PERIPAPILLARY CHOROIDAL THICKNESS IN CENTRAL SEROUS CHORIORETINOPATHY Is Choroid Outside the Macula Also Thick? CHEOLMIN YUN, MD,* JAERYUNG OH, MD, PHD,* JI YUN HAN, MD,* SOON-YOUNG HWANG, PHD,† SANG WOONG MOON, MD,‡ KUHL HUH, MD* Purpose: To investigate peripapillary choroidal thickness (CT) outside the macula in central serous chorioretinopathy (CSC). Methods: We reviewed the medical records of 34 patients with unilaterally symptomatic idiopathic CSC and 34 age-matched controls. Subfoveal and peripapillary CT were measured from images obtained by spectral domain optical coherence tomography. The nasal peripapillary CT of the choroid outside the macula was determined. Results: The subfoveal CT of CSC (369.74 ± 54.17 mm) and fellow eyes (316.18 ± 54.68 mm) of the patient group were thicker than those of the normal controls (281.90 ± 40.97 mm, all P , 0.05). The subfoveal CT in CSC was significantly thicker than those in the fellow eyes. Nasal CT was also thicker in CSC (217.59 ± 62.03 mm) and fellow eyes (206.66 ± 59.35 mm) of the patient group compared with the normal controls (179.52 ± 39.64 mm, all P , 0.05). However, there was no difference in nasal CT between CSC and fellow eyes (P = 0.150). Conclusion: This result may suggest that manifest CSC occurs in patients with thick choroids both within and outside the macula, especially when subfoveal CT is increased. RETINA 35:1860–1866, 2015
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techniques such as optical coherence tomography (OCT) and indocyanine green angiography, abnormal choroidal circulation and choroidal vascular hyperpermeability have been suggested to be associated with CSC.2,3 From recent studies with enhanced depth imaging–OCT images, subfoveal choroidal thickening on OCT is known to be associated with choroidal hyperpermeability.4,5 Imamura et al4 reported increased mean subfoveal choroidal thickness (CT) in a CSC group using enhanced depth imaging–OCT. Increased CT has been reported in fellow eyes of CSC patients in many studies.4–8 In recent studies, Pang and Freund proposed that pachychoroid neovasculopathy, including pachychoroid pigment epitheliopathy, CSC, and polypoidal choroidal vasculopathy, occurs because of a pachychoroid-driven process involving choroidal congestion and choroidal hyperpermeability manifested by choroidal thickening and dilated choroidal vessels.9,10 The result of these
entral serous chorioretinopathy (CSC) is a chorioretinal disorder that typically affects young to middle-aged men and presents as serous detachment of the neurosensory retina on the posterior pole.1 Its pathogenesis is complex and is not completely understood, but with recent advances in imaging From the Departments of *Ophthalmology, and †Biostatistics, Korea University College of Medicine, Seoul, Korea; and ‡Department of Ophthalmology, Kyung Hee University School of Medicine, Seoul, Korea. Supported by a grant (2012-108) from AJU Pharm. Co, Seoul, Korea; however, the funding organization had no role in the design or conduct of this research. None of the authors have any conflicting interests to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.retinajournal.com). Reprint requests: Jaeryung Oh, MD, PhD, Department of Ophthalmology, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Sungbuk-gu, Seoul 136-705, Korea; e-mail: [email protected]
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CHOROID OUTSIDE MACULA IN CSC YUN ET AL
previous studies may suggest that CSC occurs in patients with thick choroids. The choroid is supplied by various ciliary arteries. The nasal choroid is supplied by the medial posterior ciliary artery (PCA), whereas the lateral PCA supplies the area of the choroid not supplied by the medial PCA.11 The posterior choriocapillaries in the peripapillary and submacular region are supplied by the short PCAs. The supply areas of the short PCAs are triangular, and the triangles are separated by watersheds in various orientations.12 However, recent studies on the CT of CSC were limited to the choroid of the macular region.4–8 Therefore, it is not certain whether the increased CT in patients with CSC is a general characteristic of the choroid or a localized phenomenon limited to the macula. Investigation of the CT outside the macula will be helpful to understand the pathophysiology of CSC. In this study, we investigated the nasal peripapillary choroidal thickness (PCT) of choroid outside the macula in CSC and compared these findings between patients and controls.
Patients and Methods This retrospective study was approved by the Institutional Review Board of the Korea University Medical Center and all research and data collection was conducted in accordance with the tenets of the Declaration of Helsinki. A retrospective review of medical records was performed on consecutive patients who were diagnosed with acute idiopathic CSC between February 2011 to August 2013 and a control group of patients with normal healthy eyes. Each patient with CSC underwent a comprehensive ophthalmic examination including spectral domain (SD)-OCT and fluorescein angiography. Diagnosis of CSC was based on a fundus examination, SD-OCT, and fluorescein angiography. Acute idiopathic CSC was diagnosed when serous neurosensory retinal detachment involving the macula was present on SD-OCT with the presence of fluorescein leakage at the level of the retinal pigment epithelium (RPE) in fluorescein angiography and the onset of symptoms including metamorphopsia, visual loss, chromatopsia, and micropsia was less than 3 months. The leaking point on fluorescein angiography was classified into three groups according to the area, namely the temporal retina, nasal retina, and peripapillary area. The temporal retina and nasal retina were classified based on the optic disk, and the peripapillary area was defined as the area within 3.4 mm from the center of
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the optic disk, which is the same diameter as the circle scan. This study only included acute onset, treatmentnaive patients with unilaterally symptomatic CSC and excluded cases with bilateral history of CSC, unknown symptom duration, refractive errors less than −6.0 diopters, and any cases with a history of intraocular or refractive surgery, glaucoma, optic nerve disorder, retinal and choroidal disorders including choroidal neovascularization, vascular disease, or uveitis. Data were collected from both eyes of the patients with CSC, and data of the fellow eyes were used to compare characteristics. Age-matched controls were selected from an SD-OCT database; the exclusion criteria were high myopia, neurologic deficit or a history of retinal disease, intraocular surgery, refractive surgery, or optic disk abnormality such as glaucoma. Spectral Domain Optical Coherence Tomography This study used an SD-OCT (3D OCT-1000 Mark II, software version 4.21; Topcon Corp, Tokyo, Japan) with a wavelength of 840 nm, a horizontal resolution of less than 20 mm, and an axial resolution of up to 5 mm. A choroidal image was obtained with the choroidal mode to capture choroidal layer images. Horizontal 6-mm line scans centered on the fovea, and circle scans in a 3.4-mm zone around the optic disk were obtained. Each line scan and circle scan consisted of 1,024 A-scans. Circle scan images were scanned four times. Line scan images and circle scan images were averaged to improve the signal-to-noise ratio. Measurement of Peripapillary Choroidal Thickness A 360° 3.4-mm diameter circle scan used the standard protocol for retinal nerve fiber layer (RNFL) assessment. Each sector was numbered from 1 to 12 o’clock, clockwise in the right eye and counter clockwise in the left eye (Figure 1). Thus, the 9 o’clock area of both eyes indicated the temporal peripapillary area. Nasal and temporal PCT were defined as the mean of PCT from the 1 to 5 o’clock sectors and the 7 to 11 o’clock sectors, respectively. Peripapillary CT was measured using a previously reported method.13 Using the modification tool in the 3D OCT image viewer program, the segmentation line indicating the RPE was modified to the chorioscleral junction by the observer. With this modification, we obtained the chorioretinal thickness between the internal limiting membrane and the chorioscleral junction. The CT was calculated with the subtraction of the retinal thickness from the chorioretinal thickness at each sector. All measurements were performed by two
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Fig. 1. Measurement of peripapillary and subfoveal CT on scan images of three-dimensional optical coherence tomography (3D OCT). A 360° 3.4-mm diameter circle scan was performed that provided retinal thickness at 12 sectors around the optic disk (A and B). The subfoveal CT was measured at 5 points (center of the fovea and 500 mm and 1,500 mm both nasal and temporal from the center of the fovea) (C).
