Central serous chorioretinopathy (CSC) is one of the most common chorioretinal diseases and is characterized by serous detachment of the neurosensory retina with or without retinal pigment epithelium (RPE) detachment.1,2 Most CSC resolves spontaneously within 3 to 4 months. However, treatment should be considered in patients who suffer from persistent serous macular detachment.3–5
Indocyanine green angiography (ICGA)-guided photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis AG, Bulach, Switzerland) is effective in treating CSC,3,6,7 although adverse effects of the treatment such as RPE atrophy, secondary choroidal neovascularization, and choriocapillaris ischemia have been reported.7–9 To reduce the detrimental effects of conventional PDT on RPE and choroidal perfusion, modifications of the protocol such as reducing irradiance, exposure time, or verteporfin dose have been attempted. These modified protocols have been reported to be as effective as conventional PDT with less complication.7–12
As well as long-term effects, early changes after standard PDT, such as increase in subretinal and intraretinal fluid and transient macular function reduction, have been demonstrated.8,13–15 Worsening of visual complaints in the first week after half-dose verteporfin PDT in patients with CSC has also been reported.16 However, early post-treatment findings of half-time PDT in patients with CSC are not precisely known.
In this prospective study, we evaluated spectral-domain optical coherence tomography (SD-OCT) and microperimetry changes before half-time PDT and after 1 day, 3 days, and 1 week, as well as monthly thereafter. To the best of our knowledge, this study is the first to report immediate outcomes after half-time PDT in CSC.
Patients and Methods
We prospectively evaluated 24 eyes of 23 patients without any disease-limiting visual acuity (VA) other than symptomatic CSC of 4-month duration or more who were referred to Istanbul Retina Institute between January 2017 and October 2017. Written informed consent was obtained prior to the diagnostic and therapeutic procedures. The study protocol was approved by the Institutional Review Board of Şişli Memorial Hospital, Istanbul. The study adhered to the tenets of the Declaration of Helsinki.
The inclusion criteria were as follows: (1) a history of vision loss for at least 4 months; (2) persistence of serous retinal detachment involving the fovea for at least 4 months with or without serous pigment epithelial detachment, documented with OCT; (3) presence of active angiographic leakage caused by CSC shown on fluorescein angiography (FA); (4) abnormal dilated choroidal vasculature and other features consistent with the diagnosis of CSC, shown on ICGA; (5) no evidence of choroidal neovascularization or polypoidal choroidal vasculopathy on FA or ICGA; (6) no previous PDT, laser focal photocoagulation treatment, or intravitreal injection of anti-vascular endothelial growth factor drugs; (7) no current treatment with steroid for any other diseases.
PDT was performed by administering half the normal fluence (25 J/cm2) by halving the PDT irradiation time. All patients received an infusion of verteporfin of 6 mg/m2 body surface area during a period of 10 min, followed by laser delivery at 689 nm 5 min after the start of the infusion with the Opal Photoactivator (Coherent, Santa Clara, CA) and standard light intensity of 600 mW/cm2, as previously described.1 The standard irradiation time was shortened to 42 s. The area of irradiation was set to cover the hyperfluorescent area of the leakage shown during the mid-to-late phase of ICGA. After treatment, protective spectacles were given, and patients were instructed to avoid direct sunlight for 2 days.
Baseline and Follow-Up Examinations
All participants received a comprehensive ophthalmic examination, including measurement of best-corrected VA (BCVA) by the Early Treatment Diabetic Retinopathy Study chart, refraction and intraocular pressure (IOP) measured by applanation tonometer, detailed anterior segment and fundus examination by using slit-lamp biomicroscopy with a 90-diopter noncontact lens, SD-OCT in the enhanced depth imaging mode (Heidelberg Engineering, Heidelberg, Germany), and microperimetry (MP-1 Microperimeter; Nidek Technologies, Padua, Italy). The Spectralis OCT system was used for fundus autofluorescence, macular scans, choroidal imaging, digital FA, and ICGA. Digital FA and ICGA were performed at baseline. BCVA, fundus examination, OCT measurements, and microperimetry were obtained at baseline and after PDT at day 1, day 3, day 7, month 1, and month 3.
