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Abstract
Objective The purpose of this study was to evaluate the role of anti-vascular endothelial growth factor (anti-VEGF) treatment on the functional and structural parameters of chronic central serous retinopathy (CSR).
Methods PubMed was used to systematically review literature published from 1 January 2009 to 1 July 2022. Studies were included if patients in their cohort had symptoms for more than 3 months, anti-VEGF treatment was provided and the following outcomes were reported: best-corrected visual acuity (BCVA), central macular thickness (CMT) and proportion of subretinal fluid (SRF) resolution.
Results 339 eyes met inclusion criteria with a mean patient age of 45.8±4.9 years. The weighted mean baseline BCVA for the 20 studies was 0.39±0.23 logMAR, which improved to 0.28±0.24 after treatment with anti-VEGF injections (p=0.069). The weighted baseline CMT for the 20 studies decreased from 395.2±52.0 µm to 243.0±41.9 µm (p<0.001). The weighted overall percentage of SRF resolution was 68.4%.
Conclusion Anti-VEGF treatment demonstrated significantly decreased macular thickness and resolution of SRF in the treatment of chronic CSR without any reported adverse effects. However, BCVA did not significantly improve with pharmacotherapy.
- Retina
- Vision
- Imaging
- Macula
Data availability statement
Data are available in a public, open access repository.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Chronic central serous chorioretinopathy (CSR) typically resolves spontaneously within 3 months, but chronic cases can cause irreversible damage to photoreceptors and/or retinal pigment epithelium. Photodynamic therapy (PDT) is the mainstay of treatment and has shown to be effective in chronic cases. Anti-vascular endothelial growth factor (anti-VEGF) agents have been hypothesised to be a treatment option for patients given the pathogenesis of CSR includes choroidal hyperpermeability. There is currently limited evidence regarding the efficacy of these medications for chronic CSR.
WHAT THIS STUDY ADDS
We collected data from studies investigating anti-VEGF agents for chronic CSR in the past 13 years. Anti-VEGF treatment demonstrated significantly decreased macular thickness and resolution of subretinal fluid in the treatment of chronic CSR without any reported adverse effects. However, treatment did not significantly improve best-corrected visual acuity.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Anti-VEGF agents may be a safe and useful treatment option for patients with chronic CSR if PDT is unavailable. Patients should be considered for pharmacological treatment on a case-by-case basis.
Introduction
Central serous retinopathy (CSR) is the fourth most common retinopathy after age-related macular degeneration, diabetic retinopathy and branched retinal vein occlusion, and typically causes central vision loss or distortion in patients.1 CSR predominantly affects men compared with women with a prevalence ratio between 3:1 and 7:1, and most patients are between the ages of 30 and 51 years at diagnosis.2 Additionally, studies have shown that psychosocial factors such as ‘type A’ personality traits are correlated with the incidence of CSR.2–6 CSR may be idiopathic or develop secondary to corticosteroid therapy, long-standing hypertension and mitogen-activated protein kinase inhibitors; thus, malignant choroidal infiltration and a review of medications and medical history are important.1 7–10
CSR is marked by one or more focal active leakage sites associated with decompensated retinal pigment epithelium (RPE) and detachment of the neurosensory retina and/or the RPE.1 3 4 7 Three theories have been proposed to describe the aetiology of CSR.1 8 11 These include choroidal vascular hyperpermeability secondary to dysfunction of the outer blood–retina border, dysfunctional RPE resulting in reversed liquid transport and shedding of the outer photoreceptors causing damage to the RPE.4–6 12 CSR is included as part of the pachychoroid spectrum, a class of retinal pathologies characterised by structural and functional changes in the choroid such as thickening and inner attenuation of the choriocapillaris and vessel hyperpermeability.13 14
CSR typically resolves spontaneously; however, chronic cases recur or persist.1 3 5 Conservative management is recommended for acute CSR, with intervention classically indicated for those cases lasting longer than 3 months.3 Leakage extending greater than 3 months may result in permanent damage to the photoreceptors and/or RPE and cause foveal atrophy.5 6 15 16
