical analysis using the Kruskal-Wallis test indicated a significant difference in SFCT among these groups (P = 0.012). Further analysis with the Mann-Whitney U test revealed that SFCT was significantly greater in eyes with acute and recurrent CSC compared to unaffected fellow eyes (P = 0.032 and P = 0.009, respectively).
All eyes with acute and chronic CSC exhibited the HD sign. However, the HD sign was absent in one recurrent CSC eye and eight resolved CSC eyes. The active sign was detected with significantly higher frequency in acute CSC eyes (16/18, 88.9%) compared to non-acute CSC eyes (which includes chronic, recurrent, and resolved CSC, 21/48, 43.8%; P = 0.002, Fisher’s exact test), chronic CSC eyes (9/19, 47.4%; P = 0.013), and resolved CSC eyes (3/17, 17.6%; P = 0.000). However, there was no significant difference in the frequency of the active sign between acute CSC eyes and recurrent CSC eyes (9/12, 75%; P = 0.364). The inactive sign was observed more frequently in acute CSC eyes (17/18, 94.4%) compared to resolved CSC eyes (8/17, 47.1%; P = 0.003). However, no significant differences were found when comparing acute CSC eyes with non-acute CSC eyes (34/48, 70.8%; P = 0.051), chronic CSC eyes (18/19, 94.7%; P = 0.743), or recurrent CSC eyes (8/12, 66.7%; P = 0.128). The inactive sign without the presence of the active sign was identified in two acute CSC eyes (2/18, 11.1%) and in 18 non-acute CSC eyes (18/48, 37.5%; P = 0.069). Table 4 provides a detailed analysis of the eyes across different types of CSC.
Table 4. Prevalence of the characteristic sign in each category of CSC.
Eyes with CSC | P‡ | P§ | P║ | ||||
---|---|---|---|---|---|---|---|
Acute CSC | Chronic CSC | Recurrent CSC | Resolved CSC | ||||
Total eyes | 18 | 19 | 12 | 17 | |||
Eyes with | |||||||
Active sign* | 16 (88.9%) | 9 (47.4%) | 9 (75%) | 3 (17.6%) | 0.013 | 0.364 | 0.000 |
Inactive sign† | 17 (94.4%) | 18 (94.7%) | 8 (66.7%) | 8 (47.1%) | 0.743 | 0.128 | 0.003 |
Inactive sign only No sign | 2 (11.1%) 0 | 10 (52.6%) 0 | 2 (16.7%) 1 (8.3%) | 6 (35.3%) 8 (47.1%) | 0.013 N/A | 1.000 0.400 | 0.121 0.001 |
CSC = central serous chorioretinopathy.
N/A = not available.
*Including eyes with active sign only and eyes with both active and inactive signs.
†Including eyes with inactive sign only and eyes with both active and inactive signs.
‡Comparison between acute and chronic CSC by Fisher’s exact test.
§Comparison between acute and recurrent CSC by Fisher’s exact test.
║Comparison between acute and resolved CSC by Fisher’s exact test.
Discussion
In the initial phase of this study, morphological features of pachyvessels were evaluated at actively leaking points identified on early FA in eyes affected by acute CSC. These areas were hypothesized to be the regions most likely to exhibit early pathological vascular changes within the choroid. Analysis of relatively large choroidal blood vessels revealed distinctive morphological features that we have termed the “HD sign.” Additionally, increased reflectivity of certain portions of the vascular wall was observed in some pachyvessels (referred to as the active HD sign), though this was not present in all pachyvessels exhibiting the HD sign.
Although the definition of this characteristic morphological sign in pachyvessels associated with CSC was based on an evaluation of a limited number of eyes, significant differences in the prevalence of the HD sign were observed between the CSC and control groups. The HD sign was more frequently observed in eyes with CSC compared to unaffected fellow eyes and healthy control eyes (86.4%, 30.0%, and 9.5%, respectively). Additionally, a distinctive prevalence of the HD sign was noted among different clinical conditions within the CSC group. Moreover, the active HD sign was exclusively observed in eyes with CSC. The prevalence of the active HD sign varied significantly among different clinical conditions within the CSC group, being more frequently observed in acute CSC eyes (88.9%) than in chronic (47.4%) or resolved (17.6%) CSC eyes. The mean duration of subjective symptoms was also significantly shorter in CSC eyes with the active HD sign compared to those with inactive HD signs or without any signs. Furthermore, the active HD sign was more commonly observed in CSC eyes with active leakage on early FA (83.9%) than in those without leakage (41.7%), and in CSC eyes with SRD (69.4%) than in those without SRD (17.6%). These percentages reflect subgroup-specific frequencies and are not based on a single denominator.
