CHOROIDAL THICKNESS AFTER FULL-FLUENCE AND HALF-FLUENCE PHOTODYNAMIC THERAPY IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY BAEK-LOK OH, MD, HYEONG GON YU, MD, PHD Purpose: To compare clinical outcomes after full-fluence and half-fluence photodynamic therapy (PDT) in chronic central serous chorioretinopathy, focusing on changes in subfoveal choroidal thickness (SFCT) using enhanced depth imaging optical coherence tomography. Methods: Retrospective, comparative interventional case series. Results: In the full-fluence (n = 25) and half-fluence groups (n = 43), SFCT decreased from 351 ± 70 mm and 362 ± 63 mm at baseline to 276 ± 65 mm and 322 ± 70 mm at 3 months and remained at 267 ± 66 mm and 318 ± 76 mm at 12 months, respectively (all P , 0.001, for each comparison with baseline). The change in SFCT was greater in the fullfluence group than in the half-fluence group (P = 0.001). In the half-fluence group, SFCT was thicker in the treated eye than in the fellow eye (P = 0.045), whereas in the full-fluence group, the difference in SFCT was not significant (P = 0.209). Best-corrected visual acuity and central retinal thickness improved after PDT in both groups (all P , 0.001). However, the differences between the groups were not significant (P = 0.873 and P = 0.124, respectively). Conclusion: The results at 1 year show that full-fluence PDT reduces SFCT more than half-fluence PDT, and that SFCT after half-fluence PDT was still thicker than that in the fellow eye. The clinical implications of this finding for long-term outcomes including recurrence rate remain to be elucidated. RETINA 35:1555–1560, 2015
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hronic central serous chorioretinopathy (CSC) is characterized by long-standing serous detachment of the neurosensory retina at the posterior pole with points of leakage at the level of the retinal pigment epithelium (RPE).1 Although the pathophysiology of CSC has yet to be fully understood, one feature shared by most patients with CSC is choroidal vascular hyperpermeability.2 Previous studies have reported that photodynamic therapy (PDT) is effective for treating chronic CSC.3–6 The rationale for verteporfin
(Visudyne; Novartis AG, Büllach, Switzerland) PDT is that angio-occlusive treatment may lead to the narrowing of choroidal vessels, thereby reducing choroidal exudation and inducing vascular remodeling.4,7 However, in treating chronic CSC with PDT, complications, such as RPE atrophy, persistent choriocapillary hypoperfusion, and secondary choroidal neovascularization (CNV) have been reported,3,4,8,9 which has fostered attempts to reduce the dose of verteporfin or the power of laser emission. Several 1-year studies have demonstrated that the efficacy and safety of halffluence or half-dose PDT are comparable with those of full-fluence PDT in the management of chronic CSC.10,11 In contrast, one study found that full-fluence PDT resulted in good clinical outcomes over 4 years without any complications.12 Despite these reports, no study has yet determined which option is superior for
From the Department of Ophthalmology, Seoul National University Hospital, Seoul, South Korea. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Hyeong Gon Yu, MD, PhD, Department of Ophthalmology, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul 110-799, Korea; e-mail: [email protected]
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the treatment of chronic CSC, and no long-term prospective study has been designed to compare the treatment outcomes for full-fluence and half-fluence PDT. After Spaide et al13 showed that choroidal thickness can be evaluated with enhanced depth imaging optical coherence tomography (OCT), increasing evidence has suggested that choroidal thickness, which may reflect choroidal vascular hyperpermeability, is increased in patients with CSC.14–16 In several reports,17,18 subfoveal choroidal thickness (SFCT) decreased after PDT. It was suggested that PDT may induce constriction and occlusion of the choroidal vasculature, decreased choroidal vascular hyperpermeability, and subsequent decreases in choroidal thickness. Despite the importance of PDT fluence for changes of the choroid, there has been little discussion about the effect of PDT on the choroidal thickness in different fluence conditions. In this study, we compared the reduction in choroidal thickness in patients with CSC after full-fluence and half-fluence PDT and investigated the possible effect of the reduction in choroidal thickness on 1-year treatment results.
Methods The medical records of 68 eyes of 68 patients with chronic CSC treated by full-fluence and half-fluence PDT from January 2012 to April 2013 were retrospectively reviewed. In each case, the diagnosis of chronic CSC was based on evaluations by fundoscopy, fluorescein angiography, indocyanine green angiography (ICGA; Heidelberg Retina Angiography; Heidelberg Engineering, Heidelberg, Germany), and spectral domain OCT (Carl Zeiss Meditec Inc, Dublin, CA). The inclusion criteria were 1) best-corrected visual acuity (BCVA) of 0 logMAR to 1.0 logMAR (20/200– 20/20); 2) documented SRF in the foveal region persisting for 3 months or more, with or without serous RPE detachment on OCT image; 3) macular RPE decompensation with subtle or diffuse leaks with RPE detachment on fluorescein angiography; and 4) abnormal, dilated choroidal vasculature with hyperpermeability on ICGA. The exclusion criteria were 1) history of previous focal laser therapy or PDT; 2) any evidence of CNV; 3) branching network of choroidal vessels with aneurysm-like dilatations consistent with polypoidal choroidal vasculopathy; 4) history of other macular abnormalities related to diabetic retinopathy, retinal vein occlusion, or uveitis; 5) systemic contraindication for PDT; and 6) low-quality OCT images in which the choroidoscleral interface could not be traced.