OCT images were obtained by a single examiner experienced in performing scans using the SD-OCT device. To exclude diurnal variations, all examinations were at a similar time of day (9 AM to 1 PM). The macula was screened by taking 49 sections (512 A-scans) at 120 μm intervals within a 20° × 20° rectangular field. An average of nine images was obtained for each section. Two high-quality horizontal and vertical line scans centered on the fovea were also obtained for each eye. One hundred frames were averaged using automatic averaging, and fundus features were saved and tracked automatically to align follow-up scans. The central foveal thickness (CFT) was defined as the distance between the internal limiting membrane and the inner border of the RPE. The subfoveal choroidal thickness (SCT) was defined as the distance between the base of the RPE and the choroidoscleral boundary. Measurements were taken with the manual calipers provided with the software of the device. The central and foveal thicknesses from the horizontal and vertical line scans centered on the fovea were each measured by two of the coauthors. Disagreement between the two coauthors was resolved by open adjudication. The open adjudication was conducted in consultation with the senior investigator. The average values of horizontal and vertical line scan measurements were used for statistical analysis.
Microperimetry was used with a red cross as the fixation target and a standardized grid of 76 Goldmann III stimuli covering the central 20°, white background illumination of 1.27 cd/m2, and a projection time of 200 ms, which has been described previously.3,4 A 4-2 staircase strategy was carried out and the contralateral eye was occluded during the test. All subjects underwent microperimetry with dilated pupils. Differential light threshold values were compared by calculating selected points, which were averaged automatically by the MP-1 microperimetry software program for mean sensitivity in a polygon. For the assessment of fixation, fundus movements were tracked during examination, in which the patient gazed at the fixation target and the fixation pattern was evaluated. The fixation pattern was graded as follows: fixation stability and fixation location. Results were displayed by color digital retinography, acquired by the charge-coupled MP1 color fundus camera.
Data on sex, age, duration of symptoms, BCVA, refractive error, IOP, CFT, SCT, retinal sensitivity, fixation characteristics, PDT spot size, and verteporfin dosage were evaluated, and data for all 24 eyes were used for statistical analysis. Descriptive statistical methods (mean, standard deviation) were used for characteristics such as age, sex, and BCVA. Continuous variables such as pretreatment and post-treatment data were compared using analysis of variance for repeated test. Correlations between the size of spot area and CFT or SCT were evaluated using Spearman's rank correlation test. The Mann-Whitney U test was also used for comparing variables between patients with history of one or more previous episodes of CSC and patients with first episodes of CSC. Statistical analyses used SPSS version 20.0 (SPSS, Chicago, IL). A P value less than .05 was considered statistically significant.
All 24 eyes of 23 patients (14 male, nine female) with active CSC who underwent half-time PDT were included in the study. The mean age of patients at the time of treatment was 44.7 years ± 8.1 years (range: 28 years to 53 years). Seven of the eyes (29%) had one or more previous episodes of CSC, with a mean of 31.3 months ± 29.4 months (range: 7 months to 72 months) duration of the disease. The duration of the current episode was 4 months to 6 months. One patient (4.3%) underwent treatment in both eyes. The PDT was applied within the central 20° area in all patients. Mean PDT spot size was 4.7 mm ± 0.5 mm (range: 4.0 mm to 5.5 mm). The dosage of verteporfin was 5.5 mL ± 0.4 mL (range: 4.8 mL to 6.3 mL). Detailed baseline demographic and clinical characteristics of the patients are summarized in Table 1.
Detailed Baseline Demographic and Clinical Characteristics of Patients
Following half-time PDT, an immediate increase in CFT was seen at 1 day after treatment, and then a tendency to decrease was observed. There was a statistically significant difference between pretreatment CFT and post-treatment CFT at 1 day (P = .02) and at 3 days (P = .04). The increased CFT significantly resolved 1 month after treatment (P = .002). Subretinal fluid and intraretinal fluid resolved completely in 23 eyes (95.8%) 1 month after treatment and in 24 eyes (100%) at 3 months. Similarly, SCT increased after 1 day and subsequently decreased gradually. There was a statistically significant difference between pretreatment SCT and post-treatment SCT at 1 day (P = .013), but the increased choroidal thickness resolved 7 days after treatment (P = .011). This was sustained up to the last follow-up visit.