independent observers (C.M.Y. and J.Y.H.), and the mean of these observations was used for analysis. Measurement of Macular Choroidal Thickness Measurement of CT on the line scan images was performed manually with a caliper tool built into the image viewer program of the SD-OCT. Choroidal thickness was defined as the length between the outer surface of a hyperreflective line of the RPE and the inner margin of the chorioscleral junction, perpendicularly (Figure 1). If a hyporeflective band representing a suprachoroidal layer was seen on OCT, it was not included in the CT.14 It was measured at the center of the fovea and 500 mm and 1,500 mm both temporal and nasal from the center of the fovea. If the RPE line was not clearly defined because of pigment epithelial detachment or other abnormalities, Bruch membrane was used as the inner margin of the choroid. When Bruch membrane is also not clearly defined, the inner margin of the choroid was defined as the margin between the hyporeflective sub-RPE fluid and the mesoreflective choroid tissue. In cases of ill-defined chorioscleral junction, we used the signal-and-noise modulation tool in the OCT viewer program to define the chorioscleral junction. If the chorioretinal junction
was ill defined even after the adjustment with the signal-and-noise modulation tool, we defined the outer choroidal margin as the line connecting the outer margin of the large choroidal vessel layer. All measurements were performed by two independent observers (C.M.Y. and J.Y.H.), and the mean of these observations was used for analysis. Statistical Methods The baseline characteristics between the CSC group and the fellow eye group were compared with chisquare tests for categorical variables and paired t-tests for continuous variables. Comparisons between the CSC group and controls and the fellow eye group and controls were conducted with independent t-tests for continuous variables and chi-squared tests for categorical variables. Because each disease eye and fellow eye came from the same patient and normal eyes came from different normal controls, the comparisons of each group were done with paired t-tests and independent t-tests instead of the analysis of variance, upon the opinion of a statistician. A paired t-test was used to analyze the difference between means in the PCT of each sector. The refractive status, mean PCT, and mean macular CT of the normal controls were
CHOROID OUTSIDE MACULA IN CSC YUN ET AL
obtained for the right eye of each patient. Statistical analyses were performed using SPSS software version 20.0 for Windows (IBM Corporation, Armonk, NY). Results were considered statistically significant at P , 0.05. Results
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According to sector, the PCT in all sectors of the CSC group and fellow eye group was greater than that of the control group, with statistical significance (P values ranged from ,0.001 to 0.049). But, for the PCT from 1 to 5 o’clock, there were no statistically significant differences between the CSC group and the fellow eye group (P values ranged from 0.102 to 0.318) (Figure 2).
General Characteristics
Macular Choroidal Thickness
Thirty-four patients with acute unilateral idiopathic CSC and the same number of controls were included in this study (Table 1). The mean ages of the CSC group was 47.82 ± 7.69, and it was not different from the mean age of the control group (47.82 ± 7.93, P = 1.000, independent t-test). There was no difference in sex or refractive error between the CSC group and control group.
The mean CT was significantly greater in all macular areas in the CSC group compared with the fellow eye group and the control group (all P , 0.05). The mean CT of the fellow eye group was also greater than that of the control group (all P , 0.05) (Table 3). In the control group, subfoveal CT was negatively correlated with age (r = −0.543, P = 0.001, Pearson’s correlation test). However, the correlation was not significant in CSC and fellow eyes of CSC group (r = −0.098, P = 0.583, and r = −0.286, P = 0.101, respectively, Pearson’s correlation test).
Angiographic Findings In this study, 33 eyes demonstrated a single leaking point and only 1 eye showed 2 leakage points. All leaking points were located in the temporal retina; none were found in the nasal retina or peripapillary areas. Of the 35 leaking points, 12, 15, 2, 3, and 3 were observed in the subfovea, superonasal area, superotemporal area, inferotemporal area, and inferonasal area, respectively. Peripapillary Choroidal Thickness Table 2 shows PCT according to each sector and mean CT. The mean and temporal PCT of the CSC group was higher than that of the fellow eye group and the control group. The mean and temporal PCT of the fellow eye group was also higher than that of the control group. However, the nasal PCT of the CSC group was not significantly different from that of the fellow eye group (P = 0.150).
