A Randomized Pilot Study of Low-Fluence Photodynamic Therapy Versus Intravitreal Ranibizumab for Chronic Central Serous Chorioretinopathy

A Randomized Pilot Study of Low-Fluence Photodynamic Therapy Versus Intravitreal Ranibizumab for Chronic Central Serous Chorioretinopathy SO HYUN BAE, JANG WON HEO, CINOO KIM, TAE WAN KIM, JOO YONG LEE, SU JEONG SONG, TAE KWANN PARK, SANG WOONG MOON, AND HUM CHUNG ● PURPOSE:

To report 6-month outcomes of a prospective, randomized study comparing the efficacy and safety between low-fluence photodynamic therapy (PDT) and intravitreal injections of ranibizumab in the treatment of chronic central serous chorioretinopathy. ● DESIGN: Prospective, randomized, single-center pilot study. ● METHODS: Sixteen eyes with chronic central serous chorioretinopathy were randomized to receive either low-fluence PDT or intravitreal injections of ranibizumab: 8 eyes in the low-fluence PDT group and 8 in the ranibizumab group. Rescue treatment was considered if subretinal fluid was sustained after completion of primary treatment: low-fluence PDT for the ranibizumab group and ranibizumab injection for the low-fluence PDT group. Main outcome measures were excess foveal thickness, resolution of subretinal fluid, choroidal perfusion on indocyanine green angiography, and best-corrected visual acuity. ● RESULTS: At 3 months, the mean excess foveal thickness was reduced from 74.1 ⴞ 56.0 ␮m to ⴚ35.4 ⴞ 44.5 ␮m in the low-fluence PDT group (P ⴝ .017) and from 26.3 ⴞ 50.6 ␮m to ⴚ23.1 ⴞ 56.5 ␮m in the ranibizumab group (P ⴝ .058). After a single session of PDT, 6 eyes (75%) in the low-fluence PDT group achieved complete resolution of subretinal fluid and reduction of choroidal hyperpermeability, whereas 2 (25%) eyes in the ranibizumab group achieved this after consecutive ranibizumab injections. Four eyes (50%) in the ranibizumab group underwent additional low-fluence PDT and Accepted for publication Apr 6, 2011. From the Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Korea (S.H.B., J.W.H., T.W.K., H.C.); the Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea (S.H.B., J.W.H., C.K., H.C.); the Department of Ophthalmology, Incheon Medical Center, Incheon, Korea (C.K.); the Department of Ophthalmology, Seoul National University Boramae Medical Center, Seoul Metropolitan Government, Seoul, Korea (T.W.K.); the Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (J.Y.L.); the Department of Ophthalmology, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea (S.J.S.); the Department of Ophthalmology, Soonchunhyang University College of Medicine, Bucheon, Korea (T.K.P.); and the Department of Ophthalmology, Kyung Hee University School of Medicine, Seoul, Korea (S.W.M.). Inquiries to Jang Won Heo, Department of Ophthalmology, Seoul National University College of Medicine, 28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Korea; e-mail: [email protected]

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accomplished complete resolution. At 3 months, significant improvement of best-corrected visual acuity was not demonstrated in the low-fluence PDT group (P ⴝ .075), whereas it was observed in the ranibizumab group (P ⴝ .012). However, the tendency toward improvement of best-corrected visual acuity was not maintained. ● CONCLUSIONS: In terms of anatomic outcomes, the effect of ranibizumab injections was not promising compared with that of low-fluence PDT. (Am J Ophthalmol 2011;152:784 –792. © 2011 by Elsevier Inc. All rights reserved.)