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Informed consent for PDT was obtained from each patient, and the study protocol was approved by the Institutional Review Board of Seoul National University Hospital. The study followed the tenets of the Declaration of Helsinki. Eligible patients were offered conventional fullfluence PDT or half-fluence PDT, and physicians’ intention was not included when choosing the PDT protocol. The PDT procedure was performed by one ophthalmologist (H.G.Y.). Full-fluence PDT was performed using a 6-mg/m2 dose of verteporfin and a 689nm laser (Visulas 690S; Carl Zeiss Meditec Inc) with 50 J/cm2 of laser light delivered over a duration of 83 seconds on the area of abnormal, dilated choroidal vasculature as detected by ICGA. Half-fluence PDT was performed with the same dose of verteporfin but with a reduced fluence of 25 J/cm2 over the same 83second duration. The size of the treatment area was determined based on the findings on fluorescein angiography and ICGA, and comprised of the smallest circular area including the area showing choroidal hyperpermeability on ICGA that was attributed to the accumulation of submacular fluid. Information regarding symptom onset was identified at baseline. At baseline, BCVA was measured and the height of retinal detachment at the fovea, which was defined as the distance between the outer surface of the neurosensory retina and the inner surface of the RPE, was recorded. Subfoveal choroidal thickness in the fellow eye was also obtained by OCT. Follow-up examinations that included measurements of SFCT, BCVA, and central retinal thickness (CRT) were performed at 3, 6, and 12 months after PDT and as needed thereafter. The change in SFCT was observed by enhanced depth imaging OCT. Subfoveal choroidal thickness was measured from the outer surface of the line formed by the RPE to the inner surface of the sclera using spectral domain OCT software. Optical coherence tomography measurements from a single horizontal and vertical section under the center of the fovea were averaged. Each session was performed between 2 PM and 4 PM. The reported measurements from OCT images represent the average of measurements obtained by all coauthors (B.-L.O. and H.G.Y.), who were masked to treatment option. The primary outcome measures were changes in SFCT after PDT in each group. The secondary outcome measures were changes in BCVA and CRT in the two groups in addition to complications, including choroidal or retinal atrophy, secondary CNV, and recurrence of CSC. The visual acuity was presented as logMAR equivalents. Continuous values were expressed as the
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mean ± standard deviation. Continuous variables were compared between PDT groups by the independent t-test or Mann–Whitney U test according to the results of a normality test, whereas the chi-square or Fisher’s exact test was used for categorical variables. Longitudinal results for the measurement of SFCT, BCVA, and CRT were compared using repeated-measures analysis of variance and post hoc tests for each time point where necessary. Statistical analysis was performed using SPSS software for Windows Version 18.0 (SPSS Inc, Chicago, IL). P , 0.05 was considered statistically significant. The Bonferroni’s correction was applied when multiple comparisons were required.
Results Twenty-five patients (25 eyes) were treated with full-fluence PDT, and 43 patients (43 eyes) received half-fluence PDT. The baseline demographic data for both groups are shown in Table 1. There were no significant differences in baseline parameters between the groups. Each patient included in the study presented leakage from choroidal vessels adjacent to the fovea and therefore had undergone treatment that included the fovea area. The mean period of followup was 15.4 ± 4.9 months (range, 12–24 months) in the full-fluence PDT group and 15.8 ± 4.9 months (range, 12–24 months) in the half-fluence PDT group. Measurements of SFCT obtained at baseline and 3, 6, and 12 months after PDT are shown in Figure 1. In the full-fluence PDT group, SFCT was 351 ± 70 mm at baseline, 276 ± 65 mm at 3 months, 273 ± 68 mm at 6 Table 1. Baseline Characteristics in the Full-Fluence and Half-Fluence PDT Groups Full-Fluence Half-Fluence (n = 25) (n = 43) Male:female 19:6 34:9 Age (years) 56 ± 9 52 ± 9 Onset (months) 6±8 8±9 Baseline SFCT (mm) 351 ± 80 362 ± 63 SRD height (mm) 185 ± 89 180 ± 93 Baseline BCVA 0.33 ± 0.29 0.30 ± 0.31 (logMAR) GLD (mm) 2,772 ± 959 2,598 ± 805 SFCT in the fellow 280 ± 73 286 ± 65 eye (mm)
P 0.768* 0.185† 0.530‡ 0.516† 0.853† 0.672‡ 0.688‡ 0.747‡
*Chi-square test. †Student’s t-test after confirmation of normality by the Kolmogorov–Smirnov test. ‡Mann–Whitney U test after confirmation of nonnormality by the Kolmogorov–Smirnov test. GLD, greatest linear dimension; SRD, subretinal detachment.
Fig. 1. SFCT over time in full-fluence and half-fluence PDT groups. The dotted line represents the mean SFCT in the fellow eye. To enable visualization of the overlapped points, the data points were nudged. Error bars represent 95% confidence interval. *At 12 months after PDT, the SFCT of the half-fluence PDT group was significantly larger than that of the fellow eye (P = 0.045, t-test). **The change in SFCT was significantly greater after full-fluence PDT than after half-fluence PDT (repeated-measures analysis of variance with Greenhouse–Geisser test; P , 0.001).
months, and 267 ± 66 mm at 12 months (75.8% of baseline SFCT). In the half-fluence PDT group, SFCT was 362 ± 63 mm at baseline, 322 ± 70 mm at 3 months, 277 ± 69 mm at 6 months, and 318 ± 76 mm at 12 months (87.4% of baseline SFCT). In each group, post-PDT SFCT values were significantly reduced at 3, 6, and 12 months compared with the baseline SFCT (all P , 0.001, paired t-test with Bonferroni’s correction for multiple comparisons). The change in SFCT was significantly greater in the fullfluence PDT group than in the half-fluence PDT group (P = 0.001, repeated-measures analysis of variance, Figure 1). Post hoc analysis revealed that the differences were significant at every post-PDT time point (P = 0.010, P = 0.012, and P = 0.007 at post-PDT 3, 6, and 12 months, respectively). Notably, at 12 months, the SFCT after half-fluence treatment was still significantly thicker than the SFCT in the fellow eye (P = 0.045, t-test), whereas the SFCT after full-fluence treatment was not different from that in the fellow eye (P = 0.209, t-test). The average reduction in SFCT at 12 months in the 2 groups was 18%. Setting the reference value to 18%, reduction of SFCT by over 18% of the baseline occurred in 68% and 21% of eyes treated with full-fluence and half-fluence PDT, respectively, and this difference was statistically significant (P , 0.001, chi-square test). The measurements of BCVA (logMAR) at baseline and 3, 6, and 12 months after PDT are shown in
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Fig. 2. Serial change in (A) BCVA (logMAR) and (B) CRT in full-fluence and half-fluence PDT. To enable visualization of the overlapped points, the data points were nudged. Error bars represent 95% confidence interval.
