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Assessment of Choroidal Topographic Changes by Swept Source Optical Coherence Tomography After Photodynamic Therapy for Central Serous Chorioretinopathy
Assessment of Choroidal Topographic Changes by Swept Source Optical Coherence Tomography After Photodynamic Therapy for Central Serous Chorioretinopathy SAM RAZAVI, ERIC H. SOUIED, EDOARDO CAVALLERO, MICHEL WEBER, AND GIUSEPPE QUERQUES PURPOSE:
To investigate the relationship between choroidal thickness and angiographic abnormalities in central serous chorioretinopathy (CSC) eyes by sweptsource optical coherence tomography (swept-OCT), before and after half-fluence photodynamic therapy (PDT). DESIGN: Prospective interventional case series. METHODS: Consecutive patients presenting with treatment-naive active CSC underwent a complete ophthalmologic examination, including swept-OCT at study entry and at 7 days and 30 days after treatment with half-fluence PDT. The main outcome measures were changes in choroidal maps after PDT (mean ± SD) and the relationship between choroidal thickness and angiographic abnormalities. RESULTS: Of 12 patients (2 females, 10 males; mean age, 55.6 ± 14.0 years), 12 eyes were included. At study entry, mean choroidal thickness measured in the center of the fovea was significantly thicker in the study eyes as compared to the fellow eyes (420.7 ± 107.5 mm vs 349.2 ± 109.7 mm, respectively; P [ 0.016). Mean choroidal thickness in the center of the fovea significantly decreased in the study eyes at both 7 days (380.2 ± 113 mm; P [ 0.005) and 30 days after PDT (362.3 ± 111 mm; P [ 0.002). A similar significant choroidal thinning was recorded in each early treatment of diabetic retinopathy study (ETDRS) applied to 3D swept-OCT maps. At each time point, mean choroidal thickness was significantly thicker in sectors with than in sectors without angiographic abnormalities (421 ± 102.4 mm vs 397.6 ± 96.5 mm, P [ 0.002 at study entry; 381.2 ± 106.6 mm vs 364 ± 101.2 mm, P [ 0.01 at day 7; 366.3 ± 103.2 mm vs 347.2 ± 99.6 mm at day 30). CONCLUSIONS: Using swept-OCT, we demonstrated that in active CSC, choroidal thickness is increased to a
Accepted for publication Dec 31, 2013. From the Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France (S.R., E.H.S., E.C., G.Q.); the Transparence Eye Clinic, Tours, France (S.R.); and the Department of Ophthalmology, Hotel Dieu University Hospital, Nantes, France (M.W.). Inquiries to Giuseppe Querques, Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, 40 Avenue de Verdun, 94000 Creteil, France; e-mail: giuseppe. [email protected]
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greater extent in areas characterized by angiographic abnormalities. This increased choroidal thickness may persist even after PDT. (Am J Ophthalmol 2014;157: 852–860. Ó 2014 by Elsevier Inc. All rights reserved.)
C
ENTRAL SEROUS CHORIORETINOPATHY (CSC) IS A
relatively common retinal disorder that often occurs in patients in the professionally active age range.1 In CSC, accumulation of fluid under the retina appears to be caused by a dysfunction of the retinal pigment epithelium (RPE) as a result of hyperpermeability and swelling of the choroid.2,3 A prolonged retinal detachment in the macula of patients with CSC leads to permanent central vision loss due to photoreceptor atrophy.1,2,4–11 Therefore, several treatment options have emerged in the attempt to accelerate the resolution of subretinal fluid accumulation and to improve the visual outcomes in patients with chronic CSC.1 However, to date there is no international consensus concerning the optimal treatment protocol of CSC. Focal laser photocoagulation, the classic treatment for CSC patients, could shorten the symptom duration of w2 months.12 However, a prospective, randomized clinical trial found that the final recurrence rate in the laser photocoagulation group was unchanged.13 Recurrent attacks may lead to widespread alterations of the RPE and permanent central vision loss. A number of mainly retrospective studies suggest that treatment with photodynamic therapy (PDT) using the photosensitizing drug verteporfin (Visudyne; Novartis, Basel, Switzerland) is effective in patients with CSC in reducing subretinal fluid, with an improvement of retinal anatomy, visual acuity,1,2,14–21 and retinal sensitivity.22–26 PDT seems to reduce the leakage from the RPE as well as the recurrence rate by decreasing the hyperpermeability in the choroid.1,2,18–21 By using enhanced depth imaging optical coherence tomography (EDI-OCT),27 it has been reported that subfoveal choroidal thickness is increased in CSC eyes compared with normal eyes. Maruko and associates,28 using EDIOCT, first reported that subfoveal choroidal thickness decreased following a half dose of PDT in patients with CSC. However, EDI-OCT, which is coupled to multiple
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averaging to achieve high contrast and low speckle noise, results in less detailed raster scan images. For this reason, previous studies have focused on choroidal thickness at several points, mainly the subfovea.28–33 The recently developed swept source (swept-OCT) uses a center wavelength of >1000 nm, instead of the currently more widely diffuse OCT probing light operated at approximately 800 nm. The higher penetration of the OCT probe operating in swept-OCT, at a longer wavelength, allows the entire choroid to be visualized. Therefore, sweptOCT, which is characterized by a high-speed scan rate and a relatively low sensitivity roll-off vs depth compared with the spectral-domain OCT, is able to produce a 3dimensional (3D) high-contrast image of the choroid.34–39 In this study we scanned the whole macular area of patients with CSC by high-penetrating swept-OCT using a 3D radial scan protocol. The resultant choroidalthickness maps were used to investigate the relationship between choroidal thickness and angiographic changes before and after PDT.