C

ENTRAL SEROUS CHORIORETINOPATHY (CSC) IS

characterized by serous detachment of the neurosensory retina.1 The pathophysiologic features of CSC are not certain, and various theories have been proposed, including impaired function of retinal pigment epithelium (RPE), choroidal ischemia, and choroidal hyperpermeability leading to RPE damage.2–5 Acute CSC with monofocal or paucifocal changes of RPE usually shows spontaneous resolution and has a favorable visual outcome. Chronic CSC is characterized by multifocal or diffuse decompensation of RPE associated with persistent detachment of neurosensory retina. This may lead to cystoid macular degeneration, foveal atrophy, and damage to the foveal photoreceptor layer, consequently resulting in irreversible significant visual loss.6,7 Photodynamic therapy (PDT) was proposed for the treatment of chronic CSC based on the proposed mechanism of choroidal hypoperfusion.8 –10 Over time, PDT promotes the absorption of subretinal fluid (SRF) by choroidal vascular remodeling and reduction of choroidal hyperpermeability.11 However, irreversible damages may result from PDT, especially conventional PDT. Several reports demonstrated the risk of complications, such as RPE changes, excessive choriocapillaris hypoperfusion, and secondary choroidal neovascularization (CNV).11–15 Recently, a few studies based on modified PDT parameters demonstrated favorable results. Reduction of verteporfin dosage, shortening of the time of laser emission, and reduction of a total light energy were suggested.16 –20 It is well known that vascular endothelial growth factor (VEGF) is related with vascular permeability.21 Antibodies to VEGF may reduce choroidal hyperpermeability, one of

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the proposed mechanisms of CSC. On the basis of this hypothesis, intravitreal administration of an anti-VEGF agent was proposed as a new treatment option in the treatment of CSC, and several reports demonstrated acceptable outcomes after intravitreal bevacizumab injection.21–24 However, the clinical results with ranibizumab have not been reported yet. The purpose of the present randomized pilot study was to compare the efficacy and safety between low-fluence PDT and intravitreal injection of ranibizumab in the treatment of chronic central serous chorioretinopathy.

METHODS THIS STUDY WAS A PROSPECTIVE, RANDOMIZED, PILOT

study performed at the Department of Ophthalmology of the Seoul National University Hospital. ● STUDY PARTICIPANTS: This study enrolled patients with a history of central serous chorioretinopathy characterized by visual disturbance persisting more than 6 months or with a recurrent history of CSC. The inclusion criteria were: (1) best-corrected visual acuity (BCVA) between 0.0 and 1.0 logarithm of the minimal angle of resolution (logMAR) units, (2) presence of subfoveal fluid persisting for 3 months or more on optical coherence tomography (OCT), (3) presence of leakage and multifocal or diffuse RPE decompensation on fluorescein angiography (FA), and (4) choroidal vascular hyperpermeability and abnormal dilation of choroidal vasculature on indocyanine green angiography (ICGA). The exclusion criteria were: (1) previous treatment, such as laser photocoagulation, PDT, intravitreal injection of steroid or anti-VEGF agent; (2) evidence of CNV; (3) any other ocular diseases that could affect visual acuity; (4) systemic steroid treatment in the previous 12 months; or (5) media opacity such as cataract that could interfere with adequate acquisition of OCT, FA, and ICGA images. ● TREATMENT PROTOCOL:

Subjects were randomized to receive either low-fluence PDT or 0.5 mg/0.05 mL intravitreal injection of ranibizumab (Lucentis; Novartis AG, Basel, Switzerland). In the low-fluence PDT group, all the patients received a 6-mg/m2 infusion of verteporfin (Visudyne; Novartis AG) over 10 minutes followed by laser delivery at 689 nm for 83 seconds, 15 minutes after the start of the infusion. A total light energy of 25 J/cm2, a light dose rate of 300 mW/cm2, was delivered. To determine the PDT spot size, the authors measured the greatest linear dimension of the area of choroidal vascular hyperpermeability corresponding to the origin of subfoveal fluid on ICGA. If the multifocal lesions of choroidal hyperpermeability were responsible for the subfoveal fluid, separate nonconfluent laser irradiation was applied to the lesions consecutively. At the same time, if the multifocal lesions VOL. 152, NO. 5