Figure 2A. Best-corrected visual acuity in the fullfluence PDT group was 0.33 ± 0.29 mm at baseline, 0.18 ± 0.27 mm at 3 months, 0.16 ± 0.24 mm at 6 months, and 0.14 ± 0.23 mm at 12 months. Bestcorrected visual acuity in the half-fluence PDT group was 0.30 ± 0.31 mm at baseline, 0.18 ± 0.30 mm at 3 months, 0.17 ± 0.33 mm at 6 months, and 0.18 ± 0.34 mm at 12 months. In each group, BCVA had significantly improved at 3, 6, and 12 months post-PDT compared with the baseline (all P , 0.001, Wilcoxon test with Bonferroni’s correction for multiple comparisons). When BCVA improvement after PDT relative to the baseline was compared between groups, the difference between groups was not significant (P = 0.873, repeated-measures analysis of variance, Figure 2A). Central retinal thickness values obtained at baseline and at 3, 6, and 12 months after PDT are shown in Figure 2B. In each group, CRT was significantly reduced at 3, 6, and 12 months post-PDT relative to the baseline (all P , 0.001, Wilcoxon test with Bonferroni’s correction for multiple comparisons). When the CRT improvement after PDT was compared between groups, the difference was not significant (P = 0.124, repeated-measures analysis of variance, Figure 2B). In 6 cases, in which follow-up ICGA at 3 months after PDT was performed (n = 2 for full-fluence group; n = 4 for half-fluence group), the grading score of Michels et al19 for choriocapillary hypoperfusion was low in both groups and not different between the 2 groups (P = 0.724, linear-by-linear association). Two cases of CSC recurrence were observed in the half-fluence group, whereas there was no recurrence in the full-fluence group. However, this difference did not
reach statistical significance (P = 0.528, Fisher’s exact test). The first case of recurrence was a 57-year-old woman with SFCT measurements of 274, 200, 202, and 207 mm at baseline and 3, 6, and 12 months postPDT. At 24 months, CSC had recurred (SFCT = 346 mm). The second case of recurrence was observed in a 58-year-old man with SFCT of 322, 236, and 240 mm at baseline, 3 months, and 6 months post-PDT, respectively. At 12 months, CSC had recurred with SFCT of 270 mm. There was no instance of other complications such as RPE atrophy and CNV in both groups.
Discussion This study demonstrates that the change in SFCT was significantly greater after full-fluence PDT than after half-fluence PDT. We also observed that the SFCT after half-fluence PDT was still thicker than the SFCT in the fellow eye, whereas the SFCT after fullfluence PDT was not. Additionally, BCVA and CRT were not different between groups. Previous reports stated that full-fluence and halffluence PDT induces BCVA improvement at 12 months without significant differences between the 2 treatments.10,11 These reports are in agreement with those of this study showing that BCVA after half-fluence and full-fluence PDT was not different until 12 months. Similarly, CRT was not different in the half-fluence and full-fluence groups until 12 months after PDT, which confirms the findings of previous reports.10,11 Although the choroid is a primary contributor to the pathophysiology of the disease, most previous studies comparing half-fluence and full-fluence PDT did not
REDUCED CHOROID THICKNESS AFTER PDT OH AND YU
investigate the choroidal thickness. In this study, measuring SFCT with enhanced depth imaging OCT, SFCT was significantly reduced at 3, 6, and 12 months post-PDT compared with the baseline in both groups. Additionally, SFCT was significantly reduced in the full-fluence PDT group relative to the half-fluence PDT group at every time point. This finding shows that full-fluence PDT reduced SFCT more than halffluence PDT. We should note that the between-group differences did not apply for every individual. The SFCT reduction was lower than 18% in 8 of 25 eyes (32%) in the full-fluence group and higher than 18% in 9 of 43 eyes (21%) in the half-fluence group. Therefore, we investigated other possible factors associated with the reduction of SFCT after PDT. However, we did not find any significant factor other than PDT fluence in the logistic regression analysis. No complications including RPE atrophy and secondary CNV were detected in this study. Although no recurrence was observed in full-fluence PDT, recurrence of CSC occurred in two cases of halffluence PDT. The choroidal thickness at recurrence was larger than the previous follow-up thickness in both patients. The result implies that choroidal thickness should play a role in the recurrence of CSC. Although we found that full-fluence PDT reduced the SFCT more than half-fluence PDT, it is still unknown whether a greater reduction of choroidal thickness is favorable for the long-term prognosis of CSC. Considering that thin SFCT is known to be correlated with poor BCVA in myopia,20–23 a thinner SFCT after PDT may worsen the final BCVA. Many reports24–26 reporting a poor outcome after PDT in myopic CNV support this assumption. However, we considered that the effect of PDT-mediated SFCT reduction on the BCVA could vary according to different baseline SFCT values; in pathologically increased SFCT in CSC eyes, a reduction of the SFCT to the normal level may thus not be associated with poor BCVA. In this study, the SFCT after full-fluence PDT was not lower than that of the fellow eye, and BCVA after full-fluence PDT was not inferior to BCVA after half-fluence PDT until 1 year. Although the difference in CSC recurrence did not reach statistical significance in this study, insufficient SFCT reduction after PDT may be associated with the recurrence of CSC. However, full-fluence PDT is known to be associated with choriocapillary hypoperfusion, RPE atrophy, and secondary CNV.3,4,8,9 Recent studies evaluating retinal sensitivity27 and choroidal perfusion10,11 demonstrated that half-fluence PDT may have functional advantages over full-fluence PDT in patients with chronic CSC. Therefore, presumably, the optimal treatment for each