There was a correlation between the size of spot area and increase of choroidal thickness at 3 days (r = 0.510; P = .026), and the size of spot area and decrease of choroidal thickness at 3 months (r = 0.519; P = .023).
Compared with pretreatment BCVA (logMAR 0.23 ± 0.17), the mean post-treatment BCVA was significantly worse at 7 days (logMAR 0.35 ± 0.23), and then improved at 1 month (logMAR 0.20 ± 0.15) and 3 months (logMAR 0.14 ± 0.15). A statistically significant improvement was observed at 3 months (P = .002). However, an immediate decrease in retinal sensitivity occurred at post-treatment day 1, the greatest reduction of retinal sensitivity was observed at 3 days after treatment, and then a tendency for improvement in retinal function was seen at subsequent visits.
Significantly recovery of retinal function occurred 3 months after treatment (P = .003). All patients had predominantly central fixation before and after treatment in all examinations; 54% of eyes had stable fixation before treatment, and fixation was stable in all eyes 3 months after treatment. None of the patients developed any systemic or infusion-related adverse events.
We also compared all pre-treatment and post-treatment results between 7 patients with history of one or more previous episodes of CSC and 16 patients with first episodes of CSC. There were no significant differences in compared values between those patients, except the age and retinal sensitivity at post-treatment day 90. Patients with history of one or more previous episodes of CSC were older than patients with first episode of CSC (P = .046) and, the retinal sensitivity at post-treatment day 90 was lower in patients with history of one or more previous episodes of CSC than patients with first episode of CSC (P = .10).
Detailed OCT and microperimetry measurements after half-time PDT are shown in Table 2 and Figures 1–5.
Detailed OCT and Microperimetry Measurements After Half-Time PDT and Comparison With Pretreatment Results
Right eye of a 38-year-old man with a 10-month history of central serous chorioretinopathy. Baseline fluorescein angiography shows leaking points in the foveal area, (A) and indocyanine green angiography shows choroidal hyperpermeability areas (B). Baseline optical coherence tomography image demonstrates subretinal fluid (SRF) and retinal pigment epithelium detachment. The pretreatment central foveal thickness (CFT) was 208 μm, and the subfoveal choroidal thickness (SCT) was 453 μm, with visual acuity (VA) of 20/32 (C). One day after half-time photodynamic therapy, a prompt increase in CFT from 208 μm to 976 μm and in SCT from 453 μm to 560 μm was noted (D). Three days after treatment, persistence of increased CFT (971 μm) and SCT (535 μm) is seen (third row, left) (E). CFT decreased from 971 μm to 515 μm and SCT from 535 μm to 450 μm 1 week after treatment, with VA of 20/50 (F). One month after treatment, CFT was 194 μm and SCT was 391 μm, with VA of 20/32 (G). Complete resolution of SRF and intraretinal fluid, persistence of decreased SCT (402 μm), and improved VA from 20/32 to 20/25 is seen 3 months after treatment (H).
The MP-1 image of the patient at baseline examination indicates that the fixation was predominantly central and stable even in the presence of subretinal fluid. The retinal sensitivity at 76 locations covering the central 20° was 14.0 dB. The intensity of the stimulus inversely corresponded to the tested retinal sensitivity, expressed as a gradual change in color from dark red (corresponding to 0 dB) to dark green (corresponding to 20 dB). Each of the blue dots represents a fixation point (A). One day after half-time photodynamic therapy, a prompt decrease in retinal sensitivity from 14.0 dB to 7.4 dB was seen, with predominantly central and stable fixation (B). Three days after treatment, the greatest reduction of retinal sensitivity was observed (0.8 dB), with predominantly central but relatively unstable fixation (C). A tendency to increase in retinal function (4.3 dB), with predominantly central but relatively unstable fixation, was seen 1 week after treatment (D). One month after treatment, the retinal sensitivity was 10.6 dB, with predominantly central and stable fixation (E). The retinal sensitivity in the central 20° improved from 10.6 dB to 16.5 dB, with predominantly central and stable fixation 3 months after treatment (F).