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were too close to irradiate separately, a single spot was delivered that covered the entire area of multifocal choroidal hyperpermeability. In the ranibizumab group, ranibizumab was injected through the pars plana into the vitreous cavity under sterile conditions. The patients were treated with monthly intravitreal injections of ranibizumab for the first 3 months. If complete resolution of SRF was observed, although 3 monthly injections were not completed, reinjection was stopped until reaccumulation of SRF. Rescue treatment was considered if sustained or reaccumulated SRF was associated with visual acuity loss of at least 0.2 logMAR units. As rescue treatment, a single session of low-fluence PDT for the ranibizumab group and ranibizumab injection for the low-fluence PDT group were considered because gold standard treatment has not yet been established for chronic CSC. ● FOLLOW-UP PROTOCOL: All the patients completed 6 months of follow up. At baseline and at each monthly visit, slit-lamp examination of the anterior segment, intraocular pressure assessment, dilated fundus examination, BCVA assessment, and OCT (Cirrus; Carl Zeiss Meditec, Inc, Dublin, California, USA) imaging were performed. BCVA was assessed using Early Treatment of Diabetic Retinopathy Study charts at 4 m. Scanning with Cirrus OCT was performed using the 5-line raster scan mode to document the presence of SRF and pigment epithelial detachment. Central foveal thickness was measured with the macular cube 512 ⫻ 128 mode of the Cirrus OCT (128 lines, 512 A-scans per line). To analyze the changes of SRF, the authors calculated excess foveal thickness, referring to the amount above normal. Several studies have reported the normal range of central foveal thickness obtained by Cirrus OCT to be from 257 to 300 ␮m.25–27 The authors calculated excess foveal thickness by subtracting normal value, 250 ␮m, from the measured values of central foveal thickness. FA and ICGA (Heidelberg Retina Angiography; Heidelberg Engineering, Heidelberg, Germany) were performed at baseline, month 3, and month 6. The status of RPE was evaluated, including RPE depigmentation or atrophy based on the fundus examination and FA findings. ● STATISTICAL ANALYSIS:

The primary purpose of this study was to compare the anatomic outcomes between low-fluence PDT and intravitreal ranibizumab injection, including changes of excess foveal thickness and complete resolution of SRF. The changes in BCVA, concomitant with structural changes, also were analyzed. Both ocular and systemic adverse events related to the treatments were assessed. Serial comparisons of mean BCVA and excess foveal thickness were conducted using the Wilcoxon signed-rank test. Comparison according to treatment method was carried out using the Mann–Whitney U test and Kruskal-Wallis test. Categorized variables were analyzed by the Fisher exact test. SPSS software version 15.0

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TABLE. Demographic Characteristics and Treatment Outcomes of the Patients with Chronic Central Serous Chorioretinopathy

Patient No.

Sex

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

M M F M M M M M M M M F M M M M

Symptom Age Duration (y) (mos)

47 52 44 65 63 46 52 53 47 40 42 47 47 52 50 35

12 12 6 48 6 48 60 60 8 7 10 6 36 48 24 72

Primary Treatment

PDT PDT PDT PDT PDT PDT PDT PDT Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab

Best-Corrected Visual Acuity (logMAR)

Excess Foveal Thickness (␮m)

Baseline

3 Mos

6 Mos

Baseline

0 0.68 0.12 0.6 0.3 0.4 0.16 0.12 0.4 0.12 0.18 0.3 0.34 0.66 0.84 0.22

0.08 0.72 ⫺0.08 0.42 0.22 0.06 ⫺0.08 0.12 0.16 0.06 0.12 0.14 0.22 0.36 0.56 ⫺0.18