METHODS PATIENT SELECTION:
In this prospective study, consecutive patients presenting with unilateral treatment-naive active CSC were entered over a 6-month period at the Transparence Eye Clinic of Tours, France, and the University Eye Clinic of Creteil, France. Inclusion criteria were: age >18 years; diagnosis of active CSC for at least 1 month, defined as presence of subretinal fluid involving the macula and associated with idiopathic leaks from the RPE during fluorescein angiography (FA). Exclusion criteria were any prior treatment (such as laser photocoagulation, photodynamic therapy, or intravitreal injections of anti-VEGF), and presence of subretinal fluid due to causes other than CSC (such as polypoidal choroidal vasculopathy). Informed consent was obtained from all patients in agreement with the Declaration of Helsinki for research involving human subjects. French Society of Ophthalmology Ethics Committee approval was obtained for this study. STUDY PROTOCOL:
All patients underwent (before PDT) a complete ophthalmologic examination at study entry, including measurement of best-corrected visual acuity (BCVA) using standard early treatment of diabetic retinopathy study (ETDRS) charts, fundus biomicroscopy, and FA (in case of isolated points of leakage). Indocyanine green angiography (ICGA) was performed in association with FA, in case of diffuse or poorly defined regions of leakage originating from broad areas of RPE damage. All patients also underwent swept-OCT, a system previously described in detail (Topcon, Tokyo, Japan),37 which uses the light source of a wavelength-sweeping laser centered at 1050 nm and having a tuning range of 100 nm. This sys-
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tem has a scanning speed of 100 000 A-scans per second and a scan window depth of 2.6 mm. The axial and transverse resolutions are 8 mm and 20 mm in tissue, respectively. The swept-OCT examinations were performed by trained examiners after pupil dilation. A 3D imaging data set was acquired for each subject (both eyes) using a radial scan protocol of 12 lines (12 mm B-scans, each composed of 1024 A-scans) through the fovea were obtained, and 32 B-scan images were averaged to reduce speckle noise. The centration of the scan was achieved by an internal fixation target and confirmed by a camera built-into the swept-source OCT system. All patients were treated with FA/ICGA-guided verteporfin (6 mg/m2) PDT (Visudyne; Novartis Pharma, New York, NY, USA), with a half-fluence rate (25 J/cm2). Angiographic features (presence of leakage and choroidal vascular abnormalities or RPE atrophic changes) were evaluated by an experienced ophthalmologist (GQ) who was unaware of the swept-OCT results. The area of choroidal vascular abnormality on FA or ICGA (35 degree image-field setting) was measured with the built-in measurement software (IMAGEnet system; TRC-50IX; Topcon, Tokyo, Japan). Then a calibrated Opal PDT-Laser (Coherent, Santa Clara, CA, USA) and an indirect condensing laser lens (Mainster Wide Field; Ocular Instruments, Bellevue, WA, USA) were used for the PDT procedure. The infusion of verteporfin was performed for 10 minutes, and 15 minutes after the start of the infusion, a laser light at 689 nm was delivered at 25 J/cm2, with an intensity of 300 mW/cm2 for 83 seconds. All patients underwent repeated 3D swept-OCT assessment in the treated eye (study eye) at both 7 days and 30 days after PDT. MORPHOLOGIC CHANGES ANALYSIS BY SWEPT-OCT:
Each 3D swept-OCT imaging covered a circle area of 12 mm in diameter centered on the fovea. In each image of the 3D data set, the macular thickness was measured as the distance between 2 lines automatically determined, corresponding to the inner limiting membrane and the inner border of the RPE-Bruch membrane complex. Similarly, in each image of the 3D data set, the choroidal thickness was measured as the distance between 2 lines automatically determined, representing the outer border of the RPEBruch membrane complex and the chorioscleral border (Figure 1). Each line automatically determined was then manually corrected for any errors by one of the authors (SR). From all 12 images of each 3D data set, automated builtin calibration software (software v 9.00.003.17; Topcon) was used to determine the distance between the lines and to create 12 mm circular macular thickness and choroidal thickness maps. False colors were determined, starting from cool colors and progressing to warm colors (at the range of 0 to 500 mm), and ETDRS sectors (6 3 6 mm) were applied to the choroidal thickness map (Figure 1). The mean thickness of each sector was automatically measured in the center sector within 1 mm from the center
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FIGURE 1. Swept-source optical coherence tomography (swept-OCT) and fluorescein angiography (FA) of both right eye (fellow eye, right panels) and left eye (study eye, left panels) of Patient #1 with central serous chorioretinopathy at study entry. SweptOCT shows choroidal thickening in the study eye (left panels), on both manual and automatic measurements. Note the manual measurements (top panels) in the center of the fovea (red vertical lines), performed using the built-in caliper software, and the white dotted vertical lines, which indicate where, in 4 sectors (superior, inferior, nasal, and temporal), the other manual measurements were performed (at 1, 2 and 3 mm from the center of the fovea). Automatic measurements by built-in calibration software (software v 9.00.003.17; Topcon, Tokyo, Japan), which determines the distance between the outer border of the retinal pigment epithelium– Bruch membrane complex and the chorioscleral border (the 2 horizontal red lines), create 12 mm circular choroidal thickness maps (bottom panels). False colors were determined, starting from cool colors and progressing to warm colors (at the range of 0 to 500 mm). Note ETDRS sectors (6 3 6 mm) applied to the choroidal thickness map.
of the fovea; in 4 inner-ring sectors (superior, inferior, nasal, and temporal) 1 to 2 mm from the center of the fovea; and in 4 outer ring sectors (superior, inferior, temporal, and nasal) 2 to 3 mm from the center of the fovea. The height of the serous retinal detachment, defined as the distance between the RPE and the bottom of the detached neurosensory retina just beneath the fovea, and the choroidal thickness in the center of the fovea, as well as in 4 sectors (superior, inferior, nasal, and temporal) at 1, 2 and 3 mm from the center of the fovea, were manually measured using the built-in caliper software (software v 9.00.003.17; Topcon) (Figure 1) by 2 independent readers (SR, EHS). Mean observed values were considered.
STATISTICAL ANALYSIS STATISTICAL CALCULATIONS WERE PERFORMED USING
Statistical Package for Social Sciences (v 17.0; SPSS, 854
Chicago, IL, USA). All data are presented as mean 6 standard deviation (SD). The Wilcoxon signed-rank test was used to evaluate changes in mean BCVA (logarithm of the minimum angle of resolution [logMAR]); mean macular thickness; and mean choroidal thickness (both automatically and manually measured) from study entry to day 7 and day 30 after PDT. At study entry, the Student t test was used for comparison of mean choroidal thickness at the center of the fovea and at each sector (superior, inferior, nasal, and temporal) between study eyes and fellow eyes. The mean choroidal thickness of areas characterized by angiographic abnormalities was compared, using t test analysis, to the mean choroidal thickness of areas without them (comparing choroidal values of affected areas with the average choroidal values of all unaffected areas). The Spearman correlation test was performed to evaluate the agreement between automatic and manual measurements of mean choroidal thickness at study entry (for both study and fellow eyes), at day 7 and at day 30 (for study eyes). The chosen level of statistical significance was P < 0.05.
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TABLE 1. Mean choroidal thickness of each sector, automatically measured at study entry and 30 days after photodynamic therapy, for both study eyes with central serous chorioretinopathy and fellow eyes Study Entry
Inner superior Inner inferior Inner nasal Inner temporal Outer superior Outer inferior Outer nasal Outer temporal
30 Days a
Study Eyes
Fellow Eyes
P value
Study Eyes
Fellow Eyes
P valuea
413.5 6 93.1 mm 422.9 6 106.6 mm 401.9 6 93.8 mm 414.5 6 116.2 mm 396.7 6 77.4 mm 392.7 6 94.5 mm 333.2 6 86.8 mm 393.1 6 104.5 mm
344.2 6 86.9 mm 357.1 6 109.5 mm 324.3 6 104.5 mm 344 6 107.1 mm 326.2 6 68.1 mm 333 6 103.7 mm 268 6 96.1 mm 322.3 6 95.1 mm
0.005 0.016 0.012 0.009 0.002 0.006 0.006 0.005
356.7 6 100.5 mm 366.3 6 107.8 mm 358.7 6 96.3 mm 353.8 6 116.7 mm 347.3 6 79.6 mm 344.2 6 96.9 mm 298.3 6 90.2 mm 344.1 6 108.4 mm
336.1 6 88.9 mm 351.8 6 103.6 mm 304.3 6 101.8 mm 339.1 6 99.4 mm 303.3 6 72.4 mm 324.6 6 98.8 mm 255 6 101.3 mm 312.3 6 95.4 mm
0.16 0.275 0.038 0.288 0.036 0.116 0.022 0.081
All data are presented as mean 6 standard deviation. Student t test.
