Photodynamic therapy is bene cial for long- standing Central Serous Chorioretinopathy but the chronic damage may impair visual outcomes


 Purpose: Central serous chorioretinopathy (CSCR) patients are often referred to Photodynamic Therapy (PDT) with very long-term disease because of concerns about the potential negative effects of PDT on the retina and on the visual acuity. The purpose of this study was to analyze the results of PDT in CSCR eyes with long standing disease.Methods: The medical records of the patients that underwent PDT for CSCR between 2009 and 2019 were reviewed. Cases were divided into two groups based on the duration of disease before PDT treatment: early treatment (3 to 6 months), delayed treatment (longer than 6 months). The treatment was defined as successful when the subfoveal fluid was absorbed during follow up.Results: The PDT treatment was successful in 76% and 77% of eyes in the early and delayed treatment groups respectively. Both groups showed significant improvement in central retina measurements at the 3-months follow up which persisted to the last follow-up visit. The visual acuity (VA) at baseline was significantly worse in the delayed treatment group (0.5±0.26 vs 0.3±0.24, P=0.042) and improved in both groups but remained low in the delayed treatment group during the study.Conclusion: PDT is not associated with loss of vision in eyes with chronic CSCR, and can be safely used in eyes with relatively good VA. We suggest that if CSCR is not spontaneously improving over 3 months the patient should be offered PDT, to prevent VA loss from the long-term presence of subretinal fluid in the macula.


Introduction
Photodynamic therapy (PDT) with intravenous vertepor n has been the gold standard treatment of central serous chorioretinopathy (CSCR) for over a decade. The reported anatomic success rates vary between 80 to 90% [1][2][3][4][5] either using half of the vertepor n dose or half of the laser uence [6][7][8][9][10][11][12]. Half uence, reducing the energy from 50 J/cm 2 to 25 J/cm 2 , was achieved by either reducing the time of the PDT from 83 seconds to 42 seconds (half time) or by reducing the irradiance from 600 mW/cm 2 to 300 mW/cm 2 (half irradiance). The prognostic factors for anatomic or functional success were also studied.
Other treatment options were also suggested in numerous studies. The latest Cochrane review published looked at 25 studies including 1098 patients summarized that PDT or micropulse laser treatment appear the most promising treatment options for CSCR [18]. In a randomized controlled study published later, micropulse laser was found inferior to PDT [19]. Another more recent review study [20] concluded that the available evidence suggests that half-dose (or half-uence) photodynamic therapy should be the treatment of choice in chronic CSC. Eplenerone, a drug that was considered for a while as an alternative to PDT was recently shown to be ineffective in a randomized controlled study [21].
CSCR is typically a self-limited disease that does not require treatment in the acute phase. Recurrence rates in the absence of intervention are reported to range from 15 to 50%, depending on study type and length of follow up. Approximately third to half of the patients have a second recurrence, often within a year of the rst episode, while 10% have three or more recurrences when followed for up to 15 years [22].
In most studies the de nition of a "chronic" disease that requires treatment is persistent subfoveal uid (SRF) over 3 months [4,5,8,10]. Other studies de ne chronic disease as persistent SRF over 6 months [1,2,7,9,23]. There is no consensus in the literature concerning the best timing of PDT in eyes with CSCR, and whether it should be used early or delayed. Patients are often referred to our clinic with very long term CSCR because of concerns about the potential negative effects of PDT on the retina and on the visual acuity. Some of these patients present with signi cant retinal atrophy and poor visual acuity. PDT may probably be bene cial even in such long-standing cases, with a positive anatomic result but the visual acuity will remain poor [24]. The purpose of this study was to analyze the results of PDT in CSCR eyes with long standing subretinal uid treated at our retina service, and compare the anatomic and functional outcomes between patients with early vs delayed treatment.

Study design
Charts of patients with CSCR that received PDT at the Goldschleger Eye Institute, the Sheba Medical Center, Israel, between 2009 and 2019 were retrospectively reviewed. Only patients that were PDT naïve were included in this study. Approval for data collection and analysis was obtained from the ethics committee of the hospital, and all patients provided informed consent for the PDT procedure. The methodology of the study was designed in accordance with the tenets of the Declaration of Helsinki.

Subjects
Patients aged 18 years or older diagnosed with CSCR (based on uorescein and/or indocyanine green angiography which were performed prior to treatment) were included in the study if they had documented persistent subfoveal uid for at least 3 months prior to the PDT with a follow-up of at least 3 months post-treatment at our retina service with ocular coherence tomography (OCT) scans. We excluded cases who underwent prior retinal laser treatments or those treated by subthreshold laser. Cases in which follow-up duration was less than 3 months, diagnosis was questionable, or OCT scan were missing/poor quality were excluded.

PDT protocol
All patients were treated with half vertepor n dose or with half uence PDT (half time or half irradiance). For each case we collected the details of PDT protocol, number and size of PDT applications per session and the number of PDT sessions for each eye.

Diagnostic evaluation and follow-up examinations
The medical records of the study subjects were reviewed and the following data were retrieved: demographics (age, gender), ocular history, disease duration, use of corticosteroids, and prior treatments for CSCR (e.g. spironolactone, acetylsalicylic acid, intravitreal anti-VEGF injections). Data at the baseline examination and at the 1-and 3-months follow-up visits were recorded as well as details of the nal follow-up visit. The data retrieved from the ocular examination at each visit included: visual acuity (VA) (Snellen charts), mydriatic slit-lamp examination by a retina specialist, and spectral domain OCT ndings (Spectralis, Heidelberg Engineering, Germany, or Zirrus Carl Zeiss Meditec Inc, Dublin, CA). The OCT scans were reviewed by one of the authors (GK) and the presence of subretinal uid (SRF), subretinal hyper re ective material (SHRM), irregular retinal pigment epithelium (RPE) and pigment epithelium detachment (PED) was documented for each scan. We also measured manually the central thickness (CRT) of the fovea and the height of the central subretinal uid in each scan when available. We expected to nd signi cantly thin retina as compatible with the chronic damage. The treatment was de ned as successful when the subfoveal uid was absorbed during follow up.

