Purpose
To prospectively evaluate and compare long-term functional and structural outcomes between successful and unsuccessful first half-dose photodynamic therapy (PDT) in patients with chronic central serous chorioretinopathy (cCSC).
Design
Multicenter, prospective cohort study.
Subjects, Participants, and/or Controls
Participants with cCSC enrolled in the PLACE and SPECTRA trials and treated with half-dose PDT in the participating Dutch medical centers, with visits at 5 to 10 years after inclusion .
Methods, Intervention, or Testing
Participants were randomly assigned to half-dose PDT, oral eplerenone or high-density subthreshold micropulse laser and had protocol-defined retreatment and/or crossover treatment in case of persistent subretinal fluid (SRF). After 1 to 2 years of follow-up, patients were managed at clinicians’ discretion and recalled for a 5 to 10-year visit.
Main Outcome Measures
Best-corrected visual acuity (BCVA; measured in Early Treatment of Diabetic Retinopathy Study [ETDRS] letters), retinal sensitivity on microperimetry, presence of macular neovascularization, presence of SRF at long-term follow-up, recurrence of SRF, and retreatment during follow-up.
Results
Sixty percent (107/179) of eligible participants completed the long-term follow-up, performed at a median of 7.0 years. The first half-dose PDT was successful in 78 patients and unsuccessful in 29 patients. Due to a recurrence of SRF or persisting SRF, additional treatments were performed in 14.1% and 89.7% of patients in the successful and unsuccessful first PDT group during follow-up, respectively. BCVA at long-term follow-up was higher in the successful first PDT group ( P <.001). Between baseline and long-term follow-up, BCVA increased significantly in the successful first PDT group (81.8 ± 7.8 vs 87.2 ± 8.7 ETDRS letters, P <.001), with the highest increase observed between baseline and the first control visit, followed by stabilization of BCVA thereafter. BCVA remained stable in the unsuccessful first PDT group (73.4 ± 12.1 vs 77.2 ± 16.2 ETDRS letters, P =.108). At long-term follow-up SRF was present in 16.7% and 44.8% of eyes in the successful and unsuccessful first PDT group, respectively ( P =.005).
Conclusions
cCSC patients with a successful first PDT show better long-term clinical outcomes than those with an unsuccessful first PDT. Notably, BCVA remained stable in both groups from the first follow-up after half-dose PDT onward, which is a reassuring finding even for patients without initial treatment success.
INTRODUCTION
C entral serous chorioretinopathy (CSC) is a chorioretinal disease that is part of the pachychoroid disease spectrum. Active CSC is characterized by fluid accumulation between the neuroretina and the retinal pigment epithelium (RPE). If it affects the macula, the subretinal fluid (SRF) can lead to vision loss, metamorphopsia, and decreased contrast and color vision. The SRF is believed to occur due to RPE dysfunction caused by alterations in the choroidal circulation, including venous congestion, increased choroidal hyperpermeability and pachyvessels with local thinning of the choriocapillaris.
Various classification systems are used for categorizing CSC. Most often, a distinction is made between acute CSC (aCSC) and chronic CSC (cCSC). In aCSC, SRF resolves in most cases within several months and limited RPE alterations are visible on fluorescein angiography (FA). cCSC is characterized by longer-persisting SRF with secondary atrophic RPE and retinal changes, which may lead to a decrease in the vision-related quality of life. To prevent (further) SRF-induced damage to the RPE and neuroretina, early treatment is warranted. According to a previously published evidence-based guideline, the preferred treatment in CSC is photodynamic therapy (PDT) with reduced settings (ie, half-dose PDT, half-fluence PDT or half-time PDT). Previous studies have reported that subthreshold micropulse laser (SML) may also be an effective treatment option. However, PDT appears to be superior to SML in terms of the number of treatments required to achieve complete resolution of SRF. ,, Other frequently performed treatments for CSC are focal laser photocoagulation and oral eplerenone.
In 2 Dutch randomized controlled trials, namely the PLACE and SPECTRA trials, half-dose PDT was compared with high-density SML (HSML) and eplerenone, respectively. , The PLACE trial demonstrated the superiority of half-dose PDT over HSML in terms of retinal sensitivity on microperimetry and complete SRF resolution on optical coherence tomography (OCT) at the final follow-up visit of this trial (7-8 months). In the SPECTRA trial, half-dose PDT and eplerenone were compared, and the complete SRF resolution rate was higher after half-dose PDT at the first follow-up visit after treatment (3 months).
Limited studies are available on the long-term outcomes of cCSC patients who have received PDT. Some retrospective studies reported on best-corrected visual acuity (BCVA), recurrence of SRF, and safety after PDT in CSC patients at a follow-up after 2 to 4 years. In these studies, it was found that PDT was safe and that BCVA improved when comparing baseline (before PDT) and long-term follow-up visits. ,, When distinguishing between successful (complete SRF resolution) and unsuccessful PDT, patients with an unsuccessful response had worse outcomes. Furthermore, previous studies observed that SRF recurrence, after previous SRF resolution, occurred in 7% to 24% of patients with a follow-up of at least 2 years and that additional treatment had to be performed in most of these patients. ,, Importantly, a key limitation of retrospective studies in CSC is that the inclusion criteria have been based on the availability of a long-term follow-up visit. In CSC, patients with SRF resolution often lack a long-term follow-up visit, as routine outpatient visits are not typically scheduled once SRF has resolved. This likely results in an overrepresentation of recurrent and chronic CSC cases in available studies on this topic. Therefore, prospective studies with structured long-term follow-up are warranted.