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patient with CSC could vary, and an individually tailored approach may be required. This study was subject to certain limitations. First, in this retrospective study, patients were not fully randomized into two treatment groups, which may have affected the results. However, baseline characteristics, including age, visual acuity, choroidal thickness, and greatest linear dimension were similar between the two groups. Therefore, we consider that selection bias was likely not significant in our study. Second, SFCT measurements were not obtained at exactly the same time at each session, and diurnal variations in choroidal thickness28–30 may have distorted the results. However, because each session was performed between 2 PM and 4 PM, the amplitude of the variation in SFCT within this time interval (10 mm) was smaller than the difference in SFCT between groups (30 mm). Thus, the results of this study could be valid despite the need for confirmation. Third, the incidence of CSC recurrence during this 1-year period was too low to permit valid conclusions about recurrence. Nicolo et al31 showed that eyes treated with half-fluence PDT tended to need more treatment sessions compared with those treated with half-dose PDT, whereas Alkin et al32 did not find any differences in clinical outcomes. To overcome these limitations, a long-term prospective study to compare different dose and fluence PDT regimens is necessary to determine the optimal treatment approach for chronic CSC and the clinical implications of choroidal thickness change after PDT. In conclusion, full-fluence PDT reduced SFCT more than half-fluence PDT. Further studies are necessary to investigate the clinical implications of this difference for long-term treatment outcomes including recurrence rate. Key words: chronic central serous chorioretinopathy, photodynamic therapy, fluence, choroidal thickness. References 1. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol 1967;63:1–139. 2. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol 1994;112:1057–1062. 3. Cardillo Piccolino F, Eandi CM, Ventre L, et al. Photodynamic therapy for chronic central serous chorioretinopathy. Retina 2003;23:752–763. 4. Chan WM, Lam DS, Lai TY, et al. Choroidal vascular remodelling in central serous chorioretinopathy after indocyanine green guided photodynamic therapy with verteporfin: a novel treatment at the primary disease level. Br J Ophthalmol 2003; 87:1453–1458. 5. Taban M, Boyer DS, Thomas EL. Chronic central serous chorioretinopathy: photodynamic therapy. Am J Ophthalmol 2004; 137:1073–1080.
1560 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 6. 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;23:288–298. 7. Schmidt-Erfurth U, Laqua H, Schlotzer-Schrehard U, et al. Histopathological changes following photodynamic therapy in human eyes. Arch Ophthalmol 2002;120:835–844. 8. Colucciello M. Choroidal neovascularization complicating photodynamic therapy for central serous retinopathy. Retina 2006;26:239–242. 9. Yaman A, Arikan G, Saatci AO, Cingil G. Choroidal neovascularization following photodynamic therapy in a patient with chronic central serous chorioretinopathy. Bull Soc Belge Ophtalmol 2007;303:69–73. 10. Shin JY, Woo SJ, Yu HG, Park KH. Comparison of efficacy and safety between half-fluence and full-fluence photodynamic therapy for chronic central serous chorioretinopathy. Retina 2011;31:119–126. 11. Reibaldi M, Cardascia N, Longo A, et al. Standard-fluence versus low-fluence photodynamic therapy in chronic central serous chorioretinopathy: a nonrandomized clinical trial. Am J Ophthalmol 2010;149:307–315.e302. 12. Silva RM, Ruiz-Moreno JM, Gomez-Ulla F, et al. Photodynamic therapy for chronic central serous chorioretinopathy: a 4-year follow-up study. Retina 2013;33:309–315. 13. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. 14. 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. 15. 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. 16. Jirarattanasopa P, Ooto S, Tsujikawa A, et al. Assessment of macular choroidal thickness by optical coherence tomography and angiographic changes in central serous chorioretinopathy. Ophthalmology 2012;119:1666–1678. 17. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology 2010;117:1792–1799. 18. Maruko I, Iida T, Sugano Y, et al. One-year choroidal thickness results after photodynamic therapy for central serous chorioretinopathy. Retina 2011;31:1921–1927. 19. Michels S, Hansmann F, Geitzenauer W, Schmidt-Erfurth U. Influence of treatment parameters on selectivity of verteporfin therapy. Invest Ophthalmol Vis Sci 2006;47:371–376.
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20. Wei WB, Xu L, Jonas JB, et al. Subfoveal choroidal thickness: the Beijing eye study. Ophthalmology 2013;120:175–180. 21. Flores-Moreno I, Ruiz-Medrano J, Duker JS, Ruiz-Moreno JM. The relationship between retinal and choroidal thickness and visual acuity in highly myopic eyes. Br J Ophthalmol 2013;97: 1010–1013. 22. Ho M, Liu DT, Chan VC, Lam DS. Choroidal thickness measurement in myopic eyes by enhanced depth optical coherence tomography. Ophthalmology 2013;120:1909–1914. 23. Nishida Y, Fujiwara T, Imamura Y, et al. Choroidal thickness and visual acuity in highly myopic eyes. Retina 2012;32: 1229–1236. 24. Baba T, Kubota-Taniai M, Kitahashi M, et al. Two-year comparison of photodynamic therapy and intravitreal bevacizumab for treatment of myopic choroidal neovascularisation. Br J Ophthalmol 2010;94:864–870. 25. El Matri L, Kort F, Chebil A, et al. Intravitreal bevacizumab versus photodynamic therapy for myopic choroidal neovascularization in a North-African population. Graefes Arch Clin Exp Ophthalmol 2011;249:1287–1293. 26. Hayashi K, Ohno-Matsui K, Teramukai S, et al. Comparison of visual outcome and regression pattern of myopic choroidal neovascularization after intravitreal bevacizumab or after photodynamic therapy. Am J Ophthalmol 2009;148: 396–408. 27. Reibaldi M, Boscia F, Avitabile T, et al. Functional retinal changes measured by microperimetry in standard-fluence vs low-fluence photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophthalmol 2011;151:953–960. e952. 28. Brown JS, Flitcroft DI, Ying GS, et al. In vivo human choroidal thickness measurements: evidence for diurnal fluctuations. Invest Ophthalmol Vis Sci 2009;50:5–12. 29. Chakraborty R, Read SA, Collins MJ. Diurnal variations in axial length, choroidal thickness, intraocular pressure, and ocular biometrics. Invest Ophthalmol Vis Sci 2011;52:5121–5129. 30. Tan CS, Ouyang Y, Ruiz H, Sadda SR. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:261–266. 31. Nicolo M, Eandi CM, Alovisi C, et al. Half-fluence versus half-dose photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophthalmol 2014;157:1033–1037. 32. Alkin Z, Perente I, Ozkaya A, et al. Comparison of efficacy between low-fluence and half-dose verteporfin photodynamic therapy for chronic central serous chorioretinopathy. Clin Ophthalmol 2014;8:685–690.