Conventional and micropulse diode laser photocoagulation and photodynamic therapy (PDT), including reduced-dose and reduced-fluence PDT, have demonstrated positive results in decreasing vascular hyperpermeability and improving chronic CSR.17 18 However, as there is concern regarding safety profile with increasing limitations regarding access to new and existing machines, the reliance on PDT may become a challenge. Due to these treatment challenges, alternative modalities have been tried with inconsistent results. Medical treatments that have been trialled include eplerenone and other aldosterone receptor antagonists, acetazolamide, beta-blockers, various vitamins and non-steroidal anti-inflammatory medications.5 More recently, anti-vascular endothelial growth factor (anti-VEGF) therapies have been proposed for treatment of CSR based on the hypothetical pathogenesis of CSR related to choroidal hyperpermeability.19–21 Anti-VEGF therapies have proven to be successful in the treatment of diseases that cause intraretinal oedema and subretinal fluid (SRF), including exudative age-related macular degeneration, diabetic macular oedema and retinal venous occlusions.19 Anti-VEGF agents that have been tested in many clinical trials for these conditions include bevacizumab (Avastin; Genetech, San Francisco, California, USA), ranibizumab (Lucentis; Novartis, Basel, Switzerland) and aflibercept (Eylea; Regeneron Pharmaceuticals; Tarrytown, New York, USA) . Since the initial study described by Torres-Soriano et al, numerous prospective and retrospective interventional case series, comparative analyses and chart reviews have reported the outcomes of chronic CSR after anti-VEGF treatment.20
Methods
A review of the literature was performed using PubMed (accessed 1 July 2022), and the following terms were searched: “bevacizumab OR ranibizumab OR aflibercept” AND “central serous retinopathy” with filters for “publication date” (01/01/2009–07/01/2022), “humans” and “English”. Brolucizumab was not included due to its recent release. Articles were reviewed by three authors (MP, MM, AS) and were included if patients in the study received at least one of bevacizumab, ranibizumab or aflibercept to treat chronic CSR. If disagreement on inclusion of the paper occurred between the two authors, the paper would be reviewed by a fourth reviewer (FA). Figure 1 outlines the literature search and steps for inclusion/exclusion criteria. One hundred fifty relevant abstracts were reviewed based on results from our search criteria. Abstracts were excluded if patients had evidence of choroidal neovascularisation or subjects were given anti-VEGF for indications such as diabetic macular oedema or for other diseases along the pachychoroid spectrum. Additionally, studies were excluded if subjects were treated with combination PDT and anti-VEGF agents. Forty-four full-length articles met inclusion criteria and were fully reviewed. Papers which studied both acute and chronic CSR were included if there were separately reported data for each subgroup of patients. Papers which had insufficient data were removed (ie, did not report initial and final best-corrected visual acuity (BCVA), central macular thickness (CMT) and proportion of SRF resolution). Systematic reviews, meta-analysis and comments were not included in the final selection of 20 papers. There were no exclusions based on the number of injections, treatment regimen, age, population size or study design. For each study, the following data were extracted: number of participants, mean age of patient, mean number of injections per patient, initial and final BCVA and CMT, number of patients who had complete SRF resolution after anti-VEGF injection and average follow-up time post-treatment with these agents.
Flow chart of study exclusion methods. anti-VEGF, anti-vascular endothelial growth factor; CNV, choroidal neovascularisation; CSR, central serous retinopathy.
As each study varied in the number of eyes studied, pooled data were used to calculate a weighted mean (μ) and weighted SD (σ) for each measured variable. Each study’s extracted data (Xi) were weighted by the number of participant eyes (Ei) that were included. There were a total of 339 eyes across all included studies. M represents the number of studies which reported the specific data.
Results
A total of 20 studies were included in this systematic review (n=339 eyes).3–5 16 20 22–36 Twelve were prospective studies (n=165),3–5 22–25 29–32 34 seven were retrospective studies (n=173)16 26–28 33 35 36 and one was a case report (n=1).20 Of the 20 studies, 11 were non-comparative (n=129),3 20 25–32 34 6 studies compared anti-VEGF therapy with other treatment modalities (4 PDT, 1 diode laser, 1 with other anti-VEGF agents) (n=105),4 5 16 23 24 35 3 studies compared observation with anti-VEGF therapy (n=78),22 35 36 and 1 study compared chronic cases of CSR with acute, atypical, or recurrent presentations of the disease (n=46).33
Eleven out of 20 studies (n=196; 53.3% of all eyes)3 5 22 23 28 31–36 showed statistically significant improvements in BCVA in the anti-VEGF treatment group. Fourteen out of 20 studies (n=268; 79.0% of all eyes)3–5 16 22 23 28 30–36 showed statistically significant reductions in initial CMT after treatment.