Ratio of Choroidal Thickness Within and Outside the Macula The ratio between the subfoveal and nasal PCT was calculated for comparison between macular CT and CT outside macula. The ratio in the fellow eyes (1.65 ± 0.52) was not significantly different from that of the controls (1.60 ± 0.21) (P = 0.643). However, the ratio in the CSC eyes (1.83 ± 0.55) was greater than that of the fellow eyes and the control group (P = 0.023 and P = 0.031, respectively). There was no difference among the three groups in the ratio between the subfoveal CT and temporal PCT. Interobserver Reproducibility Intraclass correlation coefficients were obtained to assess the interobserver reproducibility. The intraclass
Table 1. Baseline Characteristics of Patients With CSC and Normal Controls P*
CSC Patients CSC Eyes No. patients Age Sex (male:female) Refractive error (D)
Fellow Eyes
34 47.82 ± 7.69 25:9 −0.79 ± 1.14 −0.81 ± 1.21 (−2.88 to 1.75) (−3.00 to 1.25)
Intereye
0.792
Continuous variables were described as mean ± SD (minimum to maximum). *P value based on paired t-test. †P value based on independent t-test. C, CSC group; D, diopter; F, fellow eye group; N, normal control group.
Normal Control Group 34 47.82 ± 7.93 20:14 −0.49 ± 0.95 (−3.00 to 1.75)
P† C-N
F-N
1.000 0.320 0.247
1.000 0.320 0.246
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Table 2. Comparison of PCT in Each Sector Between the CSC Eyes, Fellow Eyes and Controls CSC Patients P* Clock Hour
CSC Eyes
Fellow Eyes
Intereye
Mean PCT Temporal PCT Nasal PCT Clock hour 1 2 3 4 5 6 7 8 9 10 11 12
225.13 ± 61.14 238.14 ± 67.15 217.59 ± 62.03
205.31 ± 56.79 210.31 ± 59.70 206.66 ± 59.35
0.004 ,0.001 0.150
230.24 231.26 226.56 212.06 187.85 181.21 203.91 230.79 255.29 253.26 247.44 241.67
216.32 221.06 217.68 202.18 176.09 159.71 178.38 204.15 223.50 223.94 221.56 219.12
0.118 0.224 0.318 0.234 0.102 ,0.001 ,0.001 ,0.001 ,0.001 0.001 0.016 0.033
± ± ± ± ± ± ± ± ± ± ± ±
70.69 70.67 66.15 63.89 53.89 54.48 63.76 72.70 74.87 71.30 67.28 68.93
± ± ± ± ± ± ± ± ± ± ± ±
60.35 65.42 68.43 61.70 50.58 47.84 56.08 64.26 65.27 60.95 59.87 57.57
P†
Normal Control Group C-N
F-N
177.04 ± 40.44 180.09 ± 43.36 179.52 ± 39.64
,0.001 ,0.001 0.004
0.021 0.020 0.031
189.41 191.72 188.65 173.15 154.68 136.43 153.24 173.00 191.96 190.50 191.76 190.03
0.006 0.006 0.006 0.004 0.004 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.001
0.039 0.030 0.039 0.026 0.049 0.028 0.038 0.021 0.024 0.014 0.024 0.022
± ± ± ± ± ± ± ± ± ± ± ±
43.40 40.17 41.49 40.85 36.93 36.85 40.29 42.09 44.81 47.73 45.56 43.67
Nasal and temporal PCT are the mean of PCT from the 1 to 5 o’clock sectors and the 7 to 11 o’clock sectors, respectively. Each sector was numbered 1 to 12 o’clock, clockwise in the right eye and counter clockwise in the left eye. *P value based on paired t-test. †P value based on independent t-test. C, CSC group; F, fellow eye group; N, normal control group.
correlation coefficients were high and ranged from 0.970 to 0.988 (see Table, Supplemental Digital Content 1, http://links.lww.com/IAE/A333; which demonstrates the results of interobserver reproducibility).
Discussion We found that subfoveal CT of the CSC and fellow eyes of the patient group were thicker than those of normal controls (Figure 3). The results of this investigation are consistent with those of previous studies, which reported that macular CT increased not only in CSC eyes but also in unaffected fellow eyes, and suggested that CSC might be an essentially bilateral disorder.4,5,7 In this study, we measured CT outside the macula. Nasal PCT, representing CT outside the macular area, was thicker in the CSC and fellow eyes of the patient group than in normal controls. This result may suggest that the increased CT in patients with CSC is not limited to the macular area. Diffuse thickening in both peripapillary and macular choroids in both the CSC group and the fellow eye group when compared with controls may support the previous suggestion that CSC occurs in patients with thick choroids.9,10 We also measured the ratio between the subfoveal and mean nasal PCT to compare macular CT and CT outside the macula. The ratio between the fellow eyes and the controls was not significantly different.
However, the ratio in the CSC eyes was greater than those of the fellow eyes and the control group. These results may suggest that, when compared with fellow eyes, choroidal thickening in CSC eyes mainly occurs in the macular area, and not in choroid outside the macular area, although the CT of both eyes of patients with CSC was thicker than those of normal controls. These findings might suggest that choroidal hyperpermeability and dilatation exist in “pre-CSC” stage fellow eyes and subsequent abnormal thickening of the choroid in the macula is associated with the development of subretinal fluid in CSC.4,5,7,15 Our data also support the previous hypothesis that abnormal hemodynamic changes of the choroid in the posterior pole are responsible for the development of SRF and neurosensory retinal detachment in the macular region.4,16,17 Focal thickening of the choroid might be associated with the anatomy and circulatory characteristics of the eye. The PCA from the ophthalmic artery supplies the choroid around the optic nerve head and also supplies the choroid up to the equator.11 Usually, the temporal half of the choroid is supplied by the lateral PCA, and the nasal half of the choroid is supplied by the medial PCA.11 The branches of the PCA consist of the long PCAs and short PCAs (SPCAs). The temporal SPCAs, SPCAs that come from the lateral PCA, enter the eyeball in the macular region and supply the macular choroid.11 Because there are no anastomoses between the long PCAs and the short PCAs, there are
CHOROID OUTSIDE MACULA IN CSC YUN ET AL
Fig. 2. Peripapillary choroidal thickness. A. Each sector was numbered 1 to 12 o’clock, clockwise in the right eye and counter clockwise in the left eye. B. Nasal and temporal PCT are the mean of PCT from the 1 to 5 o’clock sectors and the 7 to 11 o’clock sectors, respectively. The PCT in all sectors of the CSC group and the fellow eye group were greater than that of the control group. But, for the PCT from 1 to 5 o’clock, there were no statistically significant differences between the CSC group and the fellow eye group.