0 0.74 ⫺0.08 0.42 0.42 ⫺0.04 ⫺0.08 0.16 0.18 0.04 0.14 0.02 0.08 0.38 0.02 ⫺0.12

180 9 100 108 89 32 40 35 4 98 ⫺20 69 ⫺30 2 ⫺1 88

3 Mos

6 Mos

OCT Features: Changes in Subretinal Fluid 3 Mosa

⫺19 ⫺20 Decreased ⫺106 ⫺105 Completec ⫺50 ⫺43 Complete ⫺68 ⫺77 Complete ⫺6 7 Complete ⫺40 ⫺40 Complete ⫺39 ⫺39 Complete ⫺45 ⫺48 Sustained 6 94 Sustained ⫺4 62 Decreased ⫺51 ⫺46 Complete 74 ⫺80 Sustained ⫺104 ⫺105 Complete ⫺17 ⫺35 Decreased ⫺3 ⫺70 Sustained ⫺86 ⫺84 Complete

6 Mosb

Sustained Complete Complete Complete Complete Complete Complete Decreased Increased Increased Complete Complete Complete Complete Complete Complete

Period at Retreatment (mos)

Retreatment

5

Ranibizumab

3

Ranibizumab

4 5 4 3

PDT PDT PDT PDT

F ⫽ female; logMAR ⫽ logarithm of the minimal angle of resolution; M ⫽ male; mo ⫽ months; OCT ⫽ optical coherence tomography; PDT ⫽ low-fluence photodynamic therapy; y ⫽ years. a The change in amount of subretinal fluid at 3 months was determined compared with baseline. b The change in amount of subretinal fluid at 6 months was determined compared with that at the 3-month follow-up visit. c Complete resolution of subretinal fluid.

Because rescue treatment was considered after completion of primary treatment, the same treatment method was maintained in each group until the 3-month follow-up. Rescue treatments were conducted in 6 (37.5%) of 16 eyes that showed reaccumulated or sustained SRF during the subsequent follow-up period: 2 eyes in the low-fluence PDT group and 4 eyes in the ranibizumab group. Also, rescue treatment was considered in 2 eyes in the ranibizumab group because of aggravation of SRF at the last follow-up visit. The proportion of eyes needing rescue treatment in the ranibizumab group (6 eyes; 75%) was higher than that in the low-fluence PDT group (2 eyes; 25%), but the difference was not statistically significant (P ⫽ .066). In the ranibizumab group, the mean PDT spot size as rescue treatment was 2240 ⫾ 811.2 ␮m (range, 1500 to 3500 ␮m). In 1 eye, 2 distinct lesions of choroidal hyperpermeability responsible for the subfoveal fluid were treated by separate PDT spots with widths of 2100 ␮m and 1500 ␮m.

(SPSS, Inc, Chicago, Illinois, USA) was used for data analysis, and a P value of ⬍ .05 was considered to be statistically significant.

RESULTS A TOTAL OF 16 EYES OF 15 PATIENTS WERE RECRUITED IN

this study. The mean age was 48.9 ⫾ 7.6 years (range, 35 to 65 years). Thirteen men and 2 women participated. The duration of symptoms ranged from 6 months to 6 years, with a mean of 28.9 ⫾ 23.6 months. The mean logMAR BCVA was 0.34 ⫾ 0.24, and the mean excess foveal thickness was 50.2 ⫾ 57.2 ␮m (range, ⫺30 to 180 ␮m) before treatment. At baseline, 2 eyes (12.5%) had macular pigment epithelial detachment. The study eyes were randomized into 2 treatment groups: 8 eyes in the low-fluence PDT-treated group and 8 eyes in the intravitreal injections of ranibizumab group. At baseline, no significant differences in age, gender, duration of symptoms, or logMAR BCVA were shown between the 2 treatment groups. The mean excess foveal thickness at baseline was significantly higher in the low-fluence PDT group (74.1 ⫾ 56.0 ␮m) compared with the ranibizumab group (26.3 ⫾ 50.6 ␮m; P ⫽ .046). The mean PDT spot size used on the lowfluence PDT group was 2687.5 ⫾ 1254.1 ␮m (range, 1600 to 4500 ␮m). The demographic features and outline of treatment outcomes of each study eye are presented in Table 1. 786

