Purpose
To evaluate the efficacy of low-fluence compared with standard-fluence rate photodynamic therapy (PDT) for treating chronic central serous chorioretinopathy.
Design
Prospective, multicenter, investigator-masked, nonrandomized clinical trial.
Methods
Forty-two eyes (42 patients) with chronic central serous chorioretinopathy were enrolled; 19 eyes received indocyanine green angiography-guided standard-fluence PDT (50 J/cm 2 ) and 23 eyes received indocyanine green angiography-guided low-fluence PDT (25 J/cm 2 ). Primary outcome measures were the changes in mean logarithm of the minimal angle of resolution best-corrected visual acuity and the rate of eyes with complete subretinal fluid reabsorption. Secondary outcomes were the changes in central foveal thickness and choroidal perfusion.
Results
Mean logarithm of the minimal angle of resolution best-corrected visual acuity improved significantly at all time points ( P < .01), in the standard-fluence group from 0.43 to 0.24 at 12 months and in the low-fluence-group from 0.46 to 0.16, without significant difference between the 2 groups. At 12 months, a complete subretinal fluid reabsorption was seen in 15 standard-fluence–treated and 21 low-fluence–treated eyes (79% vs 91%; P = .5). In 1 standard-fluence eye, choroidal neovascularization developed at 3 months, and this eye received further PDT; in the other eyes, at 12 months, a moderate-significant choriocapillaris nonperfusion was seen in 8 standard-fluence–treated and 0 low-fluence–treated eyes (44% vs 0%; P = .002).
Conclusions
In most of the eyes, both standard-fluence PDT and low-fluence PDT resulted in complete subretinal fluid reabsorption with visual acuity improvement. Choroidal hypoperfusion related to PDT could be reduced by low-fluence PDT.
Active central serous chorioretinopathy (CSC) is characterized by detachment of the neurosensory retina caused by accumulation of serous fluid between the photoreceptor outer segments and the retinal pigment epithelium (RPE), in combination with monofocal or multifocal changes in the RPE. The disease often resolves spontaneously, but occasionally the neurosensory detachment persists and leads to damage to the RPE and photoreceptors, with visual impairment. Chronic CSC may lead to further complications, such as diffuse RPE decompensation, subretinal precipitates, descending atrophic tracts, cystoid macular degeneration, secondary choroidal neovascularization (CNV), and fibrous scarring. Indocyanine green angiography (ICGA) has provided evidence that CSC primarily affects the choroidal circulation by showing the presence of congested and dilated choroidal veins and capillaries, choroidal staining, and leakage into extracellular spaces.
The current treatment of chronic CSC is based on only observation without experimental control. Several treatments, including medical therapy and laser photocoagulation, have been used, but they are not specific enough in tackling the choroidal vascular problem. Recently, photodynamic therapy (PDT) with verteporfin has been shown to be effective in chronic CSC by improving visual acuity and reducing subretinal fluid. It has been postulated that PDT treatment of CSC causes short-term choriocapillaris hypoperfusion and long-term choroidal vascular remodeling, leading to reduction in choroidal congestion, vascular hyperpermeability, and extravascular leakage. However, complications such as secondary CNV, persistent choriocapillaris hypoperfusion, and pigmentary RPE changes in the treated zone have been reported.
It has been suggested that modified PDT protocols, in terms of verteporfin dosage, fluence rate, the time course of delivery, or a combination thereof, may be more appropriate. In long-standing chronic CSC with foveal and gravitational atrophy, we recently observed functional improvement without significant retinal or choroidal damage by reducing the fluence rate of PDT. In the present study, we investigated the efficacy and the rate of side effects of PDT therapy with a low-fluence rate for treatment of chronic CSC as compared with standard-fluence PDT therapy.