In this study, we aimed to prospectively evaluate and compare the long-term functional and structural outcomes in cCSC patients who had a successful first half-dose PDT with those who had an insufficient response to the first half-dose PDT (no complete SRF resolution). Data for this study were collected prospectively by re-examining patients who had received half-dose PDT within 2 of the largest randomized controlled trials (PLACE or SPECTRA trial) in cCSC at 5 to 10 years after their initial half-dose PDT.
METHODS
STUDY DESIGN
This multicenter study included cCSC patients who were previously enrolled in the PLACE and SPECTRA trials and who underwent half-dose PDT within 1 year after inclusion in one of these trials. Patients in the PLACE trial were included between November 2013 and September 2016 in 5 academic medical centers in Europe. The SPECTRA trial included patients between February 2017 and August 2019 in 3 referral centers for cCSC patients in the Netherlands. In the PLACE trial, patients were randomized to half-dose PDT or HSML, and in the case of persistent SRF after the first treatment, the initial treatment was repeated. Crossover was performed if SRF was still present at the 7 to 8 month follow-up visit within that trial. In the SPECTRA trial, patients were randomized to either oral eplerenone or half-dose PDT, and a crossover treatment was performed in cases of persistent SRF. All patients who underwent half-dose PDT within 1 year after inclusion in the Dutch medical centers were contacted by mail and telephone for participation in the long-term follow-up study of these trials. This study adhered to the tenets of the Declaration of Helsinki, and written informed consent was obtained from all participants. Ethics approval was obtained from the Institutional Review Boards (MREC Oost-Nederland, Application No. 2017-3535, MREC Leiden University Medical Center, application No. P14.297/SH/sh).
PARTICIPANTS
The PLACE and SPECTRA trials included treatment-naive cCSC patients who were 18 years of age or older. SRF on OCT or symptoms had to be present for at least 6 weeks before inclusion in these trials. In addition, the following multimodal imaging findings were required to be present for inclusion: subfoveal SRF on OCT, one or more regions with active leakage and RPE window defects on FA, and corresponding hyperfluorescent changes on indocyanine green angiography (ICGA). The exclusion criteria of the PLACE and SPECTRA trials were described in previous reports. , For this long-term follow-up study, only patients treated with half-dose PDT at Dutch centers were enrolled. Patients treated at non-Dutch centers were not included. Patients who did not receive half-dose PDT within the PLACE or SPECTRA trial, due to resolution of SRF after treatment with HSML or eplerenone, were not included in this study. No minimum follow-up duration was required for inclusion in this study. Patients who previously participated in the PLACE or SPECTRA trial and returned for the long-term follow-up were classified as long-term follow-up participants. Patients were classified as nonparticipants if they were unable or declined to participate or could not be contacted for any reason.
PROCEDURES
In this study, the visit before the first half-dose PDT was designated as the baseline visit. Demographics and medical history were collected at the first visit after inclusion in the PLACE and SPECTRA trials, as well as at the long-term follow-up visit. The following ophthalmologic examinations and imaging were routinely performed during these trials and were repeated at the long-term follow-up visit: BCVA in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, retinal sensitivity (Macular Integrity Assessment microperimetry [MAIA], Centervue, Padova, Italy), OCT scans and fundus autofluorescence. Imaging was performed on Spectralis HRA + OCT (Heidelberg Engineering GmbH, Heidelberg, Germany). FA and ICGA were not performed at the long-term follow-up visit, because of the invasive nature of these examinations. Data from examinations and imaging were collected and analyzed from the last visit before half-dose PDT, the first visit after PDT, a visit at 1 year after PDT, and the long-term follow-up visit. Previous reports on the PLACE and SPECTRA trials described the treatment procedures followed during the trials. ,,,
OUTCOMES
The primary outcome of the current study was the BCVA at long-term follow-up in cCSC patients with and without a successful first PDT. The following additional outcomes were collected and analyzed between the baseline visit, the first control visit, the year 1 visit, and the long-term follow-up visit: retinal sensitivity on MAIA, recurrence of macular SRF on OCT, macular neovascularization (MNV) on OCT angiography (OCTA), and presence of macular SRF at the long-term follow-up visit. Treatment history between the 1-year visit and the long-term follow-up visit was documented. Additional treatments performed at participating centers were identified from medical records. Furthermore, all patients were asked whether they had received any interim treatment for cCSC.