a
12 patients (2 females, 10 males; mean age, 55.6 6 14.0 years; range, 36–79 years) diagnosed with active CSC fulfilled the inclusion/exclusion criteria entered the study (Table 1). At study entry, symptoms related to CSC were reported to last from a mean of 2.7 6 1.7 months (median, 2.4 months; range, 1–6 months). Mean BCVA at study entry was significantly worse in the study eyes as compared to fellow eyes (0.22 6 0.23 logMAR vs 0.03 6 0.04 logMAR, respectively; P ¼ 0.014). Mean choroidal thickness automatically measured in the center of the fovea at study entry was significantly thicker in the study eyes as compared to fellow eyes (420.7 6 107.5 mm vs 349.2 6 109.7 mm, respectively; P ¼ 0.016) (Figure 1). The mean choroidal thickness of each sector (superior, inferior, nasal, and temporal) automatically measured in the inner ring (1 to 2 mm from the center of the fovea) and in the outer ring (2 to 3 mm from the center of the fovea), for both study eyes and fellow eyes, are reported in Table 1.
both 7 days (from 385.5 6 150.2 mm to 313.2 6 93 mm, P ¼ 0.005; from 162.7 6 119.9 mm to 77 6 65 mm, P ¼ 0.002, respectively) and 30 days after PDT (from 385.5 6 150.2 mm to 219.7 6 47.3 mm, P ¼ 0.002; from 162.7 6 119.9 mm to 10.9 6 26.7 mm, P ¼ 0.002, respectively). Changes in the mean choroidal thickness of each sector (superior, inferior, nasal, and temporal), automatically measured in the inner ring (1 to 2 mm from the center of the fovea), and in the outer ring (2 to 3 mm from the center of the fovea), are reported in Table 2. At day 30, as reported in Table 1, the choroid in study eyes was still thicker than that in fellow eyes in all sectors (significantly in 3 of 8 sectors). PDT was directed to areas of choroidal abnormalities. Changes in automatically measured choroidal thickness in sectors (both inner ring and outer ring) with angiographic abnormalities at study entry (defined as those that involved more than 50% of the sector area) are reported in Table 3. Angiographic abnormalities at study entry (affected areas) in study eyes could be counted as follows: nasal sector, outer ring in 1 eye; superior sector, outer ring in 3 eyes; temporal sector, outer ring in 3 eyes; inferior sector, inner ring in 1 eye; central fovea sector in 4 eyes.
CHANGES IN FUNCTIONAL AND MORPHOLOGICAL FINDINGS DURING THE STUDY PERIOD: Mean BCVA
CORRELATIONS BETWEEN AUTOMATICALLY AND MANUALLY MEASURED CHOROIDAL THICKNESS:
improved, even though not significantly, in the study eyes 7 days (from 0.22 6 0.23 logMAR to 0.2 6 0.2 logMAR; P ¼ 0.193) and, significantly, 30 days after PDT (from 0.22 6 0.23 logMAR to 0.12 6 0.15 logMAR; P ¼ 0.014). Mean choroidal thickness automatically measured in the center of the fovea significantly decreased in the study eyes at both 7 days (from 420.7 6 107.5 mm to 380.2 6 113 mm; P ¼ 0.005) and 30 days after PDT (from 420.7 6 107.5 mm to 362.3 6 111 mm; P ¼ 0.002) (Figures 2, 3). Macular thickness and the height of the serous retinal detachment significantly decreased in the study eyes at
Choroidal thickness in the center of the fovea significantly correlated between automatic and manual (mean values of manual measurements taken at 0 to 1 mm from the center of the fovea) measurements at baseline (both study eye and fellow eye; P ¼ 0.99, P < 0.001 and P ¼ 0.987, P < 0.001, respectively), and 7 days and 30 days after PDT (study eye, P ¼ 0.956, P < 0.001 and P ¼ 0.97, P < 0.001, respectively). Correlations between automatically and manually (mean values of manual measurements taken at 0 to 1 mm from the center of the fovea) measured choroidal thickness of the inner ring sector and outer ring sector
RESULTS PATIENT DEMOGRAPHICS AND MAIN FINDINGS AT STUDY ENTRY: Twelve eyes of
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FIGURE 2. Swept-source optical coherence tomography (swept-OCT), fluorescein angiography (FA) and indocyanine angiography (ICGA) of the right eye (study eye) of Patient #10 at study entry. FA (top left panel) and ICGA (top right panel) show angiographic abnormalities in the superior sector, outer ring, matching with the area of thicker choroid (ETDRS sectors applied to the choroidal thickness map) on Swept-OCT (bottom panel).
measured at baseline (both study eye and fellow eye) and at 7 days and 30 days after PDT (study eye) are reported in Table 4. The inner ring sector values and the outer ring sector values consisted of average values derived from the combination of superior, inferior, nasal, and temporal sectors.
DISCUSSION IN THIS STUDY WE INVESTIGATED THE RELATIONSHIP
between choroidal thickness and angiographic abnormalities in CSC eyes by high-penetrating swept-OCT. Moreover, we analyzed changes in choroidal thickness 7 days and 30 days after FA/ICGA–guided half-fluence PDT (which is only one of the proposed modified PDT treatments). Overall, automatically generated maps showed the choroid to be thicker in areas of angiographic abnormalities 856
than in other areas (Table 3). At study entry, mean choroidal thickness in the center of the fovea and in each sector (superior, inferior, nasal, and temporal), automatically measured in the inner ring (1 to 2 mm from the center of the fovea) and in the outer ring (2 to 3 mm from the center of the fovea), was significantly thicker in the study eyes than in fellow eyes (Table 1). Similarly, in the study performed by Jirarattanasopa and associates38 using 3D raster scanning images obtained by swept-OCT, eyes with CSC were found to have thickened choroids in the whole macular area and focally increased choroidal thickness associated with angiographic findings. Moreover, Maruko and associates30 first reported that the subfoveal choroidal thickness in eyes with active CSC was greater than that in fellow eyes, which is consistent with our study. Analysis of choroidal thickness after PDT revealed a significant thinning at both day 7 and day 30 in sectors characterized by angiographic abnormalities (Affected Areas, Table 3). A similar significant thinning was registered
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FIGURE 3. Swept-source optical coherence tomography (swept-OCT) of the right eye (study eye) of Patient #10, 7 days and 30 days after photodynamic therapy (PDT). Swept-OCT shows an overall thinning of the choroid after PDT. Note how, at both 7 days (top panel) and 30 days (bottom panel) after PDT, a thicker choroid (ETDRS sectors applied to the choroidal thickness map) seems to match with the area of angiographic abnormalities as evaluated at study entry (Figure 2).
TABLE 2. Changes of Mean Choroidal Thickness in Each Sector of Eyes with Central Serous Chorioretinopathy, Automatically Measured, from Study Entry to 7 Days and 30 Days after Photodynamic Therapy
Inner superior Inner inferior Inner nasal Inner temporal Outer superior Outer inferior Outer nasal Outer temporal
Study Entry
7 Days
P Valuea
30 Days
P Valuea
413.5 6 93.1 mm (385 mm) 422.9 6 106.6 mm (414 mm) 401.9 6 106.6 mm (393 mm) 414.5 6 116.2 mm (390 mm) 396.7 6 77.4 mm (394.5 mm) 392.7 6 94.5 mm (391.5 mm) 333.3 6 86.8 mm (338.5 mm) 393.1 6 104.5 mm (367 mm)
367.3 6 104.9 mm (361 mm) 388.7 6 108.7 mm (374 mm) 372.4 6 99 mm (351.5 mm) 369.9 6 119.9 mm (354 mm) 363.3 6 79.1 mm (346 mm) 368.2 6 96.4 mm (359.5 mm) 315.2 6 87.9 mm (296.5 mm) 356.7 6 107.4 mm (333 mm)
0.012
356.7 6 100.5 mm (365.5 mm) 366.3 6 107.8 mm (340.5 mm) 358.7 6 96.3 mm (339 mm) 353.8 6 116.7 mm (333.5 mm) 347.3 6 79.6 mm (334.5 mm) 344.2 6 96.9 mm (314.5 mm) 298.3 6 90.2 mm (268 mm) 344.1 6 108.4 mm (331 mm)
0.002
0.007 0.022 0.005 0.005 0.008 0.037 0.005
0.002 0.003 0.002 0.002 0.002 0.002 0.002
All data are presented as mean 6 standard deviation (median). Wilcoxon signed-rank test.