Methods
This study was a prospective, multicenter, nonrandomized, investigator-masked clinical trial performed at the Department of Ophthalmology of the Universities of Bari and Catania, Italy, between January 2006 and May 2008. Inclusion criteria were: (1) best-corrected visual acuity (BCVA) between 0.2 and 1 logarithm of the minimal angle of resolution (logMAR) units; (2) presence of subretinal fluid in the foveal region persisting for 3 months or more, with or without serous pigment epithelial detachment, on optical coherence tomography (OCT); (3) macular RPE decompensation with subtle or diffuse leaks, eventually with gravitational RPE atrophy, pigment epithelial detachment, or both on fluorescein angiography (FA); and (4) abnormal dilated choroidal vasculature and choroidal vascular hyperpermeability with an active leakage area of less than 3500 μm in greatest linear dimension on ICGA. Exclusion criteria were: (1) previous focal laser or PDT treatment for CSC; (2) evidence of CNV; (3) branching network under the RPE, with aneurysm-like enlargements from polypoidal vasculopathy on ICGA; (4) cystic degeneration; (5) other chorioretinal disorders; (6) treatment with steroids for a systemic disease in the previous 12 months; (7) cataract or media opacities that could significantly interfere with OCT imaging, image analysis, and other diagnostic procedures; and (8) systemic contraindications to verteporfin or angiography dyes.
BCVA and central foveal thickness were evaluated in all patients at baseline and at 1, 3, 6, 9, and 12 months after the treatment. FA and ICGA were performed at baseline and at 3 and 12 months. BCVA was measured by certified operators with the modified Early Treatment Diabetic Retinopathy Study charts at 4 m. Vision results were quantified as logMAR units. Central foveal thickness was measured by certified operators with OCT (Stratus OCT; Carl Zeiss Meditec, Dublin, California, USA), by using the fast macular thickness program, in which 6 low-resolution scans (128 A-scans per diagonal), centered on the fovea, are performed simultaneously. The central foveal thickness measurements were obtained after it had been confirmed that the 2 boundaries delineated as the internal limiting membrane (inner boundary) and the RPE and the Bruch membrane (outer boundary) were identified appropriately by the validated internal algorithm. The foveal thickness was defined as the central point where the 6 scans intersect and did not include any fluid under the RPE. Measurements with a standard deviation (standard deviation [SD]) more than 10% of the mean value were excluded. Qualitative assessments were performed by using the macular thickness program that performs 6 high-resolution scans (512 A-scans per diagonal). In each of these scans, the presence of subretinal fluid was evaluated.
FA and ICGA used the Heidelberg scanning laser ophthalmoscope (HRA-2; Heidelberg Engineering, Heidelberg, Germany). Choriocapillaris hypoperfusion and nonperfusion detected on ICGA were graded by using the 5 scales as described by Michels and associates: 0, no effect on choriocapillaris in early and late ICGA; 1, no significant choriocapillaris nonperfusion in early ICGA and discrete hypofluorescence in late ICGA; 2, moderate nonperfusion of the choriocapillaris in early ICGA; 3, significant nonperfusion of the choriocapillaris in early ICGA; and 4, nonperfusion of larger choroidal vessels in early ICGA. Choriocapillaris perfusion was evaluated by 2 masked ophthalmologists from the 2 centers (M.R., S.F., N.C., C.F.), and in case of disagreement, a third retina specialist (F.B.) graded the changes. Ophthalmologists performing BCVA measurement and assessing or evaluating OCT, FA, and ICGA were masked as to the treatments performed.
In each center, the eligible patients were offered standard-fluence PDT or low-fluence PDT. Only 1 treatment was given, as determined by protocol. In cases of bilateral chronic CSC involving the macula, only the eye with the worse BCVA was treated. In standard PDT, a 6 mg/m 2 infusion of verteporfin (Visudyne; Novartis AG, Bülach, Switzerland) over 10 minutes was followed by delivery of diode laser at 689 nm (Visulas 690S; Carl Zeiss Meditec Inc., Dublin, California, USA) 15 minutes after the start of the infusion. A total light energy of 50 J/cm 2 , a light dose rate of 600 mW/cm 2 , and a time of photosensitization of 83 seconds were used. In low-fluence PDT, a fluence of 25 J/cm 2 , a light dose rate of 300 mW/cm 2 , and a time of photosensitization of 83 seconds were used, whereas the other parameters were maintained. This reduced light dose was selected on the basis of results of a phase I/II trial, the Visudyne in Minimally Classic Choroidal Neovascularization Study Group (VIM) study, and Michels and associates’ study. In both groups, the laser irradiation was applied on the area of choroidal vascular hyperpermeability from which subretinal macular fluid seemed to originate, as observed on ICGA. The spot size covered 1000 μm over the choroidal exudation, with a maximum of 4500 μm. In the presence of multifocal areas of leakage, consecutive nonconfluent laser spots were used. Retreatment for persistent or recurrent subretinal fluid was not performed in the study.