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hronic central serous chorioretinopathy (CSC) is characterized by long-standing serous detachment of the neurosensory retina at the posterior pole with points of leakage at the level of the retinal pigment epithelium (RPE).1 Although the pathophysiology of CSC has yet to be fully understood, one feature shared by most patients with CSC is choroidal vascular hyperpermeability.2 Previous studies have reported that photodynamic therapy (PDT) is effective for treating chronic CSC.3–6 The rationale for verteporfin
(Visudyne; Novartis AG, Büllach, Switzerland) PDT is that angio-occlusive treatment may lead to the narrowing of choroidal vessels, thereby reducing choroidal exudation and inducing vascular remodeling.4,7 However, in treating chronic CSC with PDT, complications, such as RPE atrophy, persistent choriocapillary hypoperfusion, and secondary choroidal neovascularization (CNV) have been reported,3,4,8,9 which has fostered attempts to reduce the dose of verteporfin or the power of laser emission. Several 1-year studies have demonstrated that the efficacy and safety of halffluence or half-dose PDT are comparable with those of full-fluence PDT in the management of chronic CSC.10,11 In contrast, one study found that full-fluence PDT resulted in good clinical outcomes over 4 years without any complications.12 Despite these reports, no study has yet determined which option is superior for
From the Department of Ophthalmology, Seoul National University Hospital, Seoul, South Korea. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Hyeong Gon Yu, MD, PhD, Department of Ophthalmology, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul 110-799, Korea; e-mail: [email protected]
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the treatment of chronic CSC, and no long-term prospective study has been designed to compare the treatment outcomes for full-fluence and half-fluence PDT. After Spaide et al13 showed that choroidal thickness can be evaluated with enhanced depth imaging optical coherence tomography (OCT), increasing evidence has suggested that choroidal thickness, which may reflect choroidal vascular hyperpermeability, is increased in patients with CSC.14–16 In several reports,17,18 subfoveal choroidal thickness (SFCT) decreased after PDT. It was suggested that PDT may induce constriction and occlusion of the choroidal vasculature, decreased choroidal vascular hyperpermeability, and subsequent decreases in choroidal thickness. Despite the importance of PDT fluence for changes of the choroid, there has been little discussion about the effect of PDT on the choroidal thickness in different fluence conditions. In this study, we compared the reduction in choroidal thickness in patients with CSC after full-fluence and half-fluence PDT and investigated the possible effect of the reduction in choroidal thickness on 1-year treatment results.
Methods The medical records of 68 eyes of 68 patients with chronic CSC treated by full-fluence and half-fluence PDT from January 2012 to April 2013 were retrospectively reviewed. In each case, the diagnosis of chronic CSC was based on evaluations by fundoscopy, fluorescein angiography, indocyanine green angiography (ICGA; Heidelberg Retina Angiography; Heidelberg Engineering, Heidelberg, Germany), and spectral domain OCT (Carl Zeiss Meditec Inc, Dublin, CA). The inclusion criteria were 1) best-corrected visual acuity (BCVA) of 0 logMAR to 1.0 logMAR (20/200– 20/20); 2) documented SRF in the foveal region persisting for 3 months or more, with or without serous RPE detachment on OCT image; 3) macular RPE decompensation with subtle or diffuse leaks with RPE detachment on fluorescein angiography; and 4) abnormal, dilated choroidal vasculature with hyperpermeability on ICGA. The exclusion criteria were 1) history of previous focal laser therapy or PDT; 2) any evidence of CNV; 3) branching network of choroidal vessels with aneurysm-like dilatations consistent with polypoidal choroidal vasculopathy; 4) history of other macular abnormalities related to diabetic retinopathy, retinal vein occlusion, or uveitis; 5) systemic contraindication for PDT; and 6) low-quality OCT images in which the choroidoscleral interface could not be traced.