a
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TABLE 3. Mean Choroidal Thickness and Changes of Mean Choroidal Thickness of Eyes with Central Serous Chorioretinopathy at Each Time Point in Areas with Angiographic Abnormalities (Affected Areas) and in Areas Without Angiographic Abnormalities (Unaffected Areas)
Affected areas Unaffected areas P valueb
Study Entry
7 Days
P Valuea
30 Days
P Valuea
421 6 102.4 mm (415.5 mm) 397.6 6 96.5 mm (378 mm) 0.002
381.2 6 106.6 mm (346 mm) 364 6 101.2 mm (317.5 mm) 0.01
0.007
366.3 6 103.2 mm (341 mm) 347.2 6 99.6 mm (313 mm) 0.006
0.003
0.002
0.002
All data are presented as mean 6 standard deviation (median). Wilcoxon signed-rank test. b Student t test. a
TABLE 4. Correlations Between Automatically and Manually Measured Choroidal Thickness of Inner Ring Sector and Outer Ring Sector (Average Values from the Combination of Superior, Inferior, Nasal, and Temporal Sectors) in Eyes with Central Serous Chorioretinopathy Study Entry
7 Days
Study Eyes
Automatic inner ring r P Automatic outer ring r P
Fellow Eyes
30 Days
Study Eyes
Study Eyes
Manual Inner
Manual Outer
Manual Inner
Manual Outer
Manual Inner
Manual Outer
Manual Inner
Manual Outer
0.986 <0.001
/ /
0.997 <0.001
/ /
0.961 <0.001
/ /
0.957 <0.001
/ /
/ /
0.983 <0.001
/ /
0.985 <0.001
/ /
0.958 <0.001
/ /
0.984 <0.001
P ¼ Spearman rank correlation coefficient.
also in the sectors characterized by absence of angiographic abnormalities (Unaffected Areas) at both day 7 and day 30 (Table 3). Of note, despite this similar thinning after PDT in sectors characterized by angiographic abnormalities, the automatically generated maps still showed significant choroidal thickening compared with sectors characterized by absence of angiographic abnormalities (Table 3). At day 30, in all sectors, the choroid of study eyes was still thicker than that of fellow eyes (significantly in 3 of 8 sectors). However, BCVA as well as macular thickness and the height of the serous retinal detachment significantly improved at day 30 compared with those at study entry. Taken together, these findings suggest that FA/ICGA– guided half-fluence PDT is able to reduce choroidal hyperpermeability (visualized by OCT as choroidal thickening)28 not only in areas characterized by angiographic abnormalities, but actually in the whole macular area, and that this reduced hyperpermeability is accompanied by an improvement in both retinal function (BCVA) and morphology (macular thickness and serous retinal detachment) as soon as at 1 month after treatment administration. On the other hand, in eyes with active CSC, before and after 858
PDT (up to 30 days), the choroid characterized by angiographic abnormalities was thicker than the choroid characterized by absence of angiographic abnormalities. Nonetheless, before and after PDT (up to 30 days), the choroid in eyes with active CSC was thicker than that in fellow eyes, and both eyes of CSC patients (active and inactive eyes) showed thicker choroid than normal subjects.27,38 This may explain why not only bilateralization of active disease (because of thickened choroid in inactive eyes) but also, recurrences are quite common in patients with CSC after spontaneous resolution, focal laser, and even (less frequently) after PDT.1 Indeed, despite PDT administration, the abnormal areas angiographically detected before treatment continued to show a greater extent of choroidal thickening (indicating hyperpermeability) as compared to other macular areas. Iida and associates40 found that choroidal vascular abnormalities in ICGA persisted in both eyes, even after the cessation of leakage from the RPE. Thus, the authors hypothesized that choroidal structural abnormalities may persist even after the resolution of serous retinal detachment, which may have a relationship with the well-known phenomenon of
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active CSC recurrence. Maruko and associates28 reported that focal laser photocoagulation did not result in any change in choroidal thickness, although serous retinal detachment decreased. This hypothesis is also corroborated by our current findings of a greater extent of choroidal thickening after half-dose PDT in areas of angiographic abnormalities detected before treatment. There are some limitations to this study. The series presented here is relatively small, and patients were followed for up to 30 days only. Moreover, we used halffluence PDT, which is only one of the several possibilities to reduce risks for PDT. The other possibilities include decreasing the laser treatment time, altering the interval between infusion and laser, and reducing the dose to 50% or 30%.1 All studies of reduced-fluence or reduced-dose PDT have found favorable results. So far there is no consensus on how to treat CSC by PDT, and we decided to use half-fluence PDT, which is possibly not the best way to reduce risks while obtaining good outcomes. Furthermore, we do not know what would happen to choroidal thickness using half-dose PDT instead of halffluence PDT. Maybe half-dose PDT is better than halffluence PDT; maybe half-dose PDT would reduce choroidal thickness at 30 days so it is not different from fellow eyes. However, this study was not designed to assess the longterm effects (efficacy and risks) of half-fluence PDT, but rather to investigate the relationship between choroidal thickness and angiographic abnormalities in eyes with CSC and to analyze regional changes in choroidal thickness after angiography-guided treatment. Another
limitation is represented by the localization in CSC patients of angiographic abnormalities (affected areas) in the center of the fovea, which in normal subjects is characterized by a thicker choroid.27,38 This may have eventually biased the comparative evaluation, both before and after PDT, of choroidal thickness between areas with angiographic abnormalities (affected areas) and areas without angiographic abnormalities (unaffected areas). However, only 4 eyes presented this localization, which makes irrelevant such eventuality. Finally, we used a relatively new software to generate choroidal maps automatically. However, we also measured the choroid at the fovea and at several points form the fovea manually and found significant correlations between automatically and manually measured thicknesses in the center of the fovea and in each sector (average values from the combination of superior, inferior, nasal, and temporal) for both the inner ring and the outer ring (Table 4). In conclusion, using swept-OCT, we demonstrated that in active CSC, choroidal thickness is increased to a greater extent in areas characterized by angiographic abnormalities. After PDT, the increased choroidal thickness, compared to areas characterized by absence of angiographic abnormalities, may persist even in cases of reduction or resolution of serous retinal detachment. These findings provide further evidence that local persistence of choroidal structural abnormalities indicating hyperpermeability (ie, choroidal thickening) may have a relationship with the well-known phenomenon of active CSC recurrence.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST, and none were reported. Design and conduct of study (G.Q., S.R., M.W., E.H.S.); Collection, management and analysis of data (G.Q., E.C., E.H.S.); Interpretation of data (G.Q., S.R., E.H.S.); and Preparation, review, or approval of the manuscript (G.Q., S.R., E.C., E.H.S.).