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● CHANGES IN ANATOMIC FINDINGS ASSESSED BY OPTICAL COHERENCE TOMOGRAPHY: In the low-fluence PDT group, the mean excess foveal thickness was reduced significantly from 74.1 ⫾ 56.0 ␮m at baseline to ⫺35.4 ⫾ 44.5 ␮m at 3 months (P ⫽ .017). The SRF resolved completely in 6 eyes (75%) with significant reduction of excess foveal thickness throughout the follow-up period, whereas 2 eyes (25%) showed persistent SRF despite an OF

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FIGURE 1. Graphs demonstrated the changes of excess foveal thickness in the eyes with chronic central serous chorioretinopathy during the follow-up period; the eyes of the low-fluence photodynamic therapy group (Left) and those of the ranibizumab group (Right). Arrows represented the time when the study eyes underwent rescue treatment.

additional ranibizumab injection. The excess foveal thickness of these 2 eyes also did not demonstrate significant reduction at the last follow-up visit (P ⫽ .180). In the ranibizumab group, the mean excess foveal thickness decreased from 26.3 ⫾ 50.6 ␮m at baseline to ⫺23.1 ⫾ 56.5 ␮m at 3 months, but was not considered to be statistically significant (P ⫽ .058). After completion of consecutive ranibizumab injections, only 2 eyes (25%) maintained complete resolution of SRF throughout the follow-up period. A total of 6 eyes revealed persistent SRF after completion of ranibizumab injections. Four eyes (50%) with persistent SRF underwent additional lowfluence PDT and achieved complete absorption of SRF by 6 months. In the remaining 2 eyes (25%) with sustained SRF, rescue treatment was not initiated because there was a tendency toward reduction of SRF. However, the accumulation of SRF was aggravated at 6 months. The changes of excess foveal thickness in each study eye are shown in Figure 1. ● CHANGES IN BEST-CORRECTED VISUAL ACUITY:

In the low-fluence PDT group, the mean BCVA improved from 0.30 ⫾ 0.37 at baseline to 0.18 ⫾ 0.27 at 3 months, but this was not statistically significant (P ⫽ .075). Throughout the follow-up period, a significant improvement of BCVA was not observed, regardless of whether rescue treatment was performed. In the ranibizumab group, the mean BCVA improved significantly from 0.38 ⫾ 0.25 at baseline to 0.18 ⫾ 0.22 at 3 months (P ⫽ .012). During the subsequent follow-up, a subanalysis in the ranibizumab group was performed according to the need for rescue treatment. At the last follow-up, there was improvement of BCVA in both subgroups: 0.13 ⫾ 0.17 in the eyes requiring additional low-fluence PDT and 0.06 ⫾ 0.13 in those receiving only ranibizumab injections. However, these results did not show statistical significance (P ⫽ .062 VOL. 152, NO. 5

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and P ⫽ .068). There was no significant difference of BCVA between the 2 groups at 3 months (P ⫽ .606). ● ANGIOGRAPHIC CHANGES:

Active leakage on FA was observed in 12 eyes at baseline: 6 in the low-fluence PDT group and 6 in the ranibizumab group. The remaining 4 eyes showed multiple mottled hyperfluorescent areas without active leakage at baseline. After completion of primary treatment, 5 eyes in the ranibizumab group showed persistent active leakage on FA with only moderate reduction. At 6 months, persistent leakage was regressed in 4 eyes after an additional low-fluence PDT. All eyes in the low-fluence PDT group demonstrated complete resolution of active leakage after primary treatment, regardless of the presence of SRF. On ICGA, 6 eyes (75%) with completely resolved SRF in the low-fluence PDT group showed narrowing of dilated choroidal vasculature and significant reduction of choroidal hyperfluorescence leakage at 3 and 6 months. In 2 eyes (25%) with sustained SRF, only a subtle reduction of choroidal hyperfluorescence was observed on ICGA at the last follow-up, despite an additional ranibizumab injection. In the ranibizumab group, 2 eyes (25%) that maintained complete resolution of SRF after consecutive ranibizumab injections demonstrated slight reduction of choroidal hyperfluorescence on ICGA at 3 and 6 months (Figure 2). In 6 eyes (75%) with sustained SRF after completion of 3 ranibizumab injections, intense choroidal hyperfluorescence with dilated choroidal vessels on ICGA was demonstrated, although a moderate reduction of leakage on FA was observed. Among them, 4 eyes received additional low-fluence PDT as rescue treatment, and there was a marked reduction in choroidal vascular hyperpermeability and a narrowing of dilated choroidal vessels after PDT (Figure 3).

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FIGURE 2. Images from a 35-year-old man with chronic central serous chorioretinopathy (Patient 15 in Table 1) treated with intravitreal ranibizumab injections. (Top left) Baseline late-phase fluorescein angiography (FA) image showing multiple mottled hyperfluorescence areas consistent with window defect. (Middle left) Middle-phase indocyanine green angiography (ICGA) image showing moderate choroidal hyperpermeability compatible with mottled hyperfluorescence on FA. (Bottom left) Optical coherence tomography (OCT) image showing subfoveal neurosensory detachment. (Top right) Late-phase FA image from the last follow-up visit showing sustained multiple window defects. (Middle right) Middle-phase ICGA image showing a slight reduction of choroidal hyperpermeability. (Bottom right) OCT image revealing complete resolution of subretinal fluid.

In the ranibizumab group, only 1 eye revealed a hypofluorescent area on ICGA at the site of PDT application after rescue treatment, which is compatible with choroidal hypoperfusion. However, all study eyes in the low-fluence PDT and ranibizumab groups did not reveal the changes of RPE status, including RPE depigmentation or atrophy.

group. No clinical evidence of uveitis, inflammation, or endophthalmitis was observed in the ranibizumab group.

DISCUSSION CSC IS KNOWN AS A BENIGN AND SELF-LIMITED DISEASE THAT

● ADVERSE EVENTS:

During the follow-up period, no systemic or ocular complications associated with treatment were observed, including adverse events associated with verteporfin infusion or CNV in the low-fluence PDT

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shows spontaneous resolution of serous neurosensory detachment.28 Although a high rate of spontaneous remission favors conservative management, treatment should be considered in the condition including chronic CSC with persistent subfoveal OF

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FIGURE 3. Images from a 47-year-old man with chronic central serous chorioretinopathy (Patient 13 in Table 1) treated with ranibizumab injections followed by additional low-fluence photodynamic therapy (PDT). (Top left) Baseline late-phase of fluorescein angiography (FA) image showing 2 points of active leakage and mottled hyperfluorescence consistent with an atrophic tract of the retinal pigment epithelium. (Middle left) Middle-phase indocyanine green angiography (ICGA) image showing marked choroidal hyperpermeability with dilated choroidal vessel. (Bottom left) Optical coherence tomography (OCT) image showing the presence of subretinal fluid. (Top center) FA image obtained after 3 monthly ranibizumab injections showing decreased active leakage with persistent mottled hyperfluorescence. (Middle center) ICGA revealing no definite reduction of choroidal hyperpermeability. (Bottom center) OCT image showing increased subretinal fluid. (Right column) Low-fluence PDT was conducted as a rescue treatment because of sustained subretinal fluid after 3 monthly ranibizumab injections. Single PDT spot was applied, covering the 2 points of leakage. (Top right) Late-phase FA obtained after PDT showing multiple mottled hyperfluorescence without active leakage. (Middle right) Middle-phase ICGA image showing significant reduction of choroidal hyperpermeability at the site of laser application. (Bottom right) OCT image revealing complete resolution of subretinal fluid.