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Informed consent for PDT was obtained from each patient, and the study protocol was approved by the Institutional Review Board of Seoul National University Hospital. The study followed the tenets of the Declaration of Helsinki. Eligible patients were offered conventional fullfluence PDT or half-fluence PDT, and physicians’ intention was not included when choosing the PDT protocol. The PDT procedure was performed by one ophthalmologist (H.G.Y.). Full-fluence PDT was performed using a 6-mg/m2 dose of verteporfin and a 689nm laser (Visulas 690S; Carl Zeiss Meditec Inc) with 50 J/cm2 of laser light delivered over a duration of 83 seconds on the area of abnormal, dilated choroidal vasculature as detected by ICGA. Half-fluence PDT was performed with the same dose of verteporfin but with a reduced fluence of 25 J/cm2 over the same 83second duration. The size of the treatment area was determined based on the findings on fluorescein angiography and ICGA, and comprised of the smallest circular area including the area showing choroidal hyperpermeability on ICGA that was attributed to the accumulation of submacular fluid. Information regarding symptom onset was identified at baseline. At baseline, BCVA was measured and the height of retinal detachment at the fovea, which was defined as the distance between the outer surface of the neurosensory retina and the inner surface of the RPE, was recorded. Subfoveal choroidal thickness in the fellow eye was also obtained by OCT. Follow-up examinations that included measurements of SFCT, BCVA, and central retinal thickness (CRT) were performed at 3, 6, and 12 months after PDT and as needed thereafter. The change in SFCT was observed by enhanced depth imaging OCT. Subfoveal choroidal thickness was measured from the outer surface of the line formed by the RPE to the inner surface of the sclera using spectral domain OCT software. Optical coherence tomography measurements from a single horizontal and vertical section under the center of the fovea were averaged. Each session was performed between 2 PM and 4 PM. The reported measurements from OCT images represent the average of measurements obtained by all coauthors (B.-L.O. and H.G.Y.), who were masked to treatment option. The primary outcome measures were changes in SFCT after PDT in each group. The secondary outcome measures were changes in BCVA and CRT in the two groups in addition to complications, including choroidal or retinal atrophy, secondary CNV, and recurrence of CSC. The visual acuity was presented as logMAR equivalents. Continuous values were expressed as the
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mean ± standard deviation. Continuous variables were compared between PDT groups by the independent t-test or Mann–Whitney U test according to the results of a normality test, whereas the chi-square or Fisher’s exact test was used for categorical variables. Longitudinal results for the measurement of SFCT, BCVA, and CRT were compared using repeated-measures analysis of variance and post hoc tests for each time point where necessary. Statistical analysis was performed using SPSS software for Windows Version 18.0 (SPSS Inc, Chicago, IL). P , 0.05 was considered statistically significant. The Bonferroni’s correction was applied when multiple comparisons were required.
Results Twenty-five patients (25 eyes) were treated with full-fluence PDT, and 43 patients (43 eyes) received half-fluence PDT. The baseline demographic data for both groups are shown in Table 1. There were no significant differences in baseline parameters between the groups. Each patient included in the study presented leakage from choroidal vessels adjacent to the fovea and therefore had undergone treatment that included the fovea area. The mean period of followup was 15.4 ± 4.9 months (range, 12–24 months) in the full-fluence PDT group and 15.8 ± 4.9 months (range, 12–24 months) in the half-fluence PDT group. Measurements of SFCT obtained at baseline and 3, 6, and 12 months after PDT are shown in Figure 1. In the full-fluence PDT group, SFCT was 351 ± 70 mm at baseline, 276 ± 65 mm at 3 months, 273 ± 68 mm at 6 Table 1. Baseline Characteristics in the Full-Fluence and Half-Fluence PDT Groups Full-Fluence Half-Fluence (n = 25) (n = 43) Male:female 19:6 34:9 Age (years) 56 ± 9 52 ± 9 Onset (months) 6±8 8±9 Baseline SFCT (mm) 351 ± 80 362 ± 63 SRD height (mm) 185 ± 89 180 ± 93 Baseline BCVA 0.33 ± 0.29 0.30 ± 0.31 (logMAR) GLD (mm) 2,772 ± 959 2,598 ± 805 SFCT in the fellow 280 ± 73 286 ± 65 eye (mm)
P 0.768* 0.185† 0.530‡ 0.516† 0.853† 0.672‡ 0.688‡ 0.747‡
*Chi-square test. †Student’s t-test after confirmation of normality by the Kolmogorov–Smirnov test. ‡Mann–Whitney U test after confirmation of nonnormality by the Kolmogorov–Smirnov test. GLD, greatest linear dimension; SRD, subretinal detachment.
Fig. 1. SFCT over time in full-fluence and half-fluence PDT groups. The dotted line represents the mean SFCT in the fellow eye. To enable visualization of the overlapped points, the data points were nudged. Error bars represent 95% confidence interval. *At 12 months after PDT, the SFCT of the half-fluence PDT group was significantly larger than that of the fellow eye (P = 0.045, t-test). **The change in SFCT was significantly greater after full-fluence PDT than after half-fluence PDT (repeated-measures analysis of variance with Greenhouse–Geisser test; P , 0.001).
months, and 267 ± 66 mm at 12 months (75.8% of baseline SFCT). In the half-fluence PDT group, SFCT was 362 ± 63 mm at baseline, 322 ± 70 mm at 3 months, 277 ± 69 mm at 6 months, and 318 ± 76 mm at 12 months (87.4% of baseline SFCT). In each group, post-PDT SFCT values were significantly reduced at 3, 6, and 12 months compared with the baseline SFCT (all P , 0.001, paired t-test with Bonferroni’s correction for multiple comparisons). The change in SFCT was significantly greater in the fullfluence PDT group than in the half-fluence PDT group (P = 0.001, repeated-measures analysis of variance, Figure 1). Post hoc analysis revealed that the differences were significant at every post-PDT time point (P = 0.010, P = 0.012, and P = 0.007 at post-PDT 3, 6, and 12 months, respectively). Notably, at 12 months, the SFCT after half-fluence treatment was still significantly thicker than the SFCT in the fellow eye (P = 0.045, t-test), whereas the SFCT after full-fluence treatment was not different from that in the fellow eye (P = 0.209, t-test). The average reduction in SFCT at 12 months in the 2 groups was 18%. Setting the reference value to 18%, reduction of SFCT by over 18% of the baseline occurred in 68% and 21% of eyes treated with full-fluence and half-fluence PDT, respectively, and this difference was statistically significant (P , 0.001, chi-square test). The measurements of BCVA (logMAR) at baseline and 3, 6, and 12 months after PDT are shown in
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Fig. 2. Serial change in (A) BCVA (logMAR) and (B) CRT in full-fluence and half-fluence PDT. To enable visualization of the overlapped points, the data points were nudged. Error bars represent 95% confidence interval.