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7. Wong R, Chopdar A, Brown M. Five to 15-year follow-up of resolved idiopathic central serous chorioretinopathy. Eye 2004;18(3):262–268. 8. Gilbert CM, Owens SL, Smith PD, Fine SL. Long-term follow-up of central serous chorioretinopathy. Br J Ophthalmol 1984;68(11):815–820. 9. Stewart JM. Half dose verteporfin PDT for central serous chorioretinopathy. Br J Ophthalmol 2006;90(7):805–806. 10. Brancato R, Scialdone A, Pece A, Coscas G, Binaghi M. Eight-year follow-up of central serous chorioretinopathy with and without laser treatment. Graefes Arch Clin Exp Ophthalmol 1987;225(3):166–168. 11. Otsuka S, Ohba N, Nakao K. A long-term follow-up study of severe variant of central serous chorioretinopathy. Retina 2002;22(1):25–32. 12. Robertson DM, Ilstrup D. Direct, indirect, and sham laser photocoagulation in the management of central serous chorioretinopathy. Am J Ophthalmol 1983;95(4):457–466. 13. Ficker L, Vafidis G, While A, Leaver P. Long-term follow-up of a prospective trial of argon laser photocoagulation in the
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To investigate the relationship between choroidal thickness and angiographic abnormalities in central serous chorioretinopathy (CSC) eyes by sweptsource optical coherence tomography (swept-OCT), before and after half-fluence photodynamic therapy (PDT). DESIGN: Prospective interventional case series. METHODS: Consecutive patients presenting with treatment-naive active CSC underwent a complete ophthalmologic examination, including swept-OCT at study entry and at 7 days and 30 days after treatment with half-fluence PDT. The main outcome measures were changes in choroidal maps after PDT (mean ± SD) and the relationship between choroidal thickness and angiographic abnormalities. RESULTS: Of 12 patients (2 females, 10 males; mean age, 55.6 ± 14.0 years), 12 eyes were included. At study entry, mean choroidal thickness measured in the center of the fovea was significantly thicker in the study eyes as compared to the fellow eyes (420.7 ± 107.5 mm vs 349.2 ± 109.7 mm, respectively; P [ 0.016). Mean choroidal thickness in the center of the fovea significantly decreased in the study eyes at both 7 days (380.2 ± 113 mm; P [ 0.005) and 30 days after PDT (362.3 ± 111 mm; P [ 0.002). A similar significant choroidal thinning was recorded in each early treatment of diabetic retinopathy study (ETDRS) applied to 3D swept-OCT maps. At each time point, mean choroidal thickness was significantly thicker in sectors with than in sectors without angiographic abnormalities (421 ± 102.4 mm vs 397.6 ± 96.5 mm, P [ 0.002 at study entry; 381.2 ± 106.6 mm vs 364 ± 101.2 mm, P [ 0.01 at day 7; 366.3 ± 103.2 mm vs 347.2 ± 99.6 mm at day 30). CONCLUSIONS: Using swept-OCT, we demonstrated that in active CSC, choroidal thickness is increased to a
Accepted for publication Dec 31, 2013. From the Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France (S.R., E.H.S., E.C., G.Q.); the Transparence Eye Clinic, Tours, France (S.R.); and the Department of Ophthalmology, Hotel Dieu University Hospital, Nantes, France (M.W.). Inquiries to Giuseppe Querques, Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, 40 Avenue de Verdun, 94000 Creteil, France; e-mail: giuseppe. [email protected]
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greater extent in areas characterized by angiographic abnormalities. This increased choroidal thickness may persist even after PDT. (Am J Ophthalmol 2014;157: 852–860. Ó 2014 by Elsevier Inc. All rights reserved.)
C
ENTRAL SEROUS CHORIORETINOPATHY (CSC) IS A
relatively common retinal disorder that often occurs in patients in the professionally active age range.1 In CSC, accumulation of fluid under the retina appears to be caused by a dysfunction of the retinal pigment epithelium (RPE) as a result of hyperpermeability and swelling of the choroid.2,3 A prolonged retinal detachment in the macula of patients with CSC leads to permanent central vision loss due to photoreceptor atrophy.1,2,4–11 Therefore, several treatment options have emerged in the attempt to accelerate the resolution of subretinal fluid accumulation and to improve the visual outcomes in patients with chronic CSC.1 However, to date there is no international consensus concerning the optimal treatment protocol of CSC. Focal laser photocoagulation, the classic treatment for CSC patients, could shorten the symptom duration of w2 months.12 However, a prospective, randomized clinical trial found that the final recurrence rate in the laser photocoagulation group was unchanged.13 Recurrent attacks may lead to widespread alterations of the RPE and permanent central vision loss. A number of mainly retrospective studies suggest that treatment with photodynamic therapy (PDT) using the photosensitizing drug verteporfin (Visudyne; Novartis, Basel, Switzerland) is effective in patients with CSC in reducing subretinal fluid, with an improvement of retinal anatomy, visual acuity,1,2,14–21 and retinal sensitivity.22–26 PDT seems to reduce the leakage from the RPE as well as the recurrence rate by decreasing the hyperpermeability in the choroid.1,2,18–21 By using enhanced depth imaging optical coherence tomography (EDI-OCT),27 it has been reported that subfoveal choroidal thickness is increased in CSC eyes compared with normal eyes. Maruko and associates,28 using EDIOCT, first reported that subfoveal choroidal thickness decreased following a half dose of PDT in patients with CSC. However, EDI-OCT, which is coupled to multiple
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averaging to achieve high contrast and low speckle noise, results in less detailed raster scan images. For this reason, previous studies have focused on choroidal thickness at several points, mainly the subfovea.28–33 The recently developed swept source (swept-OCT) uses a center wavelength of >1000 nm, instead of the currently more widely diffuse OCT probing light operated at approximately 800 nm. The higher penetration of the OCT probe operating in swept-OCT, at a longer wavelength, allows the entire choroid to be visualized. Therefore, sweptOCT, which is characterized by a high-speed scan rate and a relatively low sensitivity roll-off vs depth compared with the spectral-domain OCT, is able to produce a 3dimensional (3D) high-contrast image of the choroid.34–39 In this study we scanned the whole macular area of patients with CSC by high-penetrating swept-OCT using a 3D radial scan protocol. The resultant choroidalthickness maps were used to investigate the relationship between choroidal thickness and angiographic changes before and after PDT.