watershed zones between the areas that are supplied by both.11,18–20 They have a segmental distribution without anastomosis and supply a well-defined sector of the choroid.18,20,21 These anatomical characteristics might explain the focal choroidal thickening of the posterior pole except for the nasal peripapillary choroid in CSC.11 The choroid in the macula is somewhat different from the choroids of other areas. The blood supply to the choroid of the macula has two origins: branches of the short PCAs and a recurrent branch of the long PCA.22 The presence of very short posterior ciliary arteries (VSPCA), selectively directed to the macular region, has been confirmed by previous
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studies.22 The presence of VSPCA may contribute to subfoveal CT and could be assumed to be related with the development of CSC. This study has several limitations. First, because only patients with acute unilateral CSC were included and patients who had undergone intraocular surgery, refractive surgery, and cataract surgery were excluded, there may be a selection bias. Second, because CT was measured manually, there may be errors in measurement, although there was high interobserver correlation. Third, measurement of CT in the nasal retina far from the optic disk was not performed. A further prospective study measuring the nasal retinal CT is needed. Fourth, previous studies on choroidal hyperpermeability in CSC eyes reported that choroidal thickening might depend on choroidal vascular hyperpermeability.5,23 Because not all patients underwent indocyanine green angiography in this study, we could not determine the relationship between choroidal hyperpermeability and peripapillary choroidal thickening in CSC eyes. An additional study is needed to investigate the relationship between increased CT and choroidal hyperpermeability on indocyanine green angiography. Fifth, thickness differences would be easier to evaluate and appreciate where the choroid/ retina is thicker. Because the choroid is significantly thinner in the peripapillary region compared with the subfoveal region, differences between the fellow eye and the CSC eye might be very subtle. However, considering the similarity of nasal and temporal PCT in both normal controls and fellow eyes of the CSC group, the increased temporal PCT in CSC eyes was clear, and the difference in temporal PCT, but not nasal PCT, between CSC eyes and fellow eyes was statistically significant in this study. Further studies with a large sample size may be needed to confirm this finding. In conclusion, the choroid of the macular and peripapillary area of acute idiopathic unilateral CSC and fellow eyes were diffusely thickened when compared with controls. The choroid of the macular
Table 3. Comparison of Macular CT in Each Sector Among the CSC Eyes, Fellow Eyes, and Controls P*
CSC Patients CSC Eyes Subfoveal Nasal 500 mm Nasal 1,500 mm Temporal 500 mm Temporal 1,500 mm
369.74 335.44 290.47 345.24 322.03
± ± ± ± ±
54.17 60.05 57.75 54.73 53.90
Fellow Eyes 316.18 296.50 251.21 309.47 295.12
± ± ± ± ±
54.68 54.78 53.52 52.89 45.83
*P value based on paired t-test. †P based on independent t-test. C, CSC group; F, fellow eye group; N, normal control group.
Intereye ,0.001 ,0.001 ,0.001 ,0.001 0.008
P†
Normal Control Group 281.90 257.65 218.69 270.29 256.51
± ± ± ± ±
40.97 41.39 41.43 43.61 41.10
C-N
F-N
,0.001 ,0.001 ,0.001 ,0.001 ,0.001
0.005 0.002 0.007 0.001 0.001
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Fig. 3. Representative images of the peripapillary and macular choroid images using 3D OCT. In the CSC eye (A and D), the peripapillary and macular CT were increased diffusely, and the temporal peripapillary choroid was especially thickened. In the fellow eye of the same patient, the peripapillary and macular CT is diffusely increased (B and E) when compared with controls (C and F). I, inferior; N, nasal; S, superior; T, temporal.
area in CSC eyes was significantly thicker than those in the fellow eyes. However, the nasal choroid outside the macula did not vary between CSC and fellow eyes. The results of this study might suggest that a thicker choroid in the posterior pole and further thickening of the choroid in the macular area of patients with CSC are associated with SRF. This finding might be helpful in understanding the pathophysiology of CSC. Key words: central serous chorioretinopathy, choroidal thickness, optical coherence tomography, peripapillary choroidal thickness. References 1. Nicholson B, Noble J, Forooghian F, Meyrele C. Central serous chorioretinopathy: update on pathophysiology and treatment. Surv Ophthalmol 2013;58:103–126. 2. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol 1994;112:1057–1062. 3. Spaide RF, Goldbaum M, Wong DW, et al. Serous detachment of the retina. Retina 2003;23:820–846. 4. Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina 2009;29:1469– 1473. 5. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness in fellow eyes of patients with central serous chorioretinopathy. Retina 2011;31:1603–1608. 6. Kim SW, Oh J, Kwon SS, et al. Comparison of choroidal thickness among patients with healthy eyes, early age-related maculopathy, neovascular age-related macular degeneration, central serous chorioretinopathy, and polypoidal choroidal vasculopathy. Retina 2011;31:1904–1911. 7. Kim YT, Kang SW, Bai KH. Choroidal thickness in both eyes of patients with unilaterally active central serous chorioretinopathy. Eye 2011;25:1635–1640.
8. Kuroda S, Ikuno Y, Yasuno Y, et al. Choroidal thickness in central serous chorioretinopathy. Retina 2013;33:302–308. 9. Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina 2013;33:1659–1672. 10. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina 2015;35:1–9. 11. Hayreh SS. Posterior ciliary artery circulation in health and disease: the Weisenfeld lecture. Invest Ophthalmol Vis Sci 2004;45:749–757. 12. Amalric P. Choroidal vascular ischaemia. Eye 1991;5:519–527. 13. Oh J, Yoo C, Yun CM, et al. Simplified method to measure the peripapillary choroidal thickness using three-dimensional optical coherence tomography. Korean J Ophthalmol 2013;27: 172–177. 14. Yiu G, Pecen P, Sarin N, et al. Characterization of the choroidscleral junction and suprachoroidal layer in healthy individuals on enhanced-depth imaging optical coherence tomography. JAMA Ophthalmol 2014;132:174–181. 15. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology 2010;117:1792–1799. 16. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol 1967;63(Suppl):1–139. 17. Prunte C. Indocyanine green angiographic findings in central serous chorioretinopathy. Int Ophthalmol 1995;19:77–82. 18. Hayreh SS. In vivo choroidal circulation and its watershed zones. Eye 1990;4:273–289. 19. Hayreh SS. Inter-individual variation in blood supply of the optic nerve head. Its importance in various ischemic disorders of the optic nerve head, and glaucoma, low-tension glaucoma and allied disorders. Doc Ophthalmol 1985;59:217–246. 20. Hayreh SS. Segmental nature of the choroidal vasculature. Br J Ophthalmol 1975;59:631–648. 21. Hayreh SS. Physiological anatomy of the choroidal vascular bed. Int Ophthalmol 1983;6:85–93. 22. Yannuzzi LA, Flower RW, Slakter JS. Indocyanine green angiography.St.Louis, MO: Mosby; 1997:24–25. 23. Iida T, Kishi S, Hagimura N, Shimizu K. Persistent and bilateral choroidal vascular abnormalities in central serous chorioretinopathy. Retina 1999;19:508–512.