Mean central foveal thickness at different times before and after half-time photodynamic therapy.
Mean subfoveal choroidal thickness (SCT) at different times before and after half-time photodynamic therapy.
Mean retinal sensitivity at 76 locations covering the central 20° at different times before and after half-time photodynamic therapy.
Early effects of half-dose and half-fluence PDT, which have been used to minimize adverse effects of standard PDT, are not fully known. This study is the first to demonstrate results immediately after half-time PDT in CSC. Following half-time PDT, a prompt increase in SCT and CFT, and a decrease in retinal sensitivity was observed 1 day after treatment. Retinal and choroidal thickness decreased gradually at subsequent visits, and a concomitant tendency for improved retinal sensitivity was seen after the third day of treatment. Significant reduction in choroidal thickness occurred 7 days after treatment and significant decrease in CFT at 1 month. Significant recovery of retinal function and improvement of VA was achieved 3 months after treatment.
Because there were no available reports of early outcomes after half-time or half-dose PDT treatment for CSC, our data can be compared with data from patients with choroidal neovascularization treated with a standard PDT protocol. Early retinal and choroidal changes related to acute inflammatory response and ischemic changes after standard PDT have been reported.8,13–15,18 Increased retinal thickness, with subretinal and intraretinal fluid, within the first week of treatment has been demonstrated in the OCT studies,8,15 and immediate massive exudation within hours after verteporfin therapy and subsequent occlusion of the choriocapillaris have been shown by FA and ICGA.14 It was demonstrated that the exudative response diminished substantially at 1 week.14 Transient reduction in retinal function, as reflected by the multifocal electroretinography response, was also shown within 4 days after PDT.13 In the present study, early anatomical and functional results, such as an immediate increase in SCT and CFT and decrease in retinal sensitivity 1 day after treatment and a tendency to decrease in retinal and choroidal thickness and increase in retinal sensitivity at subsequent visits are comparable to results in previous published reports.
Van Dijk et al.16 assessed the short-term outcome of half-dose verteporfin PDT in patients with CSC. They reported worsening of visual complaints, with no significant changes in CFT and SCT on OCT imaging and retinal sensitivity on microperimetry in some of the patients 1 week after treatment.16 Similarly, there was no significant difference in CFT 1 week after half-time PDT in the present study. However, the significant decreases in BCVA, retinal sensitivity, and choroidal thickness demonstrated at post-treatment week 1, differ from the results of the previous study. PDT-induced vascular damage depends on verteporfin dose, and half-time PDT could produce a higher inflammation reaction and more leakage than half-dose PDT.17 The difference between the two studies in choroidal thickness, BCVA, and retinal sensitivity 1 week after treatment may be related to the difference between the PDT protocols.
It had been shown that PDT caused long-term choroidal vascular remodeling and decreased choroidal permeability following short-term choriocapillaris hypoperfusion.18 In the present study, a significant reduction of choroidal thickness was observed as early as 7 days after half-time PDT and persisted during 3-month follow-up, similar to previous reports.14,18
Microperimetry is an accurate test for the assessment of macular function in patients with CSC, with strict correspondence of VA and macular morphology.3,19,20 Improvement of retinal sensitivity after half-dose PDT in patients with CSC has been shown in the previous studies.3,20 In our previous report, we demonstrated that the mean retinal sensitivity within the central 20° field increased from baseline after half-dose PDT in all patients, and the retinal sensitivity in the treated area improved.3 In the present study, impairment of central retinal function was detected immediately after half-time PDT, consistent with anatomical deterioration. Despite those early anatomical and functional impairments, retinal sensitivity improved significantly 3 months after treatment, similar to our previous study.3
In conclusion, an increase in CFT and SCT, and decrease in retinal sensitivity were demonstrated by OCT and microperimetry as early as 1 day after half-time PDT in patients with CSC. Morphological recovery occurred 1 month after treatment, and functional improvement could be achieved by 3 months. Despite early anatomical and functional impairments, not only BCVA but also retinal sensitivity improved significantly 3 months after treatment. The increased retinal sensitivity after treatment may indicate that no side-effect related to half-time PDT occurred.