fluid, which may result in permanent deterioration of functional and anatomic outcomes.29,30 However, this study has a limitation in assessing the effect of treatment in CSC compared with conservative management because of the tendency of spontaneous resolution in CSC and the lack of a control group. A number of hypotheses have been suggested regarding the pathophysiology of CSC. RPE dysfunction or defect may play a role in the development of serous retinal detachment in CSC.6,31 Several studies based on ICGA findings demonstrated evidence of choroidal vascular hyperpermeability and ischemia in CSC2,3; choroidal hyperpermeability causes decompensation and mechanical damage of RPE, subsequently leading to fluid VOL. 152, NO. 5

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accumulation in the subretinal space.4 Chronic CSC is characterized by diffuse pigment epithelial impairment with persistent SRF, which may lead to an unfavorable natural course.29 Persistent serous retinal detachment in chronic CSC could also induce photoreceptor atrophy in the fovea, consequently resulting in permanent visual impairment.30 No established treatment methods for CSC exist. PDT with verteporfin has been used in the treatment of chronic CSC based on the action of PDT to reduce choroidal hyperpermeability.11 Several studies have reported favorable treatment outcomes in the eyes treated by PDT.11,12,32 Using conventional PDT, irreversible damages may develop, such as

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RPE changes, choriocapillaris hypoperfusion, and secondary CNV.11–15 To improve PDT safety in CSC, various modified PDT protocols were introduced, such as reduction of the dosage of verteporfin or the total energy, and shortening of the irradiation time or the interval between infusion and laser application.16 –20 The reports demonstrated good efficacy and safety of modified PDT compared with conventional PDT. In this study, there was complete resolution of SRF in 10 (83.3%) of 12 eyes that underwent low-fluence PDT as primary or rescue treatment. No eyes showed the changes of RPE after low-fluence PDT. Only 1 eye showed choroidal hypoperfusion after additional low-fluence PDT as rescue treatment. VEGF is well known as a potent inducer of vascular permeability.21 Ranibizumab is a recombinant, humanized monoclonal antibody Fab that neutralizes all active forms of VEGF-A. The effect of ranibizumab in the treatment of CNV in age-related macular degeneration has been established.33–35 Possible benefits of an anti-VEGF agent in CSC were proposed by several studies on the basis of choroidal hyperpermeability as the pathogenesis of CSC.21–24 In this prospective pilot study, we evaluated the efficacy and safety between low-fluence PDT and intravitreal ranibizumab injections in the treatment of chronic CSC. Regarding anatomic outcome, most of the eyes (75%) in the low-fluence PDT group achieved complete resolution of SRF with marked decrease of choroidal hyperpermeability on ICGA after a single session of PDT. In the ranibizumab group, 2 (25%) of 8 eyes achieved complete resolution of SRF after consecutive ranibizumab injections accompanied by a slight reduction of choroidal hyperpermeability. Four eyes in the ranibizumab group required additional low-fluence PDT to achieve complete resolution of SRF and significant reduction of choroidal hyperfluorescence. Although the effect of ranibizumab has been established in the treatment of CNV of age-related macular degeneration, the effect of ranibizumab in chronic CSC was not promising in this study. The findings of our study based on the OCT and ICGA results suggested that the anatomic outcome of ranibizumab may be less effective than lowfluence PDT. Several explanations for these results are proposed. First, the role of VEGF is unclear in the pathogenesis of CSC. Although several reports supported the efficacy and safety of intravitreal injection of bevacizumab, an anti-VEGF agent,21–24 no studies demonstrated an increased level of VEGF in CSC. One study even