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techniques such as optical coherence tomography (OCT) and indocyanine green angiography, abnormal choroidal circulation and choroidal vascular hyperpermeability have been suggested to be associated with CSC.2,3 From recent studies with enhanced depth imaging–OCT images, subfoveal choroidal thickening on OCT is known to be associated with choroidal hyperpermeability.4,5 Imamura et al4 reported increased mean subfoveal choroidal thickness (CT) in a CSC group using enhanced depth imaging–OCT. Increased CT has been reported in fellow eyes of CSC patients in many studies.4–8 In recent studies, Pang and Freund proposed that pachychoroid neovasculopathy, including pachychoroid pigment epitheliopathy, CSC, and polypoidal choroidal vasculopathy, occurs because of a pachychoroid-driven process involving choroidal congestion and choroidal hyperpermeability manifested by choroidal thickening and dilated choroidal vessels.9,10 The result of these
entral serous chorioretinopathy (CSC) is a chorioretinal disorder that typically affects young to middle-aged men and presents as serous detachment of the neurosensory retina on the posterior pole.1 Its pathogenesis is complex and is not completely understood, but with recent advances in imaging From the Departments of *Ophthalmology, and †Biostatistics, Korea University College of Medicine, Seoul, Korea; and ‡Department of Ophthalmology, Kyung Hee University School of Medicine, Seoul, Korea. Supported by a grant (2012-108) from AJU Pharm. Co, Seoul, Korea; however, the funding organization had no role in the design or conduct of this research. None of the authors have any conflicting interests to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.retinajournal.com). Reprint requests: Jaeryung Oh, MD, PhD, Department of Ophthalmology, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Sungbuk-gu, Seoul 136-705, Korea; e-mail: [email protected]
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CHOROID OUTSIDE MACULA IN CSC YUN ET AL
previous studies may suggest that CSC occurs in patients with thick choroids. The choroid is supplied by various ciliary arteries. The nasal choroid is supplied by the medial posterior ciliary artery (PCA), whereas the lateral PCA supplies the area of the choroid not supplied by the medial PCA.11 The posterior choriocapillaries in the peripapillary and submacular region are supplied by the short PCAs. The supply areas of the short PCAs are triangular, and the triangles are separated by watersheds in various orientations.12 However, recent studies on the CT of CSC were limited to the choroid of the macular region.4–8 Therefore, it is not certain whether the increased CT in patients with CSC is a general characteristic of the choroid or a localized phenomenon limited to the macula. Investigation of the CT outside the macula will be helpful to understand the pathophysiology of CSC. In this study, we investigated the nasal peripapillary choroidal thickness (PCT) of choroid outside the macula in CSC and compared these findings between patients and controls.
Patients and Methods This retrospective study was approved by the Institutional Review Board of the Korea University Medical Center and all research and data collection was conducted in accordance with the tenets of the Declaration of Helsinki. A retrospective review of medical records was performed on consecutive patients who were diagnosed with acute idiopathic CSC between February 2011 to August 2013 and a control group of patients with normal healthy eyes. Each patient with CSC underwent a comprehensive ophthalmic examination including spectral domain (SD)-OCT and fluorescein angiography. Diagnosis of CSC was based on a fundus examination, SD-OCT, and fluorescein angiography. Acute idiopathic CSC was diagnosed when serous neurosensory retinal detachment involving the macula was present on SD-OCT with the presence of fluorescein leakage at the level of the retinal pigment epithelium (RPE) in fluorescein angiography and the onset of symptoms including metamorphopsia, visual loss, chromatopsia, and micropsia was less than 3 months. The leaking point on fluorescein angiography was classified into three groups according to the area, namely the temporal retina, nasal retina, and peripapillary area. The temporal retina and nasal retina were classified based on the optic disk, and the peripapillary area was defined as the area within 3.4 mm from the center of
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the optic disk, which is the same diameter as the circle scan. This study only included acute onset, treatmentnaive patients with unilaterally symptomatic CSC and excluded cases with bilateral history of CSC, unknown symptom duration, refractive errors less than −6.0 diopters, and any cases with a history of intraocular or refractive surgery, glaucoma, optic nerve disorder, retinal and choroidal disorders including choroidal neovascularization, vascular disease, or uveitis. Data were collected from both eyes of the patients with CSC, and data of the fellow eyes were used to compare characteristics. Age-matched controls were selected from an SD-OCT database; the exclusion criteria were high myopia, neurologic deficit or a history of retinal disease, intraocular surgery, refractive surgery, or optic disk abnormality such as glaucoma. Spectral Domain Optical Coherence Tomography This study used an SD-OCT (3D OCT-1000 Mark II, software version 4.21; Topcon Corp, Tokyo, Japan) with a wavelength of 840 nm, a horizontal resolution of less than 20 mm, and an axial resolution of up to 5 mm. A choroidal image was obtained with the choroidal mode to capture choroidal layer images. Horizontal 6-mm line scans centered on the fovea, and circle scans in a 3.4-mm zone around the optic disk were obtained. Each line scan and circle scan consisted of 1,024 A-scans. Circle scan images were scanned four times. Line scan images and circle scan images were averaged to improve the signal-to-noise ratio. Measurement of Peripapillary Choroidal Thickness A 360° 3.4-mm diameter circle scan used the standard protocol for retinal nerve fiber layer (RNFL) assessment. Each sector was numbered from 1 to 12 o’clock, clockwise in the right eye and counter clockwise in the left eye (Figure 1). Thus, the 9 o’clock area of both eyes indicated the temporal peripapillary area. Nasal and temporal PCT were defined as the mean of PCT from the 1 to 5 o’clock sectors and the 7 to 11 o’clock sectors, respectively. Peripapillary CT was measured using a previously reported method.13 Using the modification tool in the 3D OCT image viewer program, the segmentation line indicating the RPE was modified to the chorioscleral junction by the observer. With this modification, we obtained the chorioretinal thickness between the internal limiting membrane and the chorioscleral junction. The CT was calculated with the subtraction of the retinal thickness from the chorioretinal thickness at each sector. All measurements were performed by two
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Fig. 1. Measurement of peripapillary and subfoveal CT on scan images of three-dimensional optical coherence tomography (3D OCT). A 360° 3.4-mm diameter circle scan was performed that provided retinal thickness at 12 sectors around the optic disk (A and B). The subfoveal CT was measured at 5 points (center of the fovea and 500 mm and 1,500 mm both nasal and temporal from the center of the fovea) (C).