Primary outcome measures were the changes in mean logMAR BCVA and the proportion of eyes with complete resolution of subretinal fluid. Secondary outcome measures were the changes in mean central foveal thickness and the rate of eyes with post-PDT changes in choroidal perfusion (as detected by ICGA). Tertiary outcome measures were systemic and ocular complications.
Our hypothesis was that the 2 treatments could lead to a visual acuity improvement from baseline and could have a similar effect. For testing such hypothesis, with an α of 0.05, a β of 0.10, and a power of 90% (2-tailed), a sample size of at least 16 eyes for each group was determined from our preliminary data to detect a 0.20-logMAR increase in visual acuity from baseline. In each group, the values of BCVA and central foveal thickness detected before and after treatment were compared by analysis of variance (ANOVA), and if the difference was significant, multiple comparisons were performed with the Tukey–Kramer test. BCVA and central foveal thickness values detected in the 2 groups at each measurement were compared by t test. The proportion of eyes with complete resolution of subretinal fluid and with changes in choroidal perfusion in the 2 groups were compared by the chi-square test. Differences with P values lower than .05 were considered to be statistically significant.
Results
Of the overall 53 patients with chronic CSC, 7 did not meet the inclusion criteria; a further 4 patients declined study participation. The remaining 42 patients (34 male [81%]; mean age [SD], 49.2 [6.8] years; range, 37 to 64 years), of whom 19 received standard-fluence PDT and 23 received low-fluence PDT, were recruited. At baseline, 35 (83%) eyes had subretinal fluid without serous macular pigment epithelial detachment and 7 (17%) eyes had both subretinal fluid and macular pigment epithelial detachment on OCT examination, of which 5 (12%) eyes had evidence of subretinal deposits of fibrin. At baseline, no difference in age, sex, duration of symptoms, logMAR BCVA, central foveal thickness, or the proportion of eyes with macular pigment epithelial detachment and subretinal deposits was seen between the 2 treatment groups ( Table 1 ).
| Standard-Fluence Group (n = 19) | Low-Fluence Group (n = 23) | P Value | |
|---|---|---|---|
| Mean age ± SD (yrs) | 48 ± 8 | 50 ± 6 | NS a |
| Gender (male/female) | 16/3 | 18/5 | NS b |
| Mean ± SD BCVA (logMAR) | 0.43 ± 0.1 | 0.46 ± 0.2 | NS a |
| Mean ± SD central foveal thickness (μm) | 324 ± 83 | 315 ± 95 | NS a |
| Mean duration of symptoms ± SD (mos) | 8.5 ± 7.3 | 8.9 ± 7.8 | NS a |
| No. of eyes with PED | 3 (15.8%) | 4 (17.4%) | NS c |
| No. of eyes with deposits of fibrin | 2 (10.5%) | 3 (13%) | NS c |
| No. of eyes with deposits of lipids | 2 (10.5%) | 1 (4.3%) | NS c |
| No. of eyes with fine dotlike subretinal material | 10 (52.6%) | 14 (60.9%) | NS c |
| Mean no. ± SD of PDT spots | 1.26 ± 0.5 | 1.30 ± 0.5 | NS a |
| Mean PDT spot size ± SD (mm) | 2.5 ± 0.5 | 2.8 ± 0.7 | NS a |
Best-Corrected Visual Acuity Changes
At baseline, the mean (SD) logMAR BCVA was 0.43 (0.13) in the standard-fluence group and 0.46 (0.18) in the low-fluence group. After treatment, BCVA improved significantly in both groups ( P < .001, ANOVA). One month after treatment, the mean (SD) logMAR BCVA was 0.27 (0.12) in the standard-fluence group and 0.28 (0.17) in the low-fluence group; at the later time points, a trend of further BCVA improvement was seen in the low-fluence group (to 0.16 [0.18] at 12 months), but not in the standard-fluence group. Compared with baseline, a significant BCVA improvement was seen in both groups on all measurements ( P < .01, Tukey–Kramer test), with no significant difference between the 2 groups at any time point ( Figure 1 ).