reported no significant difference in aqueous humor level of VEGF compared with a control group.36 Thus, it is difficult to infer the possible mechanism in which ranibizumab effectively may work to treat CSC. Even if VEGF ameliorated choroidal vascular hyperpermeability in CSC by an unknown mechanism, we do not know the adequate dose of intravitreal ranibizumab injection in CSC. The dose of ranibizumab used in this study was based on the results for the management of CNV in AMD.33–35 The area of choroidal hyperpermeability and impaired RPE in chronic CSC is much more extensive than that of CNV, the treatment target in exudative AMD. The dose of ranibizumab used in this study, 0.5 mg/0.05 mL, may be insufficient for the management of choroidal hyperpermeability in chronic CSC. In this study, the excess foveal thickness was reduced significantly in the low-fluence PDT group compared with the ranibizumab group, although the mean excess foveal thickness of low-fluence PDT group was higher at baseline. Regarding the aspect of functional outcome, our data revealed a discrepancy between anatomic and functional results. In the low-fluence PDT group, improvement of visual acuity was limited despite a significant reduction of excess foveal thickness. Visual acuity was improved significantly in the ranibizumab group at 3 months, but was not sustained through subsequent follow-up visits. Various factors have been associated with visual outcome besides resolution of SRF and reduction of excess foveal thickness. The risk factors associated with poor visual outcome in CSC that have been proposed in PDT-treated eyes include prolonged symptom duration, pigment epithelial detachment, confluent RPE atrophy, disintegration of the junction between the photoreceptor inner and outer segments, and progression of RPE atrophy after PDT.20,37 In this study, we did not evaluate all these factors, which can hinder the improvement of visual acuity. The eyes with sustained subfoveal fluid underwent rescue treatment regardless of the extent of subfoveal fluid. This may be a limitation in the interpretation of treatment outcomes because of the lack of a preset level of decrease in central foveal thickness that would require rescue treatment. In addition, there are several limitations, including the small number of patients and a short follow-up period. Further investigations are needed to demonstrate the role of VEGF in the development of CSC and to understand the long-term treatment outcomes.

PUBLICATION OF THIS ARTICLE WAS SUPPORTED BY FUNDING AND INVESTIGATION DRUGS FROM NOVARTIS KOREA, SEOUL, Korea. The authors indicate no financial conflict of interest. Involved in Design of study (J.H.); Collection and management of data (S.B., C.K., T.K., J.L., S.S., S.M., T.P., H.C., J.H.); Analysis and interpretation of data (S.B., H.C., J.H.); Preparation of manuscript and statistical analysis and interpretation (S.B., H.C., J.H.); and Review and approval of manuscript (S.B., C.K., T.K., J.L., S.S., S.M., T.P., H.C., J.H.). This study was approved by the Korean Food and Drug Administration and is registered at www.clinicaltrial.gov (identifier NCT01325181). Before enrollment into this clinical trial, additional approval was acquired from the Institutional Review Board at Seoul National University Hospital. This study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from each participants.

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related macular degeneration: year 2 of the PrONTO study. Am J Ophthalmol 2009;148(1):43–58. 34. MARINA Study Group. Ranibizumab for neovascular agerelated macular degeneration. N Engl J Med 2006;355(14): 1419 –1431. 35. Anchor Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1432–1444.

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Biosketch Jang Won Heo, MD, received his medical degree from Dong-A University College of Medicine, Busan, Korea in 1995. He completed retina fellowship in Seoul National University Hospital, Seoul, Korea in 2002. He is currently an Assistant Professor at the Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea. His research interests include various vitreoretinal diseases, including uveitis.

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Biosketch So Hyun Bae, MD, received her medical degree from Seoul National University College of Medicine, Seoul, Korea in 2004. She completed residency at Kangnam Sacred Heart Hospital, Hallym University, Korea. She is currently pursuing a retinal fellowship in Ophthalmology at Seoul National University Hospital, Seoul, Korea. Her field of interest includes surgical procedures associated with vitreoretinal disease.

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