independent observers (C.M.Y. and J.Y.H.), and the mean of these observations was used for analysis. Measurement of Macular Choroidal Thickness Measurement of CT on the line scan images was performed manually with a caliper tool built into the image viewer program of the SD-OCT. Choroidal thickness was defined as the length between the outer surface of a hyperreflective line of the RPE and the inner margin of the chorioscleral junction, perpendicularly (Figure 1). If a hyporeflective band representing a suprachoroidal layer was seen on OCT, it was not included in the CT.14 It was measured at the center of the fovea and 500 mm and 1,500 mm both temporal and nasal from the center of the fovea. If the RPE line was not clearly defined because of pigment epithelial detachment or other abnormalities, Bruch membrane was used as the inner margin of the choroid. When Bruch membrane is also not clearly defined, the inner margin of the choroid was defined as the margin between the hyporeflective sub-RPE fluid and the mesoreflective choroid tissue. In cases of ill-defined chorioscleral junction, we used the signal-and-noise modulation tool in the OCT viewer program to define the chorioscleral junction. If the chorioretinal junction
was ill defined even after the adjustment with the signal-and-noise modulation tool, we defined the outer choroidal margin as the line connecting the outer margin of the large choroidal vessel layer. All measurements were performed by two independent observers (C.M.Y. and J.Y.H.), and the mean of these observations was used for analysis. Statistical Methods The baseline characteristics between the CSC group and the fellow eye group were compared with chisquare tests for categorical variables and paired t-tests for continuous variables. Comparisons between the CSC group and controls and the fellow eye group and controls were conducted with independent t-tests for continuous variables and chi-squared tests for categorical variables. Because each disease eye and fellow eye came from the same patient and normal eyes came from different normal controls, the comparisons of each group were done with paired t-tests and independent t-tests instead of the analysis of variance, upon the opinion of a statistician. A paired t-test was used to analyze the difference between means in the PCT of each sector. The refractive status, mean PCT, and mean macular CT of the normal controls were
CHOROID OUTSIDE MACULA IN CSC YUN ET AL
obtained for the right eye of each patient. Statistical analyses were performed using SPSS software version 20.0 for Windows (IBM Corporation, Armonk, NY). Results were considered statistically significant at P , 0.05. Results
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According to sector, the PCT in all sectors of the CSC group and fellow eye group was greater than that of the control group, with statistical significance (P values ranged from ,0.001 to 0.049). But, for the PCT from 1 to 5 o’clock, there were no statistically significant differences between the CSC group and the fellow eye group (P values ranged from 0.102 to 0.318) (Figure 2).
General Characteristics
Macular Choroidal Thickness
Thirty-four patients with acute unilateral idiopathic CSC and the same number of controls were included in this study (Table 1). The mean ages of the CSC group was 47.82 ± 7.69, and it was not different from the mean age of the control group (47.82 ± 7.93, P = 1.000, independent t-test). There was no difference in sex or refractive error between the CSC group and control group.
The mean CT was significantly greater in all macular areas in the CSC group compared with the fellow eye group and the control group (all P , 0.05). The mean CT of the fellow eye group was also greater than that of the control group (all P , 0.05) (Table 3). In the control group, subfoveal CT was negatively correlated with age (r = −0.543, P = 0.001, Pearson’s correlation test). However, the correlation was not significant in CSC and fellow eyes of CSC group (r = −0.098, P = 0.583, and r = −0.286, P = 0.101, respectively, Pearson’s correlation test).
Angiographic Findings In this study, 33 eyes demonstrated a single leaking point and only 1 eye showed 2 leakage points. All leaking points were located in the temporal retina; none were found in the nasal retina or peripapillary areas. Of the 35 leaking points, 12, 15, 2, 3, and 3 were observed in the subfovea, superonasal area, superotemporal area, inferotemporal area, and inferonasal area, respectively. Peripapillary Choroidal Thickness Table 2 shows PCT according to each sector and mean CT. The mean and temporal PCT of the CSC group was higher than that of the fellow eye group and the control group. The mean and temporal PCT of the fellow eye group was also higher than that of the control group. However, the nasal PCT of the CSC group was not significantly different from that of the fellow eye group (P = 0.150).
Ratio of Choroidal Thickness Within and Outside the Macula The ratio between the subfoveal and nasal PCT was calculated for comparison between macular CT and CT outside macula. The ratio in the fellow eyes (1.65 ± 0.52) was not significantly different from that of the controls (1.60 ± 0.21) (P = 0.643). However, the ratio in the CSC eyes (1.83 ± 0.55) was greater than that of the fellow eyes and the control group (P = 0.023 and P = 0.031, respectively). There was no difference among the three groups in the ratio between the subfoveal CT and temporal PCT. Interobserver Reproducibility Intraclass correlation coefficients were obtained to assess the interobserver reproducibility. The intraclass
Table 1. Baseline Characteristics of Patients With CSC and Normal Controls P*
CSC Patients CSC Eyes No. patients Age Sex (male:female) Refractive error (D)
Fellow Eyes
34 47.82 ± 7.69 25:9 −0.79 ± 1.14 −0.81 ± 1.21 (−2.88 to 1.75) (−3.00 to 1.25)
Intereye
0.792
Continuous variables were described as mean ± SD (minimum to maximum). *P value based on paired t-test. †P value based on independent t-test. C, CSC group; D, diopter; F, fellow eye group; N, normal control group.