- Arf S, Hocaoglu M, Sayman Muslubas I, Karacorlu M. Efficacy of reduced-fluence photodynamic therapy for central serous retinal detachment associated with combined serous retinal detachment and fovea-involving pigment epithelial detachment. Int Ophthalmol. 2017;37(3):483–489. doi:10.1007/s10792-016-0286-4 [CrossRef]
- Daruich A, Matet A, Dirani A, et al. Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis. Prog Retin Eye Res. 2015;48:82–118. doi:10.1016/j.preteyeres.2015.05.003 [CrossRef]
- Senturk F, Karacorlu M, Ozdemir H, Karacorlu SA, Uysal O. Microperimetric changes after photodynamic therapy for central serous chorioretinopathy. Am J Ophthalmol. 2011;151(2):303–309.e1. doi:10.1016/j.ajo.2010.08.019 [CrossRef]
- Levine R, Brucker AJ, Robinson F. Long-term follow-up of idiopathic central serous chorioretinopathy by fluorescein angiography. Ophthalmol. 1989;96(6):854–859. doi:10.1016/S0161-6420(89)32810-7 [CrossRef]
- Loo RH, Scott IU, Flynn HW Jr, et al. Factors associated with reduced visual acuity during long-term follow-up of patients with idiopathic central serous chorioretinopathy. Retina. 2002;22(1):19–24. doi:10.1097/00006982-200202000-00004 [CrossRef]
- Yannuzzi LA, Slakter JS, Gross NE, et al. Indocyanine green angiography-guided photodynamic therapy for treatment of chronic central serous chorioretinopathy: A pilot study. Retina. 2003;23(3):288–298. doi:10.1097/00006982-200306000-00002 [CrossRef]
- Nicholson B, Noble J, Forooghian F, Meyerle C. Central serous chorioretinopathy: Update on pathophysiology and treatment. Surv Ophthalmol. 2013;58(2):103–126. doi:10.1016/j.survophthal.2012.07.004 [CrossRef]
- Rogers AH, Martidis A, Greenberg PB, Puliafito CA. Optical coherence tomography findings following photodynamic therapy of choroidal neovascularization. Am J Ophthalmol. 2002;134(4):566–576. doi:10.1016/S0002-9394(02)01566-0 [CrossRef]
- Schlotzer-Schrehardt U, Viestenz A, Naumann GO, et al. Dose-related structural effects of photodynamic therapy on choroidal and structural effects of human eyes. Graefes Arch Clin Exp Ophtalmol. 2002;240(9):748–757. doi:10.1007/s00417-002-0517-4 [CrossRef]
- Liu HY, Yang CH, Yang CM, et al. Half-dose versus half time photodynamic therapy for central serous chorioretinopathy. Am J Ophtalmol. 2016;167:57–64. doi:10.1016/j.ajo.2016.04.001 [CrossRef]
- Cheng CK, Chang CK, Peng CH. Comparison of photodynamic therapy using half-dose of verteporfin or half-fluence of laser light for the treatment of chronic serous chorioretinopathy. Retina. 2017;37(2):324–333. doi:10.1097/IAE.0000000000001138 [CrossRef]
- Shiode Y, Morizane Y, Kimura S, et al. Comparison of halving the irradiation time or the verteporfin dose in photodynamic therapy for chronic serous chorioretinopathy. Retina. 2015;35(12):2498–2504. doi:10.1097/IAE.0000000000000621 [CrossRef]
- Lai TYY, Chan W, Lam DSC. Transient reduction in retinal function revealed by multifocal electroretinogram after photodynamic therapy. Am J Ophthalmol. 2004;137(1):826–833. doi:10.1016/j.ajo.2003.11.079 [CrossRef]