Figure 2A. Best-corrected visual acuity in the fullfluence PDT group was 0.33 ± 0.29 mm at baseline, 0.18 ± 0.27 mm at 3 months, 0.16 ± 0.24 mm at 6 months, and 0.14 ± 0.23 mm at 12 months. Bestcorrected visual acuity in the half-fluence PDT group was 0.30 ± 0.31 mm at baseline, 0.18 ± 0.30 mm at 3 months, 0.17 ± 0.33 mm at 6 months, and 0.18 ± 0.34 mm at 12 months. In each group, BCVA had significantly improved at 3, 6, and 12 months post-PDT compared with the baseline (all P , 0.001, Wilcoxon test with Bonferroni’s correction for multiple comparisons). When BCVA improvement after PDT relative to the baseline was compared between groups, the difference between groups was not significant (P = 0.873, repeated-measures analysis of variance, Figure 2A). Central retinal thickness values obtained at baseline and at 3, 6, and 12 months after PDT are shown in Figure 2B. In each group, CRT was significantly reduced at 3, 6, and 12 months post-PDT relative to the baseline (all P , 0.001, Wilcoxon test with Bonferroni’s correction for multiple comparisons). When the CRT improvement after PDT was compared between groups, the difference was not significant (P = 0.124, repeated-measures analysis of variance, Figure 2B). In 6 cases, in which follow-up ICGA at 3 months after PDT was performed (n = 2 for full-fluence group; n = 4 for half-fluence group), the grading score of Michels et al19 for choriocapillary hypoperfusion was low in both groups and not different between the 2 groups (P = 0.724, linear-by-linear association). Two cases of CSC recurrence were observed in the half-fluence group, whereas there was no recurrence in the full-fluence group. However, this difference did not
reach statistical significance (P = 0.528, Fisher’s exact test). The first case of recurrence was a 57-year-old woman with SFCT measurements of 274, 200, 202, and 207 mm at baseline and 3, 6, and 12 months postPDT. At 24 months, CSC had recurred (SFCT = 346 mm). The second case of recurrence was observed in a 58-year-old man with SFCT of 322, 236, and 240 mm at baseline, 3 months, and 6 months post-PDT, respectively. At 12 months, CSC had recurred with SFCT of 270 mm. There was no instance of other complications such as RPE atrophy and CNV in both groups.
Discussion This study demonstrates that the change in SFCT was significantly greater after full-fluence PDT than after half-fluence PDT. We also observed that the SFCT after half-fluence PDT was still thicker than the SFCT in the fellow eye, whereas the SFCT after fullfluence PDT was not. Additionally, BCVA and CRT were not different between groups. Previous reports stated that full-fluence and halffluence PDT induces BCVA improvement at 12 months without significant differences between the 2 treatments.10,11 These reports are in agreement with those of this study showing that BCVA after half-fluence and full-fluence PDT was not different until 12 months. Similarly, CRT was not different in the half-fluence and full-fluence groups until 12 months after PDT, which confirms the findings of previous reports.10,11 Although the choroid is a primary contributor to the pathophysiology of the disease, most previous studies comparing half-fluence and full-fluence PDT did not
REDUCED CHOROID THICKNESS AFTER PDT OH AND YU
investigate the choroidal thickness. In this study, measuring SFCT with enhanced depth imaging OCT, SFCT was significantly reduced at 3, 6, and 12 months post-PDT compared with the baseline in both groups. Additionally, SFCT was significantly reduced in the full-fluence PDT group relative to the half-fluence PDT group at every time point. This finding shows that full-fluence PDT reduced SFCT more than halffluence PDT. We should note that the between-group differences did not apply for every individual. The SFCT reduction was lower than 18% in 8 of 25 eyes (32%) in the full-fluence group and higher than 18% in 9 of 43 eyes (21%) in the half-fluence group. Therefore, we investigated other possible factors associated with the reduction of SFCT after PDT. However, we did not find any significant factor other than PDT fluence in the logistic regression analysis. No complications including RPE atrophy and secondary CNV were detected in this study. Although no recurrence was observed in full-fluence PDT, recurrence of CSC occurred in two cases of halffluence PDT. The choroidal thickness at recurrence was larger than the previous follow-up thickness in both patients. The result implies that choroidal thickness should play a role in the recurrence of CSC. Although we found that full-fluence PDT reduced the SFCT more than half-fluence PDT, it is still unknown whether a greater reduction of choroidal thickness is favorable for the long-term prognosis of CSC. Considering that thin SFCT is known to be correlated with poor BCVA in myopia,20–23 a thinner SFCT after PDT may worsen the final BCVA. Many reports24–26 reporting a poor outcome after PDT in myopic CNV support this assumption. However, we considered that the effect of PDT-mediated SFCT reduction on the BCVA could vary according to different baseline SFCT values; in pathologically increased SFCT in CSC eyes, a reduction of the SFCT to the normal level may thus not be associated with poor BCVA. In this study, the SFCT after full-fluence PDT was not lower than that of the fellow eye, and BCVA after full-fluence PDT was not inferior to BCVA after half-fluence PDT until 1 year. Although the difference in CSC recurrence did not reach statistical significance in this study, insufficient SFCT reduction after PDT may be associated with the recurrence of CSC. However, full-fluence PDT is known to be associated with choriocapillary hypoperfusion, RPE atrophy, and secondary CNV.3,4,8,9 Recent studies evaluating retinal sensitivity27 and choroidal perfusion10,11 demonstrated that half-fluence PDT may have functional advantages over full-fluence PDT in patients with chronic CSC. Therefore, presumably, the optimal treatment for each
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patient with CSC could vary, and an individually tailored approach may be required. This study was subject to certain limitations. First, in this retrospective study, patients were not fully randomized into two treatment groups, which may have affected the results. However, baseline characteristics, including age, visual acuity, choroidal thickness, and greatest linear dimension were similar between the two groups. Therefore, we consider that selection bias was likely not significant in our study. Second, SFCT measurements were not obtained at exactly the same time at each session, and diurnal variations in choroidal thickness28–30 may have distorted the results. However, because each session was performed between 2 PM and 4 PM, the amplitude of the variation in SFCT within this time interval (10 mm) was smaller than the difference in SFCT between groups (30 mm). Thus, the results of this study could be valid despite the need for confirmation. Third, the incidence of CSC recurrence during this 1-year period was too low to permit valid conclusions about recurrence. Nicolo et al31 showed that eyes treated with half-fluence PDT tended to need more treatment sessions compared with those treated with half-dose PDT, whereas Alkin et al32 did not find any differences in clinical outcomes. To overcome these limitations, a long-term prospective study to compare different dose and fluence PDT regimens is necessary to determine the optimal treatment approach for chronic CSC and the clinical implications of choroidal thickness change after PDT. In conclusion, full-fluence PDT reduced SFCT more than half-fluence PDT. Further studies are necessary to investigate the clinical implications of this difference for long-term treatment outcomes including recurrence rate. Key words: chronic central serous chorioretinopathy, photodynamic therapy, fluence, choroidal thickness. References 1. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol 1967;63:1–139. 2. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol 1994;112:1057–1062. 3. Cardillo Piccolino F, Eandi CM, Ventre L, et al. Photodynamic therapy for chronic central serous chorioretinopathy. Retina 2003;23:752–763. 4. Chan WM, Lam DS, Lai TY, et al. Choroidal vascular remodelling in central serous chorioretinopathy after indocyanine green guided photodynamic therapy with verteporfin: a novel treatment at the primary disease level. Br J Ophthalmol 2003; 87:1453–1458. 5. Taban M, Boyer DS, Thomas EL. Chronic central serous chorioretinopathy: photodynamic therapy. Am J Ophthalmol 2004; 137:1073–1080.