Normal Control Group 34 47.82 ± 7.93 20:14 −0.49 ± 0.95 (−3.00 to 1.75)
P† C-N
F-N
1.000 0.320 0.247
1.000 0.320 0.246
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Table 2. Comparison of PCT in Each Sector Between the CSC Eyes, Fellow Eyes and Controls CSC Patients P* Clock Hour
CSC Eyes
Fellow Eyes
Intereye
Mean PCT Temporal PCT Nasal PCT Clock hour 1 2 3 4 5 6 7 8 9 10 11 12
225.13 ± 61.14 238.14 ± 67.15 217.59 ± 62.03
205.31 ± 56.79 210.31 ± 59.70 206.66 ± 59.35
0.004 ,0.001 0.150
230.24 231.26 226.56 212.06 187.85 181.21 203.91 230.79 255.29 253.26 247.44 241.67
216.32 221.06 217.68 202.18 176.09 159.71 178.38 204.15 223.50 223.94 221.56 219.12
0.118 0.224 0.318 0.234 0.102 ,0.001 ,0.001 ,0.001 ,0.001 0.001 0.016 0.033
± ± ± ± ± ± ± ± ± ± ± ±
70.69 70.67 66.15 63.89 53.89 54.48 63.76 72.70 74.87 71.30 67.28 68.93
± ± ± ± ± ± ± ± ± ± ± ±
60.35 65.42 68.43 61.70 50.58 47.84 56.08 64.26 65.27 60.95 59.87 57.57
P†
Normal Control Group C-N
F-N
177.04 ± 40.44 180.09 ± 43.36 179.52 ± 39.64
,0.001 ,0.001 0.004
0.021 0.020 0.031
189.41 191.72 188.65 173.15 154.68 136.43 153.24 173.00 191.96 190.50 191.76 190.03
0.006 0.006 0.006 0.004 0.004 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.001
0.039 0.030 0.039 0.026 0.049 0.028 0.038 0.021 0.024 0.014 0.024 0.022
± ± ± ± ± ± ± ± ± ± ± ±
43.40 40.17 41.49 40.85 36.93 36.85 40.29 42.09 44.81 47.73 45.56 43.67
Nasal and temporal PCT are the mean of PCT from the 1 to 5 o’clock sectors and the 7 to 11 o’clock sectors, respectively. Each sector was numbered 1 to 12 o’clock, clockwise in the right eye and counter clockwise in the left eye. *P value based on paired t-test. †P value based on independent t-test. C, CSC group; F, fellow eye group; N, normal control group.
correlation coefficients were high and ranged from 0.970 to 0.988 (see Table, Supplemental Digital Content 1, http://links.lww.com/IAE/A333; which demonstrates the results of interobserver reproducibility).
Discussion We found that subfoveal CT of the CSC and fellow eyes of the patient group were thicker than those of normal controls (Figure 3). The results of this investigation are consistent with those of previous studies, which reported that macular CT increased not only in CSC eyes but also in unaffected fellow eyes, and suggested that CSC might be an essentially bilateral disorder.4,5,7 In this study, we measured CT outside the macula. Nasal PCT, representing CT outside the macular area, was thicker in the CSC and fellow eyes of the patient group than in normal controls. This result may suggest that the increased CT in patients with CSC is not limited to the macular area. Diffuse thickening in both peripapillary and macular choroids in both the CSC group and the fellow eye group when compared with controls may support the previous suggestion that CSC occurs in patients with thick choroids.9,10 We also measured the ratio between the subfoveal and mean nasal PCT to compare macular CT and CT outside the macula. The ratio between the fellow eyes and the controls was not significantly different.
However, the ratio in the CSC eyes was greater than those of the fellow eyes and the control group. These results may suggest that, when compared with fellow eyes, choroidal thickening in CSC eyes mainly occurs in the macular area, and not in choroid outside the macular area, although the CT of both eyes of patients with CSC was thicker than those of normal controls. These findings might suggest that choroidal hyperpermeability and dilatation exist in “pre-CSC” stage fellow eyes and subsequent abnormal thickening of the choroid in the macula is associated with the development of subretinal fluid in CSC.4,5,7,15 Our data also support the previous hypothesis that abnormal hemodynamic changes of the choroid in the posterior pole are responsible for the development of SRF and neurosensory retinal detachment in the macular region.4,16,17 Focal thickening of the choroid might be associated with the anatomy and circulatory characteristics of the eye. The PCA from the ophthalmic artery supplies the choroid around the optic nerve head and also supplies the choroid up to the equator.11 Usually, the temporal half of the choroid is supplied by the lateral PCA, and the nasal half of the choroid is supplied by the medial PCA.11 The branches of the PCA consist of the long PCAs and short PCAs (SPCAs). The temporal SPCAs, SPCAs that come from the lateral PCA, enter the eyeball in the macular region and supply the macular choroid.11 Because there are no anastomoses between the long PCAs and the short PCAs, there are
CHOROID OUTSIDE MACULA IN CSC YUN ET AL
Fig. 2. Peripapillary choroidal thickness. A. Each sector was numbered 1 to 12 o’clock, clockwise in the right eye and counter clockwise in the left eye. B. Nasal and temporal PCT are the mean of PCT from the 1 to 5 o’clock sectors and the 7 to 11 o’clock sectors, respectively. The PCT in all sectors of the CSC group and the fellow eye group were greater than that of the control group. But, for the PCT from 1 to 5 o’clock, there were no statistically significant differences between the CSC group and the fellow eye group.