The presence of the HD sign, irrespective of its subtype, is more strongly associated with a diagnosis of CSC, while its absence reduces the likelihood of CSC. In cases where the active HD sign is observed in CSC eyes, there is a greater likelihood of an acute clinical condition characterized by active leakage and SRD.
The HD sign represents a two-dimensional morphological indicator of a three-dimensional vascular abnormality, which is challenging to detect using conventional angiography or single cross-sectional OCT. Therefore, EDI OCT raster scanning is necessary to identify the HD sign, as it requires the assessment of multiple consecutive B-scan images to confirm the presence of this distinctive blood vessel. Advanced choroidal OCT with higher resolution, utilizing en face scanning, has the potential to more accurately reveal the morphology of choroidal blood vessels, thereby increasing the detection rate of abnormal vessels exhibiting these characteristics. It is important to note that the control group in this study underwent ophthalmic examinations in 2012, at a time when commercially available OCT machines did not support en face OCT imaging. Consequently, this imaging technique could not be included in the study. Further research is required to refine scanning methods and to establish a more precise definition of the HD sign.
Previous studies utilizing ICGA and FA have suggested that the primary pathophysiological mechanism of CSC is a disturbance in choroidal circulation. Prünte et al. reported that a localized delay in arterial filling was frequently associated with dilated choroidal blood vessels in areas corresponding to PED or focal RPE leakage11. Iida et al. similarly identified choroidal filling delays, venous dilation, and focal choroidal hyperfluorescence surrounding areas of RPE leakage6. Kitaya et al. proposed that the primary cause of CSC is occlusion of the choriocapillaris, based on the observation of small hypofluorescent areas during ICGA around the leakage points and decreased blood flow in the choriocapillaris7. In the current study, both the HD sign and characteristic choroidal ICGA findings were observed around the active leakage points on FA, although only a limited number of CSC eyes were evaluated using ICGA. The HD sign, which represents a distinct morphological indicator of a dilated pachyvessel with nearly collapsed choriocapillaris, accounts for the choroidal changes observed on ICGA and appears to be associated with choroidal circulatory disturbances. However, the prevalence of pachyvessels reported in previous studies was lower than the prevalence of the HD sign observed in the current study (61% versus 83.4%, respectively). This discrepancy is likely due to differences in CSC subpopulations and the lack of a clear definition of dilated large choroidal blood vessels on ICGA6,10. A previous study by Sahoo et al. also emphasized localized choroidal vascular changes at the leakage sites in acute CSC, reporting a significantly increased choroidal vessel diameter-to-thickness ratio at the leakage point compared to the subfoveal region, with partial regression following resolution of subretinal fluid42. While their findings underscored the structural prominence of dilated vessels at sites of active leakage, our study further builds upon this by introducing a morphologically defined vascular configuration—the “hanging drop sign”—and analyzing its relationship with disease activity and angiographic leakage. This complements the location-based vascular analyses of previous work by adding a shape- and function-oriented perspective.
The HD sign exhibited a strong association with RPE abnormalities, one of the characteristic OCT findings in CSC. Fujimoto et al. identified RPE abnormalities in 96% of fluorescein leakage sites on FA16, and Montero and Ruiz-Moreno observed RPE bulges in 90% of CSC eyes43. In the current study, all eyes or images displaying the active HD sign, and nearly two-thirds of those with the inactive HD sign, exhibited RPE abnormalities. Moreover, both the HD sign and RPE abnormalities were present in all images scanned at or near active RPE leakage sites. These findings suggest that the HD sign, particularly the active sign, may be associated with the development of RPE abnormalities and RPE leakage in CSC, further supporting its role as a biomarker of active disease. Although hypertransmission in the active HD sign may suggest increased choroidal signal penetration, we cannot exclude the contribution of localized RPE atrophy, as fundus autofluorescence imaging was not performed in most cases. Other mechanisms may also underlie this hyperreflectivity. These include structural remodeling of the choroidal vessel wall, increased vascular permeability, proteinaceous or cellular infiltration, or reactive fibrotic changes associated with choroidal vascular stress. These interpretations remain speculative, but may be consistent with the observed association between the active HD sign and disease activity. This remains a potential limitation in interpreting the hyperreflective vessel wall signal.