1560 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 6. 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;23:288–298. 7. Schmidt-Erfurth U, Laqua H, Schlotzer-Schrehard U, et al. Histopathological changes following photodynamic therapy in human eyes. Arch Ophthalmol 2002;120:835–844. 8. Colucciello M. Choroidal neovascularization complicating photodynamic therapy for central serous retinopathy. Retina 2006;26:239–242. 9. Yaman A, Arikan G, Saatci AO, Cingil G. Choroidal neovascularization following photodynamic therapy in a patient with chronic central serous chorioretinopathy. Bull Soc Belge Ophtalmol 2007;303:69–73. 10. Shin JY, Woo SJ, Yu HG, Park KH. Comparison of efficacy and safety between half-fluence and full-fluence photodynamic therapy for chronic central serous chorioretinopathy. Retina 2011;31:119–126. 11. Reibaldi M, Cardascia N, Longo A, et al. Standard-fluence versus low-fluence photodynamic therapy in chronic central serous chorioretinopathy: a nonrandomized clinical trial. Am J Ophthalmol 2010;149:307–315.e302. 12. Silva RM, Ruiz-Moreno JM, Gomez-Ulla F, et al. Photodynamic therapy for chronic central serous chorioretinopathy: a 4-year follow-up study. Retina 2013;33:309–315. 13. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. 14. 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. 15. 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. 16. Jirarattanasopa P, Ooto S, Tsujikawa A, et al. Assessment of macular choroidal thickness by optical coherence tomography and angiographic changes in central serous chorioretinopathy. Ophthalmology 2012;119:1666–1678. 17. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology 2010;117:1792–1799. 18. Maruko I, Iida T, Sugano Y, et al. One-year choroidal thickness results after photodynamic therapy for central serous chorioretinopathy. Retina 2011;31:1921–1927. 19. Michels S, Hansmann F, Geitzenauer W, Schmidt-Erfurth U. Influence of treatment parameters on selectivity of verteporfin therapy. Invest Ophthalmol Vis Sci 2006;47:371–376.
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20. Wei WB, Xu L, Jonas JB, et al. Subfoveal choroidal thickness: the Beijing eye study. Ophthalmology 2013;120:175–180. 21. Flores-Moreno I, Ruiz-Medrano J, Duker JS, Ruiz-Moreno JM. The relationship between retinal and choroidal thickness and visual acuity in highly myopic eyes. Br J Ophthalmol 2013;97: 1010–1013. 22. Ho M, Liu DT, Chan VC, Lam DS. Choroidal thickness measurement in myopic eyes by enhanced depth optical coherence tomography. Ophthalmology 2013;120:1909–1914. 23. Nishida Y, Fujiwara T, Imamura Y, et al. Choroidal thickness and visual acuity in highly myopic eyes. Retina 2012;32: 1229–1236. 24. Baba T, Kubota-Taniai M, Kitahashi M, et al. Two-year comparison of photodynamic therapy and intravitreal bevacizumab for treatment of myopic choroidal neovascularisation. Br J Ophthalmol 2010;94:864–870. 25. El Matri L, Kort F, Chebil A, et al. Intravitreal bevacizumab versus photodynamic therapy for myopic choroidal neovascularization in a North-African population. Graefes Arch Clin Exp Ophthalmol 2011;249:1287–1293. 26. Hayashi K, Ohno-Matsui K, Teramukai S, et al. Comparison of visual outcome and regression pattern of myopic choroidal neovascularization after intravitreal bevacizumab or after photodynamic therapy. Am J Ophthalmol 2009;148: 396–408. 27. Reibaldi M, Boscia F, Avitabile T, et al. Functional retinal changes measured by microperimetry in standard-fluence vs low-fluence photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophthalmol 2011;151:953–960. e952. 28. Brown JS, Flitcroft DI, Ying GS, et al. In vivo human choroidal thickness measurements: evidence for diurnal fluctuations. Invest Ophthalmol Vis Sci 2009;50:5–12. 29. Chakraborty R, Read SA, Collins MJ. Diurnal variations in axial length, choroidal thickness, intraocular pressure, and ocular biometrics. Invest Ophthalmol Vis Sci 2011;52:5121–5129. 30. Tan CS, Ouyang Y, Ruiz H, Sadda SR. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:261–266. 31. Nicolo M, Eandi CM, Alovisi C, et al. Half-fluence versus half-dose photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophthalmol 2014;157:1033–1037. 32. Alkin Z, Perente I, Ozkaya A, et al. Comparison of efficacy between low-fluence and half-dose verteporfin photodynamic therapy for chronic central serous chorioretinopathy. Clin Ophthalmol 2014;8:685–690.