- Schmidt-Erfurth U, Niemeyer M, Geitzenauer W, Michels S. Time course and morphology of vascular effects associated with photodynamic therapy. Ophthalmology. 2005;112(23):2061–2069. doi:10.1016/j.ophtha.2005.09.007 [CrossRef]
- Ozdemir H, Karacorlu SA, Karacorlu M. Early optical coherence tomography changes after photodynamic therapy in patients with age-related macular degeneration. Am J Ophthalmol. 2006;141(3):574–576. doi:10.1016/j.ajo.2005.09.031 [CrossRef]
- Van Dijk EHC, Dijkman G, Theelen T, Hoyng CB, Boon CJF. Short-term findings on optical coherence tomography and microperimetry in chronic central serous chorioretinopathy patients treated with half-dose photodynamic therapy. Retin Cases Brief Report. 2018;12(4):266–271. doi:10.1097/ICB.0000000000000498 [CrossRef]
- Nicolo M, Eandi CM, Alovisi C, et al. Half-fluence versus half-dose photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophtalmol. 2014;157(5):1033–1037. doi:10.1016/j.ajo.2014.01.022 [CrossRef]
- Chan WM, Lam DSC, Lai TYY, et al. Choroidal vascular remodeling in central serous chorioretinopathy after indocyanine green guided photodynamic therapy with verteporfin: A novel treatment at the primary disease level. Br J Ophtahlmol. 2003;87(12):1453–1458. doi:10.1136/bjo.87.12.1453 [CrossRef]
- Ozdemir H, Karacorlu SA, Sentürk F, et al. Assessment of macular function by microperimetry in unilateral resolved central serous chorioretinopathy. Eye (Lond). 2008;22(2):204–208. doi:10.1038/sj.eye.6702563 [CrossRef]
- Fujita K, Yuzawa M, Mori R. Retinal sensitivity after photodynamic therapy with half-dose verteporfin for chronic central serous chorioretinopathy: Short-term results. Retina. 2011;31(4):772–778. doi:10.1097/IAE.0b013e3181f049d3 [CrossRef]
Detailed Baseline Demographic and Clinical Characteristics of Patients
|Age (Years, Range)||44.7 ± 8.1 (28 to 53)|
|Male Sex (%)||14 (61%)|
|Disease Duration (Months, Range)||14.1 ± 21.7 (4 to 72)|
|BCVA (logMAR)||0.2 ± 0.2 (0.6 to 0.1)|
|BCVA (Snellen)||20/32 (20/80 to 20/25)|
|CFT||361 ± 151.2 (163 to 876)|
|SCT||527.8 ± 111.6 (310 to 720)|
|Retinal Sensitivity (dB)||11.6 ± 3 (4.8 to 16.7)|
| Predominantly central (%)||24 (100)|
| Poor central (%)||-|
| Predominantly eccentric (%)||-|
| Stable (%)||13 (54.2%)|
| Relatively unstable (%)||11 (45.8%)|
| Unstable (%)||-|
|PDT Laser Spot Size (mm, Range)||4.7 ± 0.5 (4.0 to 5.5)|
|Visudyne (mL, Range)||5.5 ± 0.4 (4.8 to 6.3)|
Detailed OCT and Microperimetry Measurements After Half-Time PDT and Comparison With Pretreatment Results
|1 Day||3 Days||7 Days||1 Month||3 Months|
|BCVA (LogMAR)||-||-||0.35 ± 0.23||0.20 ± 0.15||0.14 ± 0.15|
|CFT (μm)||499 ± 239.4 (142–976)||484.1 ± 215.5 (203–983)||340.6 ± 122.7 (184–680)||196.9 ± 46.3 (143–342)||193.6 ± 41.2 (143–322)|
|SCT (μm)||601.5 ± 122.9 (398–998)||548.1 ± 103 (330–740)||478 ± 107.6 (270–634)||455.1 ± 118.2 (261–743)||468.8 ± 115.5 (261–618)|
|Retinal Sensitivity (dB)||8.8 ± 3.9 (0.0–15.6)||7.7 ± 4.2 (0.0–13–4)||9.3 ± 4 (3.2–15.2)||12.1 ± 2.7 (5.6–15.8)||13.8 ± 2.8 (7.4–17.9)|