STATISTICAL ANALYSIS
To compare baseline variables between participants and nonparticipants of the long-term follow-up, the student’s t-test and Mann–Whitney U test were performed for continuous data and chi-square tests for categorical data. The same tests were used to compare outcomes between the successful and unsuccessful first PDT groups. Paired t-tests and Wilcoxon signed rank tests were employed to evaluate BCVA and retinal sensitivity over time in the successful and unsuccessful first PDT group. A linear mixed model was used to compare differences in BCVA and retinal sensitivity change over time between the 2 groups. A P value of <.05 was considered statistically significant, with Bonferroni correction applied per table.
RESULTS
PATIENTS
In total, 179 patients with cCSC who participated in the PLACE or SPECTRA trial at the Dutch medical centers underwent half-dose PDT within 1 year after inclusion in one of the trials. Of these patients, 107 (59.8%) participated in this long-term follow-up study, which was conducted at a median of 7.0 years (IQR = 5.9-8.5) after the first half-dose PDT. The minimal follow-up duration was 4.6 years, and the maximal follow-up duration was 10.2 years. The characteristics at baseline and at the first control visit of patients who did and did not participate in this study are displayed in Supplemental Table 1. Age, gender, BCVA, and SRF resolution after HD-PDT were comparable between participants and nonparticipants. The nonparticipants had a lower retinal sensitivity on microperimetry at baseline ( P =.013) and after the first half-dose PDT ( P =.027) when compared with the long-term follow-up participants, but the difference did not remain significant after Bonferroni correction.
The long-term follow-up participants were divided into a successful ( n = 78) and an unsuccessful first PDT group ( n = 29). At baseline, no significant differences were observed in age, gender, and retinal sensitivity on microperimetry between the 2 groups ( Table 1 ). However, baseline BCVA was significantly higher in patients with a successful first PDT (81.8 ± 7.8 vs 73.4 ± 12.1 ETDRS letters, P <.001).
TABLE 1
Characteristics at Baseline and at Long-Term Follow-Up Visit of Patients With Successful and Unsuccessful First Half-Dose Photodynamic Therapy for Chronic Central Serous Chorioretinopathy.
| Characteristics | Overall ( n = 107) | Successful First PDT ( n = 78) | Unsuccessful First PDT ( n = 29) | P Value |
|---|---|---|---|---|
| Baseline | ||||
| Age ± SD, years | 47.2 ± 8.7 | 46.7 ± 9.1 | 48.6 ± 7.5 | .324 |
| Female, No. (%) | 10 (9.3%) | 6 (7.7%) | 4 (13.8%) | .454 |
| Best-corrected visual acuity (ETDRS letters) | 79.5 ± 9.8 | 81.8 ± 7.8 | 73.4 ± 12.1 | <.001 |
| Retinal sensitivity on microperimetry (dB) | 24.0 (21.8-26.0) | 24.0 (22.0-26.0) | 22.5 (19.0-27.5) | .265 |
| Long-term follow-up | ||||
| Age ± SD, years | 54.5 ± 9.1 | 53.7 ± 9.6 | 56.6 ± 7.4 | .144 |
| Best-corrected visual acuity (ETDRS letters), compared to baseline | .055 | |||
| > 15 loss | 4 (3.7%) | 2 (2.6%) | 2 (6.9%) | |
| 10-14 loss | 3 (2.8%) | 1 (1.3%) | 2 (6.9%) | |
| 5-9 loss | 5 (4.7%) | 2 (2.6%) | 3 (10.3%) | |
| 4 loss to 4 gain | 40 (37.4%) | 34 (43.6%) | 6 (20.7%) | |
| 5-9 gain | 21 (19.6%) | 17 (21.8%) | 4 (13.8%) | |
| 10-14 gain | 23 (21.5%) | 15 (19.2%) | 8 (27.6%) | |
| >15 gain | 11 (10.3%) | 7 (9.0%) | 4 (13.8%) | |
| Treatment before the first PDT | .225 | |||
| High-density subthreshold | ||||
| micropulse laser | 24 (22.4%) | 17 (21.8%) | 7 (24.1%) | |
| Oral eplerenone | 23 (21.5%) | 20 (25.6%) | 3 (10.3%) | |
| None | 60 (56.1%) | 41 (52.6%) | 19 (65.5%) | |
| Complete SRF resolution in study eye during follow-up | 98/107 (91.6%) | 78/78 (100%) | 20/29 (69.0%) | N/A |
| Presence of macular neovascularization | 13/107 (12.1%) | 8/78 (10.3%) | 5/29 (17.2%) | .333 |
| Recurrence of SRF | 29/98 (29.6%) | 20/78 (25.6%) | 9/20 (45.0%) | .091 |
| Number of additionally performed treatment types after first PDT | <.001 | |||
| 0 | 70 (65.4%) | 67 (85.9%) | 3 (10.3%) | |
| 1 | 22 (20.6%) | 10 (12.8%) | 12 (41.4%) | |
| 2 | 9 (8.4%) | 0 (0.0%) | 9 (31.0%) | |
| 3 | 6 (5.6%) | 1 (1.3%) | 5 (17.2%) | |
| SRF at long-term follow-up visit | 26/107 (24.3%) | 13/78 (16.7%) | 13/29 (44.8%) | .005 |
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