METHODS PATIENT SELECTION:
In this prospective study, consecutive patients presenting with unilateral treatment-naive active CSC were entered over a 6-month period at the Transparence Eye Clinic of Tours, France, and the University Eye Clinic of Creteil, France. Inclusion criteria were: age >18 years; diagnosis of active CSC for at least 1 month, defined as presence of subretinal fluid involving the macula and associated with idiopathic leaks from the RPE during fluorescein angiography (FA). Exclusion criteria were any prior treatment (such as laser photocoagulation, photodynamic therapy, or intravitreal injections of anti-VEGF), and presence of subretinal fluid due to causes other than CSC (such as polypoidal choroidal vasculopathy). Informed consent was obtained from all patients in agreement with the Declaration of Helsinki for research involving human subjects. French Society of Ophthalmology Ethics Committee approval was obtained for this study. STUDY PROTOCOL:
All patients underwent (before PDT) a complete ophthalmologic examination at study entry, including measurement of best-corrected visual acuity (BCVA) using standard early treatment of diabetic retinopathy study (ETDRS) charts, fundus biomicroscopy, and FA (in case of isolated points of leakage). Indocyanine green angiography (ICGA) was performed in association with FA, in case of diffuse or poorly defined regions of leakage originating from broad areas of RPE damage. All patients also underwent swept-OCT, a system previously described in detail (Topcon, Tokyo, Japan),37 which uses the light source of a wavelength-sweeping laser centered at 1050 nm and having a tuning range of 100 nm. This sys-
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tem has a scanning speed of 100 000 A-scans per second and a scan window depth of 2.6 mm. The axial and transverse resolutions are 8 mm and 20 mm in tissue, respectively. The swept-OCT examinations were performed by trained examiners after pupil dilation. A 3D imaging data set was acquired for each subject (both eyes) using a radial scan protocol of 12 lines (12 mm B-scans, each composed of 1024 A-scans) through the fovea were obtained, and 32 B-scan images were averaged to reduce speckle noise. The centration of the scan was achieved by an internal fixation target and confirmed by a camera built-into the swept-source OCT system. All patients were treated with FA/ICGA-guided verteporfin (6 mg/m2) PDT (Visudyne; Novartis Pharma, New York, NY, USA), with a half-fluence rate (25 J/cm2). Angiographic features (presence of leakage and choroidal vascular abnormalities or RPE atrophic changes) were evaluated by an experienced ophthalmologist (GQ) who was unaware of the swept-OCT results. The area of choroidal vascular abnormality on FA or ICGA (35 degree image-field setting) was measured with the built-in measurement software (IMAGEnet system; TRC-50IX; Topcon, Tokyo, Japan). Then a calibrated Opal PDT-Laser (Coherent, Santa Clara, CA, USA) and an indirect condensing laser lens (Mainster Wide Field; Ocular Instruments, Bellevue, WA, USA) were used for the PDT procedure. The infusion of verteporfin was performed for 10 minutes, and 15 minutes after the start of the infusion, a laser light at 689 nm was delivered at 25 J/cm2, with an intensity of 300 mW/cm2 for 83 seconds. All patients underwent repeated 3D swept-OCT assessment in the treated eye (study eye) at both 7 days and 30 days after PDT. MORPHOLOGIC CHANGES ANALYSIS BY SWEPT-OCT:
Each 3D swept-OCT imaging covered a circle area of 12 mm in diameter centered on the fovea. In each image of the 3D data set, the macular thickness was measured as the distance between 2 lines automatically determined, corresponding to the inner limiting membrane and the inner border of the RPE-Bruch membrane complex. Similarly, in each image of the 3D data set, the choroidal thickness was measured as the distance between 2 lines automatically determined, representing the outer border of the RPEBruch membrane complex and the chorioscleral border (Figure 1). Each line automatically determined was then manually corrected for any errors by one of the authors (SR). From all 12 images of each 3D data set, automated builtin calibration software (software v 9.00.003.17; Topcon) was used to determine the distance between the lines and to create 12 mm circular macular thickness and choroidal thickness maps. False colors were determined, starting from cool colors and progressing to warm colors (at the range of 0 to 500 mm), and ETDRS sectors (6 3 6 mm) were applied to the choroidal thickness map (Figure 1). The mean thickness of each sector was automatically measured in the center sector within 1 mm from the center
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FIGURE 1. Swept-source optical coherence tomography (swept-OCT) and fluorescein angiography (FA) of both right eye (fellow eye, right panels) and left eye (study eye, left panels) of Patient #1 with central serous chorioretinopathy at study entry. SweptOCT shows choroidal thickening in the study eye (left panels), on both manual and automatic measurements. Note the manual measurements (top panels) in the center of the fovea (red vertical lines), performed using the built-in caliper software, and the white dotted vertical lines, which indicate where, in 4 sectors (superior, inferior, nasal, and temporal), the other manual measurements were performed (at 1, 2 and 3 mm from the center of the fovea). Automatic measurements by built-in calibration software (software v 9.00.003.17; Topcon, Tokyo, Japan), which determines the distance between the outer border of the retinal pigment epithelium– Bruch membrane complex and the chorioscleral border (the 2 horizontal red lines), create 12 mm circular choroidal thickness maps (bottom panels). False colors were determined, starting from cool colors and progressing to warm colors (at the range of 0 to 500 mm). Note ETDRS sectors (6 3 6 mm) applied to the choroidal thickness map.
of the fovea; in 4 inner-ring sectors (superior, inferior, nasal, and temporal) 1 to 2 mm from the center of the fovea; and in 4 outer ring sectors (superior, inferior, temporal, and nasal) 2 to 3 mm from the center of the fovea. The height of the serous retinal detachment, defined as the distance between the RPE and the bottom of the detached neurosensory retina just beneath the fovea, and the choroidal thickness in the center of the fovea, as well as in 4 sectors (superior, inferior, nasal, and temporal) at 1, 2 and 3 mm from the center of the fovea, were manually measured using the built-in caliper software (software v 9.00.003.17; Topcon) (Figure 1) by 2 independent readers (SR, EHS). Mean observed values were considered.
STATISTICAL ANALYSIS STATISTICAL CALCULATIONS WERE PERFORMED USING
Statistical Package for Social Sciences (v 17.0; SPSS, 854
Chicago, IL, USA). All data are presented as mean 6 standard deviation (SD). The Wilcoxon signed-rank test was used to evaluate changes in mean BCVA (logarithm of the minimum angle of resolution [logMAR]); mean macular thickness; and mean choroidal thickness (both automatically and manually measured) from study entry to day 7 and day 30 after PDT. At study entry, the Student t test was used for comparison of mean choroidal thickness at the center of the fovea and at each sector (superior, inferior, nasal, and temporal) between study eyes and fellow eyes. The mean choroidal thickness of areas characterized by angiographic abnormalities was compared, using t test analysis, to the mean choroidal thickness of areas without them (comparing choroidal values of affected areas with the average choroidal values of all unaffected areas). The Spearman correlation test was performed to evaluate the agreement between automatic and manual measurements of mean choroidal thickness at study entry (for both study and fellow eyes), at day 7 and at day 30 (for study eyes). The chosen level of statistical significance was P < 0.05.
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TABLE 1. Mean choroidal thickness of each sector, automatically measured at study entry and 30 days after photodynamic therapy, for both study eyes with central serous chorioretinopathy and fellow eyes Study Entry
Inner superior Inner inferior Inner nasal Inner temporal Outer superior Outer inferior Outer nasal Outer temporal
30 Days a
Study Eyes
Fellow Eyes
P value
Study Eyes
Fellow Eyes
P valuea
413.5 6 93.1 mm 422.9 6 106.6 mm 401.9 6 93.8 mm 414.5 6 116.2 mm 396.7 6 77.4 mm 392.7 6 94.5 mm 333.2 6 86.8 mm 393.1 6 104.5 mm
344.2 6 86.9 mm 357.1 6 109.5 mm 324.3 6 104.5 mm 344 6 107.1 mm 326.2 6 68.1 mm 333 6 103.7 mm 268 6 96.1 mm 322.3 6 95.1 mm
0.005 0.016 0.012 0.009 0.002 0.006 0.006 0.005
356.7 6 100.5 mm 366.3 6 107.8 mm 358.7 6 96.3 mm 353.8 6 116.7 mm 347.3 6 79.6 mm 344.2 6 96.9 mm 298.3 6 90.2 mm 344.1 6 108.4 mm
336.1 6 88.9 mm 351.8 6 103.6 mm 304.3 6 101.8 mm 339.1 6 99.4 mm 303.3 6 72.4 mm 324.6 6 98.8 mm 255 6 101.3 mm 312.3 6 95.4 mm
0.16 0.275 0.038 0.288 0.036 0.116 0.022 0.081
All data are presented as mean 6 standard deviation. Student t test.