Interestingly, aspects of the active HD sign appear to have been observed in a few previous studies on CSC21,44. Shinojima et al. identified highly reflective substances beneath the RPE using conventional spectral-domain OCT in CSC eyes21, which were hypothesized to be significant amounts of fibrin within the Bruch’s membrane, according to a report from an experimental animal model45. We propose that these highly reflective sub-RPE substances correspond to the hyperreflective walls of enlarged choroidal blood vessels associated with the active HD sign, given the similarity in shape between the two findings. Enhanced depth imaging (EDI) OCT can reveal the entire structure of an enlarged blood vessel, which conventional OCT is unable to show. Daruich et al. also supported this view, noting that in chronic cases, the walls of large vessels exhibit granular hyperreflectivity, suggesting potential changes in vascular wall structure46.
The primary morphological difference between the active and inactive HD signs lies in the reflectivity of the vascular wall. Most acute CSC eyes and nearly half of chronic CSC eyes exhibited both the active and inactive signs. The frequency of the active sign decreased in correlation with the degree of acuteness and disease activity. The inactive sign, on the other hand, was observed in most acute and chronic CSC eyes, but in less than half of resolved CSC eyes, with its frequency decreasing solely in relation to disease activity. Additionally, the inactive sign was present in some unaffected fellow eyes and healthy eyes. This suggests that the inactive sign may represent a precursor or regressed form of the active sign, rather than an independent pathological marker, and it may disappear upon the resolution of CSC. Further longitudinal studies are needed to confirm this hypothesis.
RPE and retinal morphological abnormalities in eyes with CSC have been reported as useful for diagnosing and assessing the chronicity of CSC16, 17, 18, 19, 20, 21–22. However, classifying CSC remains challenging, as evidenced by substantial discrepancies reported by Singh et al.47 Thus, it may be advantageous to focus more on choroidal changes, including active and inactive HD signs, alongside RPE and retinal changes when evaluating CSC. This is because primary pathological changes are likely to occur first in the choroid, followed by alterations in the RPE and retina. Although increased SFCT in CSC eyes has been reported, this study found no significant differences between CSC and unaffected fellow eyes, nor between acute and chronic CSC eyes. However, the morphological sign of pachyvessels showed significant differences and may be useful for diagnosing and evaluating the chronicity of CSC. Further research is needed to investigate the progressive, time-dependent changes in the choroid in relation to retinal and RPE changes.
Numerous studies have reported that choroidal thickness is significantly greater in eyes with CSC compared to unaffected fellow eyes15,23,48. However, in the present study, choroidal thickness measurements revealed no significant differences between CSC eyes and unaffected fellow eyes, which may be attributed to the inclusion of various subpopulations of CSC, including resolved cases not covered in previous research. Notably, eyes with acute CSC exhibited greater choroidal thickness compared to unaffected fellow eyes, consistent with earlier findings.
Eyes with recurrent CSC did not show statistically significant differences from eyes with acute CSC regarding the prevalence of HD signs (Table 4). This may be due to the inclusion of many eyes with the active form of CSC within the recurrent CSC group. Further investigation with a larger sample size is necessary to determine if active recurrent CSC presents morphological features similar to those of acute CSC.
The identification of distinct CSC signs in clinical practice using the methods proposed in this study is challenging. It is recommended to use standard photographic techniques, akin to those employed in the evaluation of diabetic retinopathy, as a potential solution. Utilizing standardized photographs and imaging methods could significantly enhance the assessment of characteristic CSC signs in EDI OCT images.