When considering the subgroup of 7 eyes with pigment epithelium detachment (treated either with standard or low-fluence PDT), no significant logMAR BCVA improvement was seen (not significant, ANOVA) although a trend to improvement was detected (from 0.44 [0.14] at baseline to 0.30 [0.14] at 12 months). Only 1 eye of the subgroup with both pigment epithelium detachment and fibrin demonstrated a visual decline from 0.38 to 0.48 logMAR after the standard-fluence treatment. In the 35 eyes without pigment epithelium detachment, a significant BCVA improvement was seen ( P < .001, ANOVA).
Resolution of Subretinal Fluid
Complete resolution of subretinal fluid was observed at 1 month in 17 standard-fluence–treated eyes and in 22 low-fluence–treated eyes (89% vs 96%; P = .8, chi-square test). Overall, at 12 months in 15 eyes in the standard-fluence group and 21 eyes in the low-fluence group, there was a complete resolution of subretinal fluid (79% vs 91%; P = .5, chi-square). In 2 standard-fluence–treated eyes and 1 low-fluence–treated eye, subretinal fluid persisted up to 12 months; recurrence of macular serous detachment was seen in 2 standard-fluence–treated eyes (at 3 and 6 months, respectively) and in 1 low-fluence–treated eye (at 3 months); in all cases, it lasted until 12 months later. In the subgroup of eyes with pigment epithelium detachment, 5 eyes (also with subretinal fibrin) had a complete reabsorption of the subretinal fluid and of the pigment epithelium detachment at 12 months, whereas pigment epithelium detachment and subretinal fluid were seen at 12 months in 2 eyes (1 eye treated with standard-fluence PDT had persistent fluid, and 1 eye treated with low-fluence PDT had recurrence of macular serous detachment). In 1 eye treated with standard-fluence PDT, CNV developed at 3 months that resolved after a second PDT treatment.
Changes in Central Foveal Thickness
The mean (SD) baseline central foveal thickness was 324 (83) μm in the standard-fluence group and 315 (95) μm in the low-fluence group. After treatment, it decreased significantly in both groups ( P < .001, ANOVA). At 1 month, it was 198 (73) μm in the standard-fluence group and 174 (32) μm in the low-fluence group and did not change significantly over follow-up. Compared with baseline, at all measurements, central foveal thickness decreased significantly ( P < .01, Tukey–Kramer test), with no significant difference between the 2 groups at any time point ( Figure 2 ).
Changes in Choroidal Perfusion
The eye in the standard-fluence group in which CNV developed (3 months after PDT) and that received further PDT treatment was excluded from the analysis of angiographic results. On ICGA, 3 months after treatment, high grades of malperfusion (≥grade II) were significantly more common in the standard-fluence group compared with the low-fluence group (12 [67%] vs 2 [9%]; P < .001); at 12 months, a moderate to significant nonperfusion effect (≥grade II) was still evident in 8 standard-fluence eyes, of which 1 eye had subretinal fibrin; this effect was not evident in the low-fluence group, in which choroidal perfusion recovered progressively (44% vs 0%; P = .002; Table 2 ). Examples of the serial changes in FA, ICGA, and OCT findings of the patients in the standard-fluence and low-fluence groups are displayed in Figures 3 and 4 .
| Standard-Fluence Group (n = 18) a | Low-Fluence Group (n = 23) | |
|---|---|---|
| 3 mos | ||
| Grade 0 | 2 (11.1%) | 15 (65.2%) |
| Grade I | 4 (22.2%) | 6 (26.1%) |
| Grade II | 7 (38.9%) | 2 (8.7%) |
| Grade III | 5 (27.8%) | Nil |
| Grade IV | Nil | Nil |
| 12 mos | ||
| Grade 0 | 7 (38.9%) | 19 (82.6%) |
| Grade I | 3 (16.7%) | 4 (17.4%) |
| Grade II | 5 (27.8%) | Nil |
| Grade III | 3 (16.7%) | Nil |
| Grade IV | Nil | Nil |
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