a
12 patients (2 females, 10 males; mean age, 55.6 6 14.0 years; range, 36–79 years) diagnosed with active CSC fulfilled the inclusion/exclusion criteria entered the study (Table 1). At study entry, symptoms related to CSC were reported to last from a mean of 2.7 6 1.7 months (median, 2.4 months; range, 1–6 months). Mean BCVA at study entry was significantly worse in the study eyes as compared to fellow eyes (0.22 6 0.23 logMAR vs 0.03 6 0.04 logMAR, respectively; P ¼ 0.014). Mean choroidal thickness automatically measured in the center of the fovea at study entry was significantly thicker in the study eyes as compared to fellow eyes (420.7 6 107.5 mm vs 349.2 6 109.7 mm, respectively; P ¼ 0.016) (Figure 1). The mean choroidal thickness of each sector (superior, inferior, nasal, and temporal) automatically measured in the inner ring (1 to 2 mm from the center of the fovea) and in the outer ring (2 to 3 mm from the center of the fovea), for both study eyes and fellow eyes, are reported in Table 1.
both 7 days (from 385.5 6 150.2 mm to 313.2 6 93 mm, P ¼ 0.005; from 162.7 6 119.9 mm to 77 6 65 mm, P ¼ 0.002, respectively) and 30 days after PDT (from 385.5 6 150.2 mm to 219.7 6 47.3 mm, P ¼ 0.002; from 162.7 6 119.9 mm to 10.9 6 26.7 mm, P ¼ 0.002, respectively). Changes in the mean choroidal thickness of each sector (superior, inferior, nasal, and temporal), automatically measured in the inner ring (1 to 2 mm from the center of the fovea), and in the outer ring (2 to 3 mm from the center of the fovea), are reported in Table 2. At day 30, as reported in Table 1, the choroid in study eyes was still thicker than that in fellow eyes in all sectors (significantly in 3 of 8 sectors). PDT was directed to areas of choroidal abnormalities. Changes in automatically measured choroidal thickness in sectors (both inner ring and outer ring) with angiographic abnormalities at study entry (defined as those that involved more than 50% of the sector area) are reported in Table 3. Angiographic abnormalities at study entry (affected areas) in study eyes could be counted as follows: nasal sector, outer ring in 1 eye; superior sector, outer ring in 3 eyes; temporal sector, outer ring in 3 eyes; inferior sector, inner ring in 1 eye; central fovea sector in 4 eyes.
CHANGES IN FUNCTIONAL AND MORPHOLOGICAL FINDINGS DURING THE STUDY PERIOD: Mean BCVA
CORRELATIONS BETWEEN AUTOMATICALLY AND MANUALLY MEASURED CHOROIDAL THICKNESS:
improved, even though not significantly, in the study eyes 7 days (from 0.22 6 0.23 logMAR to 0.2 6 0.2 logMAR; P ¼ 0.193) and, significantly, 30 days after PDT (from 0.22 6 0.23 logMAR to 0.12 6 0.15 logMAR; P ¼ 0.014). Mean choroidal thickness automatically measured in the center of the fovea significantly decreased in the study eyes at both 7 days (from 420.7 6 107.5 mm to 380.2 6 113 mm; P ¼ 0.005) and 30 days after PDT (from 420.7 6 107.5 mm to 362.3 6 111 mm; P ¼ 0.002) (Figures 2, 3). Macular thickness and the height of the serous retinal detachment significantly decreased in the study eyes at
Choroidal thickness in the center of the fovea significantly correlated between automatic and manual (mean values of manual measurements taken at 0 to 1 mm from the center of the fovea) measurements at baseline (both study eye and fellow eye; P ¼ 0.99, P < 0.001 and P ¼ 0.987, P < 0.001, respectively), and 7 days and 30 days after PDT (study eye, P ¼ 0.956, P < 0.001 and P ¼ 0.97, P < 0.001, respectively). Correlations between automatically and manually (mean values of manual measurements taken at 0 to 1 mm from the center of the fovea) measured choroidal thickness of the inner ring sector and outer ring sector
RESULTS PATIENT DEMOGRAPHICS AND MAIN FINDINGS AT STUDY ENTRY: Twelve eyes of
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FIGURE 2. Swept-source optical coherence tomography (swept-OCT), fluorescein angiography (FA) and indocyanine angiography (ICGA) of the right eye (study eye) of Patient #10 at study entry. FA (top left panel) and ICGA (top right panel) show angiographic abnormalities in the superior sector, outer ring, matching with the area of thicker choroid (ETDRS sectors applied to the choroidal thickness map) on Swept-OCT (bottom panel).
measured at baseline (both study eye and fellow eye) and at 7 days and 30 days after PDT (study eye) are reported in Table 4. The inner ring sector values and the outer ring sector values consisted of average values derived from the combination of superior, inferior, nasal, and temporal sectors.
DISCUSSION IN THIS STUDY WE INVESTIGATED THE RELATIONSHIP
between choroidal thickness and angiographic abnormalities in CSC eyes by high-penetrating swept-OCT. Moreover, we analyzed changes in choroidal thickness 7 days and 30 days after FA/ICGA–guided half-fluence PDT (which is only one of the proposed modified PDT treatments). Overall, automatically generated maps showed the choroid to be thicker in areas of angiographic abnormalities 856
than in other areas (Table 3). At study entry, mean choroidal thickness in the center of the fovea and in each sector (superior, inferior, nasal, and temporal), automatically measured in the inner ring (1 to 2 mm from the center of the fovea) and in the outer ring (2 to 3 mm from the center of the fovea), was significantly thicker in the study eyes than in fellow eyes (Table 1). Similarly, in the study performed by Jirarattanasopa and associates38 using 3D raster scanning images obtained by swept-OCT, eyes with CSC were found to have thickened choroids in the whole macular area and focally increased choroidal thickness associated with angiographic findings. Moreover, Maruko and associates30 first reported that the subfoveal choroidal thickness in eyes with active CSC was greater than that in fellow eyes, which is consistent with our study. Analysis of choroidal thickness after PDT revealed a significant thinning at both day 7 and day 30 in sectors characterized by angiographic abnormalities (Affected Areas, Table 3). A similar significant thinning was registered
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FIGURE 3. Swept-source optical coherence tomography (swept-OCT) of the right eye (study eye) of Patient #10, 7 days and 30 days after photodynamic therapy (PDT). Swept-OCT shows an overall thinning of the choroid after PDT. Note how, at both 7 days (top panel) and 30 days (bottom panel) after PDT, a thicker choroid (ETDRS sectors applied to the choroidal thickness map) seems to match with the area of angiographic abnormalities as evaluated at study entry (Figure 2).