Statistical analysis
The statistical software SPSS version 25.0 (SPSS, Inc., Chicago, IL, USA) was used for data analysis. Statistical signi cance was set at P < 0.05. According to the different approaches in the literature, cases were divided into two groups based on the duration of disease before PDT treatment: early treatment (3 to 6 months), delayed treatment (longer than 6 months). If a subject suffered from bilateral disease and both eyes quali ed based on the inclusion and exclusion criteria one eye was randomly selected for the analysis.
Due to the relatively small sample size of each independent group non-parametric tests were used. Mann-Whitney and Pearsons' Chi square tests were applied for comparison of continuous and categorical variables respectively between groups at each speci c time point. The Wilcoxon signed rank test and McNemar test were applied for comparison of continuous and categorical variables respectively between baseline and follow-up visits within each group. Repeated measures analysis was applied to determine differences in trends over time in terms of BCVA and CRT. Spearmans' correlation coe cient and multivariant analysis were applied to detect possible prognostic factors for BCVA at the last follow-up visit.

Results
One hundred and two patients were coded as receiving PDT for CSCR between 2009 and 2019. Fifty-three cases (55 patients) were excluded for the following reasons: unclear diagnosis and/or suspected choroidal neovascularization (10 patients), insu cient data or follow up shorter than 3 months (38 patients), not central PDT (3 patients), previously treated (4 patients).
Forty-seven eyes (47 patients) were included in the nal analysis, 21 eyes in the early treatment group and 26 eyes in the delayed treatment group. The baseline characteristics of the two groups are detailed in table 1.
There was a signi cantly higher percentage of women in the long duration group (4.8% vs 38.5%, P=0.007) but the mean age was similar. The BCVA at baseline was signi cantly worse in the delayed treatment group (0.500±0.26 vs 0.331±0.24, P=0.042). The delayed treatment group had longer follow-up duration post PDT treatment (Table 1), but the difference between the two groups was not statistically signi cant (P=0.195).
Prior to PDT treatment, CRT was higher among subjects in the early treatment group as compared to those in delayed treatment group, almost reaching statistical signi cance (P=0.052). No other signi cant differences were observed in baseline OCT scans or PDT treatment parameters. Most treatments in both groups were performed using half uence (66%). There was also no difference between the groups in terms of recurrent treatments (1.5 vs 1.2). Prior oral treaments or intravitreal injections had no signi cant effect on the PDT treatment outcomes.

Treatment success
The PDT treatment was successful (i.e. absorption of SRF -P<0.001) in 76% and 77% of eyes in the early and delayed treatment groups respectively. A statistically signi cant resolution of SHRM and RPE irregularities was also observed in the delayed treatment group (P<0.001). Both groups showed signi cant improvement in CRT measurements at the 3-months follow up which persisted to the last follow-up visit (Fig. 1). Both CRT and max retinal thickness decreased signi cantly after the PDT treatment (P<0.001) and the gap between the two groups narrowed ( gure 1a and 1b respectively). It should be noted that we did not detect any case of immediate vision loss after treatment and at the last follow-up visit only a minor reduction in BCVA was observed in less than 5% of cases overall. As this reduction develop only long after the PDT treatment it seems to result from the longstanding disease and its natural course rather than the treatment itself.
The pre-PDT height of the SRF was similar in both groups, but the central retinal thickness was signi cantly reduced in the delayed treatment eyes (370 vs 311 microns), re ecting a more severe loss of retinal tissue. While PDT induces resolution of SRF whether it is used early or late in CSCR, the nal VA is determined by the extent of irreversible damage to the macula and is directly associated with the duration of the disease and the baseline visual acuity.
These ndings are compatible with the reported prognostic factors in previous studies on PDT treatment for CSCR [13]. Scholz et al. recently published a review of 12 studies regarding subthreshold laser in chronic CSCR [25]. The results were slightly lower than ours: overall, 79.6% of 191 patients showed reduction of CMT and 63.6% a complete resolution of SRF. In the PDT arm complete uid resolution was observed in 46% of cases, signi cantly lower than our series.
Another important nding was that in general the VA either improved or remained stable in most treated eyes. None of the treated patients suffered medium vision loss (>3 ETDRS lines) at the 3 months follow up. Due to the chronic nature of CSCR, around 4% of patients experienced medium vision loss at the end of follow up in both groups. This nding indicates that PDT is not associated with loss of vision in eyes with chronic CSCR, and can be safely used in eyes with relatively good VA. We suggest that if CSCR is not spontaneously improving over 3 months the patient should be offered PDT, to prevent VA loss from the long-term presence of SRF in the macular area.

Declarations
All authors certify that they have no a liations with or involvement in any organization or entity with any nancial interest or non-nancial con ict of interest in the subject matter or materials discussed in this manuscript. No funding was received for conducting this study.
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Efrat Gur, Gabriel Katz and Ari Leshno. The rst draft of the manuscript was written by Gabriel Katz and all authors commented on previous versions of the manuscript. All authors read and approved the nal manuscript

Ethics approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Bioethics Committee of Sheba Medical Center (No. 623-19-SMC).

Consent to participate
This was a retrospective study on electronic data. There was no intervention within the study and therefore informed consent was not required.