watershed zones between the areas that are supplied by both.11,18–20 They have a segmental distribution without anastomosis and supply a well-defined sector of the choroid.18,20,21 These anatomical characteristics might explain the focal choroidal thickening of the posterior pole except for the nasal peripapillary choroid in CSC.11 The choroid in the macula is somewhat different from the choroids of other areas. The blood supply to the choroid of the macula has two origins: branches of the short PCAs and a recurrent branch of the long PCA.22 The presence of very short posterior ciliary arteries (VSPCA), selectively directed to the macular region, has been confirmed by previous
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studies.22 The presence of VSPCA may contribute to subfoveal CT and could be assumed to be related with the development of CSC. This study has several limitations. First, because only patients with acute unilateral CSC were included and patients who had undergone intraocular surgery, refractive surgery, and cataract surgery were excluded, there may be a selection bias. Second, because CT was measured manually, there may be errors in measurement, although there was high interobserver correlation. Third, measurement of CT in the nasal retina far from the optic disk was not performed. A further prospective study measuring the nasal retinal CT is needed. Fourth, previous studies on choroidal hyperpermeability in CSC eyes reported that choroidal thickening might depend on choroidal vascular hyperpermeability.5,23 Because not all patients underwent indocyanine green angiography in this study, we could not determine the relationship between choroidal hyperpermeability and peripapillary choroidal thickening in CSC eyes. An additional study is needed to investigate the relationship between increased CT and choroidal hyperpermeability on indocyanine green angiography. Fifth, thickness differences would be easier to evaluate and appreciate where the choroid/ retina is thicker. Because the choroid is significantly thinner in the peripapillary region compared with the subfoveal region, differences between the fellow eye and the CSC eye might be very subtle. However, considering the similarity of nasal and temporal PCT in both normal controls and fellow eyes of the CSC group, the increased temporal PCT in CSC eyes was clear, and the difference in temporal PCT, but not nasal PCT, between CSC eyes and fellow eyes was statistically significant in this study. Further studies with a large sample size may be needed to confirm this finding. In conclusion, the choroid of the macular and peripapillary area of acute idiopathic unilateral CSC and fellow eyes were diffusely thickened when compared with controls. The choroid of the macular
Table 3. Comparison of Macular CT in Each Sector Among the CSC Eyes, Fellow Eyes, and Controls P*
CSC Patients CSC Eyes Subfoveal Nasal 500 mm Nasal 1,500 mm Temporal 500 mm Temporal 1,500 mm
369.74 335.44 290.47 345.24 322.03
± ± ± ± ±
54.17 60.05 57.75 54.73 53.90
Fellow Eyes 316.18 296.50 251.21 309.47 295.12
± ± ± ± ±
54.68 54.78 53.52 52.89 45.83
*P value based on paired t-test. †P based on independent t-test. C, CSC group; F, fellow eye group; N, normal control group.
Intereye ,0.001 ,0.001 ,0.001 ,0.001 0.008
P†
Normal Control Group 281.90 257.65 218.69 270.29 256.51
± ± ± ± ±
40.97 41.39 41.43 43.61 41.10
C-N
F-N
,0.001 ,0.001 ,0.001 ,0.001 ,0.001
0.005 0.002 0.007 0.001 0.001
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Fig. 3. Representative images of the peripapillary and macular choroid images using 3D OCT. In the CSC eye (A and D), the peripapillary and macular CT were increased diffusely, and the temporal peripapillary choroid was especially thickened. In the fellow eye of the same patient, the peripapillary and macular CT is diffusely increased (B and E) when compared with controls (C and F). I, inferior; N, nasal; S, superior; T, temporal.
area in CSC eyes was significantly thicker than those in the fellow eyes. However, the nasal choroid outside the macula did not vary between CSC and fellow eyes. The results of this study might suggest that a thicker choroid in the posterior pole and further thickening of the choroid in the macular area of patients with CSC are associated with SRF. This finding might be helpful in understanding the pathophysiology of CSC. Key words: central serous chorioretinopathy, choroidal thickness, optical coherence tomography, peripapillary choroidal thickness. References 1. Nicholson B, Noble J, Forooghian F, Meyrele C. Central serous chorioretinopathy: update on pathophysiology and treatment. Surv Ophthalmol 2013;58:103–126. 2. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol 1994;112:1057–1062. 3. Spaide RF, Goldbaum M, Wong DW, et al. Serous detachment of the retina. Retina 2003;23:820–846. 4. Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina 2009;29:1469– 1473. 5. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness in fellow eyes of patients with central serous chorioretinopathy. Retina 2011;31:1603–1608. 6. Kim SW, Oh J, Kwon SS, et al. Comparison of choroidal thickness among patients with healthy eyes, early age-related maculopathy, neovascular age-related macular degeneration, central serous chorioretinopathy, and polypoidal choroidal vasculopathy. Retina 2011;31:1904–1911. 7. Kim YT, Kang SW, Bai KH. Choroidal thickness in both eyes of patients with unilaterally active central serous chorioretinopathy. Eye 2011;25:1635–1640.
8. Kuroda S, Ikuno Y, Yasuno Y, et al. Choroidal thickness in central serous chorioretinopathy. Retina 2013;33:302–308. 9. Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina 2013;33:1659–1672. 10. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina 2015;35:1–9. 11. Hayreh SS. Posterior ciliary artery circulation in health and disease: the Weisenfeld lecture. Invest Ophthalmol Vis Sci 2004;45:749–757. 12. Amalric P. Choroidal vascular ischaemia. Eye 1991;5:519–527. 13. Oh J, Yoo C, Yun CM, et al. Simplified method to measure the peripapillary choroidal thickness using three-dimensional optical coherence tomography. Korean J Ophthalmol 2013;27: 172–177. 14. Yiu G, Pecen P, Sarin N, et al. Characterization of the choroidscleral junction and suprachoroidal layer in healthy individuals on enhanced-depth imaging optical coherence tomography. JAMA Ophthalmol 2014;132:174–181. 15. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology 2010;117:1792–1799. 16. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol 1967;63(Suppl):1–139. 17. Prunte C. Indocyanine green angiographic findings in central serous chorioretinopathy. Int Ophthalmol 1995;19:77–82. 18. Hayreh SS. In vivo choroidal circulation and its watershed zones. Eye 1990;4:273–289. 19. Hayreh SS. Inter-individual variation in blood supply of the optic nerve head. Its importance in various ischemic disorders of the optic nerve head, and glaucoma, low-tension glaucoma and allied disorders. Doc Ophthalmol 1985;59:217–246. 20. Hayreh SS. Segmental nature of the choroidal vasculature. Br J Ophthalmol 1975;59:631–648. 21. Hayreh SS. Physiological anatomy of the choroidal vascular bed. Int Ophthalmol 1983;6:85–93. 22. Yannuzzi LA, Flower RW, Slakter JS. Indocyanine green angiography.St.Louis, MO: Mosby; 1997:24–25. 23. Iida T, Kishi S, Hagimura N, Shimizu K. Persistent and bilateral choroidal vascular abnormalities in central serous chorioretinopathy. Retina 1999;19:508–512.