TABLE 2. Changes of Mean Choroidal Thickness in Each Sector of Eyes with Central Serous Chorioretinopathy, Automatically Measured, from Study Entry to 7 Days and 30 Days after Photodynamic Therapy
Inner superior Inner inferior Inner nasal Inner temporal Outer superior Outer inferior Outer nasal Outer temporal
Study Entry
7 Days
P Valuea
30 Days
P Valuea
413.5 6 93.1 mm (385 mm) 422.9 6 106.6 mm (414 mm) 401.9 6 106.6 mm (393 mm) 414.5 6 116.2 mm (390 mm) 396.7 6 77.4 mm (394.5 mm) 392.7 6 94.5 mm (391.5 mm) 333.3 6 86.8 mm (338.5 mm) 393.1 6 104.5 mm (367 mm)
367.3 6 104.9 mm (361 mm) 388.7 6 108.7 mm (374 mm) 372.4 6 99 mm (351.5 mm) 369.9 6 119.9 mm (354 mm) 363.3 6 79.1 mm (346 mm) 368.2 6 96.4 mm (359.5 mm) 315.2 6 87.9 mm (296.5 mm) 356.7 6 107.4 mm (333 mm)
0.012
356.7 6 100.5 mm (365.5 mm) 366.3 6 107.8 mm (340.5 mm) 358.7 6 96.3 mm (339 mm) 353.8 6 116.7 mm (333.5 mm) 347.3 6 79.6 mm (334.5 mm) 344.2 6 96.9 mm (314.5 mm) 298.3 6 90.2 mm (268 mm) 344.1 6 108.4 mm (331 mm)
0.002
0.007 0.022 0.005 0.005 0.008 0.037 0.005
0.002 0.003 0.002 0.002 0.002 0.002 0.002
All data are presented as mean 6 standard deviation (median). Wilcoxon signed-rank test.
a
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TABLE 3. Mean Choroidal Thickness and Changes of Mean Choroidal Thickness of Eyes with Central Serous Chorioretinopathy at Each Time Point in Areas with Angiographic Abnormalities (Affected Areas) and in Areas Without Angiographic Abnormalities (Unaffected Areas)
Affected areas Unaffected areas P valueb
Study Entry
7 Days
P Valuea
30 Days
P Valuea
421 6 102.4 mm (415.5 mm) 397.6 6 96.5 mm (378 mm) 0.002
381.2 6 106.6 mm (346 mm) 364 6 101.2 mm (317.5 mm) 0.01
0.007
366.3 6 103.2 mm (341 mm) 347.2 6 99.6 mm (313 mm) 0.006
0.003
0.002
0.002
All data are presented as mean 6 standard deviation (median). Wilcoxon signed-rank test. b Student t test. a
TABLE 4. Correlations Between Automatically and Manually Measured Choroidal Thickness of Inner Ring Sector and Outer Ring Sector (Average Values from the Combination of Superior, Inferior, Nasal, and Temporal Sectors) in Eyes with Central Serous Chorioretinopathy Study Entry
7 Days
Study Eyes
Automatic inner ring r P Automatic outer ring r P
Fellow Eyes
30 Days
Study Eyes
Study Eyes
Manual Inner
Manual Outer
Manual Inner
Manual Outer
Manual Inner
Manual Outer
Manual Inner
Manual Outer
0.986 <0.001
/ /
0.997 <0.001
/ /
0.961 <0.001
/ /
0.957 <0.001
/ /
/ /
0.983 <0.001
/ /
0.985 <0.001
/ /
0.958 <0.001
/ /
0.984 <0.001
P ¼ Spearman rank correlation coefficient.
also in the sectors characterized by absence of angiographic abnormalities (Unaffected Areas) at both day 7 and day 30 (Table 3). Of note, despite this similar thinning after PDT in sectors characterized by angiographic abnormalities, the automatically generated maps still showed significant choroidal thickening compared with sectors characterized by absence of angiographic abnormalities (Table 3). At day 30, in all sectors, the choroid of study eyes was still thicker than that of fellow eyes (significantly in 3 of 8 sectors). However, BCVA as well as macular thickness and the height of the serous retinal detachment significantly improved at day 30 compared with those at study entry. Taken together, these findings suggest that FA/ICGA– guided half-fluence PDT is able to reduce choroidal hyperpermeability (visualized by OCT as choroidal thickening)28 not only in areas characterized by angiographic abnormalities, but actually in the whole macular area, and that this reduced hyperpermeability is accompanied by an improvement in both retinal function (BCVA) and morphology (macular thickness and serous retinal detachment) as soon as at 1 month after treatment administration. On the other hand, in eyes with active CSC, before and after 858
PDT (up to 30 days), the choroid characterized by angiographic abnormalities was thicker than the choroid characterized by absence of angiographic abnormalities. Nonetheless, before and after PDT (up to 30 days), the choroid in eyes with active CSC was thicker than that in fellow eyes, and both eyes of CSC patients (active and inactive eyes) showed thicker choroid than normal subjects.27,38 This may explain why not only bilateralization of active disease (because of thickened choroid in inactive eyes) but also, recurrences are quite common in patients with CSC after spontaneous resolution, focal laser, and even (less frequently) after PDT.1 Indeed, despite PDT administration, the abnormal areas angiographically detected before treatment continued to show a greater extent of choroidal thickening (indicating hyperpermeability) as compared to other macular areas. Iida and associates40 found that choroidal vascular abnormalities in ICGA persisted in both eyes, even after the cessation of leakage from the RPE. Thus, the authors hypothesized that choroidal structural abnormalities may persist even after the resolution of serous retinal detachment, which may have a relationship with the well-known phenomenon of
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active CSC recurrence. Maruko and associates28 reported that focal laser photocoagulation did not result in any change in choroidal thickness, although serous retinal detachment decreased. This hypothesis is also corroborated by our current findings of a greater extent of choroidal thickening after half-dose PDT in areas of angiographic abnormalities detected before treatment. There are some limitations to this study. The series presented here is relatively small, and patients were followed for up to 30 days only. Moreover, we used halffluence PDT, which is only one of the several possibilities to reduce risks for PDT. The other possibilities include decreasing the laser treatment time, altering the interval between infusion and laser, and reducing the dose to 50% or 30%.1 All studies of reduced-fluence or reduced-dose PDT have found favorable results. So far there is no consensus on how to treat CSC by PDT, and we decided to use half-fluence PDT, which is possibly not the best way to reduce risks while obtaining good outcomes. Furthermore, we do not know what would happen to choroidal thickness using half-dose PDT instead of halffluence PDT. Maybe half-dose PDT is better than halffluence PDT; maybe half-dose PDT would reduce choroidal thickness at 30 days so it is not different from fellow eyes. However, this study was not designed to assess the longterm effects (efficacy and risks) of half-fluence PDT, but rather to investigate the relationship between choroidal thickness and angiographic abnormalities in eyes with CSC and to analyze regional changes in choroidal thickness after angiography-guided treatment. Another
limitation is represented by the localization in CSC patients of angiographic abnormalities (affected areas) in the center of the fovea, which in normal subjects is characterized by a thicker choroid.27,38 This may have eventually biased the comparative evaluation, both before and after PDT, of choroidal thickness between areas with angiographic abnormalities (affected areas) and areas without angiographic abnormalities (unaffected areas). However, only 4 eyes presented this localization, which makes irrelevant such eventuality. Finally, we used a relatively new software to generate choroidal maps automatically. However, we also measured the choroid at the fovea and at several points form the fovea manually and found significant correlations between automatically and manually measured thicknesses in the center of the fovea and in each sector (average values from the combination of superior, inferior, nasal, and temporal) for both the inner ring and the outer ring (Table 4). In conclusion, using swept-OCT, we demonstrated that in active CSC, choroidal thickness is increased to a greater extent in areas characterized by angiographic abnormalities. After PDT, the increased choroidal thickness, compared to areas characterized by absence of angiographic abnormalities, may persist even in cases of reduction or resolution of serous retinal detachment. These findings provide further evidence that local persistence of choroidal structural abnormalities indicating hyperpermeability (ie, choroidal thickening) may have a relationship with the well-known phenomenon of active CSC recurrence.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST, and none were reported. Design and conduct of study (G.Q., S.R., M.W., E.H.S.); Collection, management and analysis of data (G.Q., E.C., E.H.S.); Interpretation of data (G.Q., S.R., E.H.S.); and Preparation, review, or approval of the manuscript (G.Q., S.R., E.C., E.H.S.).
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