This study had several limitations. Firstly, it was both cross-sectional and retrospective in nature, and the sample size was relatively small. Although both eyes were included for a small number of patients with bilateral CSC (8 eyes), this may introduce minor intra-subject correlation. However, given the limited proportion, we believe the overall impact on the results is minimal. Secondly, the classification system used in this study integrated dimensions of activity, duration, and recurrence, which may not reflect a standardized scheme. However, given the current lack of consensus on CSC classification47, we adopted a pragmatic approach grounded in prior literature. Additionally, the 3-month threshold for defining chronic CSC, while not universally accepted, remains commonly used in previously published studies37,38. Thirdly, the EDI OCT raster scans were typically centered on the fovea with a fixed number of lines, and higher-density scans were applied only to hyperfluorescent lesions identified in early FA in a limited number of CSC eyes. Fourthly, fundus autofluorescence imaging was not available, which limits our ability to evaluate potential RPE abnormalities at the location of the HD sign. Furthermore, only a subset of eyes underwent ICGA, which may limit the strength of cross-modality correlation analyses. Another limitation of this study is that EDI-OCT, being a structural imaging modality, does not provide information on choroidal blood flow. Therefore, we could not determine whether the dilated vessels identified as the hanging drop sign represent intervortex venous anastomoses or venous overload choroidopathy34. Additionally, there were variations in the raster scan protocols between the search for characteristic signs and the assessment of prevalence, though no issues were encountered in applying the HD sign during the prevalence study. The study did not investigate the presence and prevalence of the defined signs in chorioretinal disorders other than CSC. Furthermore, the hyperreflective vascular wall was not examined using other OCT devices. In statistical analysis, multiple subgroup comparisons were performed without post-hoc correction, such as Bonferroni adjustment, which may increase the risk of type I error. This should be considered when interpreting the results. Finally, while multimodal correlation with FA and ICGA was partially assessed, the absence of additional imaging modalities, such as OCT angiography or en face OCT, limited our ability to fully delineate the vascular structure and functional significance of the HD sign. A follow-up study including these modalities is in progress.
In conclusion, EDI OCT raster scans revealed the characteristic morphological sign of pachyvessels, which appears to be associated with the pathogenesis of CSC. These morphological features may be valuable for diagnosing and assessing the chronicity of CSC. Further research with larger sample sizes is required to validate these findings and to achieve a clearer understanding of the causes and factors influencing pachyvessels and their association with CSC.
Author contributions
M.K. and S.Y.P. designed the research and wrote the main manuscript. M.K., S.Y.P., S.Y.H., Y.-M. S., and D.-I. H. performed the data collection and statistical analysis. M.K., S.Y.P, and D.-I. H. reviewed the design, the results, and the final paper. All authors read and approved the final manuscript.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
Ethics approval and patient consent
This study was performed in accordance with the principles of the Declaration of Helsinki. The institutional review board (IRB) of Samsung Medical Center gave its approval to this study and waived the requirement to obtain informed consent from study participants given the retrospective nature of the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Abstract
The purpose of this study was to identify characteristic morphological features of large choroidal blood vessels (pachyvessels) in eyes with central serous chorioretinopathy (CSC) using enhanced depth imaging (EDI) optical coherence tomography (OCT). A total of 116 eyes from 58 patients with CSC and 116 eyes from 58 age- and gender-matched healthy subjects were included. EDI OCT raster scan images were analyzed for the presence of characteristic features of pachyvessels and accompanying retinal pigment epithelial (RPE) abnormalities, with additional imaging data obtained from fluorescein angiography (FA) and indocyanine green angiography (ICGA). Severely dilated pachyvessels abutting the RPE-Bruch’s membrane-choriocapillaris complex, referred to as the “Hanging Drop (HD) sign,” were identified in all acute CSC eyes and 86.4% of CSC eyes overall. The HD sign was observed either with (“active”) or without (“inactive”) vascular wall hyperreflectivity along the RPE-Bruch’s membrane-choriocapillaris complex. The active HD sign was present exclusively in CSC eyes (56.1%) and was significantly more frequent in acute CSC compared to chronic and resolved CSC (88.9%, 47.4%, and 17.6%, respectively; P < 0.05). While the inactive HD sign was also more common in CSC eyes than in unaffected fellow eyes and healthy eyes (77.3%, 30.0%, and 9.5%, respectively), its prevalence did not differ significantly among CSC eyes with varying clinical conditions (P > 0.05). RPE abnormalities were consistently observed in OCT images showing the active HD sign. These findings suggest that characteristic morphological features of pachyvessels discerned using EDI OCT raster scans can aid in the diagnosis and evaluation of CSC.
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Details
1 Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-ro, Jongno-gu, 03181, Seoul, Korea (ROR: https://ror.org/04q78tk20) (GRID: grid.264381.a) (ISNI: 0000 0001 2181 989X)
2 Department of Family Medicine, Center for Clinical Research, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea (ROR: https://ror.org/04q78tk20) (GRID: grid.264381.a) (ISNI: 0000 0001 2181 989X)
3 Yesung Jung Eye Clinic, Seoul, Korea
4 Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, 135-710, Seoul, Korea (ROR: https://ror.org/05a15z872) (GRID: grid.414964.a) (ISNI: 0000 0001 0640 5613)