A comprehensive summary of the results of all the included studies may be found in online supplemental table 1.37 The weighted mean number of injections for all studies was 2.18 with an average follow-up of 9.53 months. Most studies treated CSR with bevacizumab (n=15), with a dose ranging from 1.25 mg to 2.5 mg. The remaining papers used ranibizumab (n=4) and aflibercept (n=2), and one study investigated efficacy of both bevacizumab and ranibizumab (n=1) (online supplemental table 1).37 The weighted mean BCVA for the 20 studies was 0.39±0.23 logMAR and 0.28±0.24 (p=0.069) before and after treatment, respectively. The weighted baseline CMT for the 20 studies decreased from 395.2±52.0 µm to 243.0±41.9 µm (p<0.001). The weighted overall percentage of SRF resolution after treatment was 68.4%.
Supplemental material
Drug therapy
The dose and frequency of anti-VEGF used varied in the reviewed studies (online supplemental table 2).37 Three anti-VEGF agents were used to treat CSR in the 20 studies reviewed: intravitreal ranibizumab (IVR), intravitreal bevacizumab (IVB) and intravitreal aflibercept (IVA) (online supplemental table 3).37
Supplemental material
Supplemental material
Ranibizumab
Two studies, by Bae et al23 (n=8) and Bae et al24 (n=16), used IVR to treat chronic CSR at a dose of 0.5 mg/0.05 mL.23 24 These two studies were prospective randomised controlled trials comparing IVR with PDT 6 mg/m2. Bae et al23 demonstrated significantly improved BCVA with IVR (p=0.012) at 3 months; however, these gains were not sustained at 6-month follow-up.23 Bae et al24 had the same injection protocol as their earlier study but with a larger sample size (n=16) and added low-fluence PDT as a rescue therapy alternative for the ranibizumab group should there be persistent SRF.24 Although the study showed efficacy of IVR, the results revealed relative superiority of low-fluence PDT. Yumusak et al (n=20) measured changes in BCVA, foveal thickness (FT) and choroidal thickness (CT) in chronic presentations of CSR after IVR administration.36 Patients with chronic presentations had a significantly improved BCVA and decreased FT after treatment with IVR; these results were similar to the final BCVA (p=0.96) and FT (p=0.50) of patients with acute presentations of CSR whose SRF spontaneously resolved without treatment (n=12). Tekin et al 201835 compared visual outcomes in patients given IVR (n=20) with patients given IVB (n=23) and patients observed without treatment (n=27). The time to resolution of SRF was significantly increased in control subjects compared with those treated with anti-VEGF agents (p<0.001). Furthermore, while the CMT was significantly thicker in the observation cohort compared with IVR and IVB groups at 1-month follow-up, the thickness was similar after 3-month, 6-month and 12-month follow-up.35
Bevacizumab
Fifteen studies (cumulative sample size n=253) used IVB as their treatment modality (online supplemental table 2 and online supplemental table 4).3–5 16 20 22 25–29 31–33 35 37 There were two variables in the treatment regimen of bevacizumab: dosage and frequency of injections. Online supplemental table 438 outlines pooled data from the studies with IVB as their treatment modality.
Supplemental material
Aflibercept
Two studies used IVA as their treatment modality.30 34 Pitcher et al included 12 patients and compared two injection frequency regimens: 6 patients received IVA 2.0 mg/0.05 mL monthly for 6 months, whereas the remaining 6 patients received intravitreal injections at 0, 1, 2 and 4 months.30 The frequency of IVA injections did not alter visual acuity or anatomical outcomes (p=0.50). Additionally, while there was not a significant improvement in overall BCVA across all patients after treatment with IVA (p=0.56), there was a significant decrease in CMT (p=0.03).30 Tekin et al34 prospectively studied IVA response in 10 patients and found a significant improvement in mean and median BCVA and CMT during each follow-up point (1, 3 and 6 months post-injection).34
Frequency of injections
The number of injections and protocol for re-injection varied across the selected studies. There was an initial injection followed by re-injection at intervals ranging from 4 weeks to 10 months.4 5 16 23–26 28–31 33 34 39 Some protocols had criteria regarding when to re-inject, while others had standard protocol with only one injection used.3 20 22 27 32 35
Discussion
CSR is classified as part of the pachychoroid spectrum, which also includes other retinal pathologies such as pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy and polypoidal choroidal vasculopathy. Pachychoroid pathologies present with three common findings: increased CT, dilation of outer choroidal vessels (‘pachyvessels’) and thinning of choriocapillaris and middle choroidal vessels (Sattler layer).39 In patients with CSR, indocyanine green angiography shows dilated choroidal vessels with hyperpermeability, and fluorescein angiography shows corresponding leakage at the level of the RPE.39 Given the pathophysiology of CSR and aforementioned challenges with PDT access, anti-VEGF injections are currently being trialled as a therapeutic option by retinal specialists. Therefore, the purpose of this review was to analyse all studies which measured clinically significant pretreatment and post-treatment variables in patients with chronic CSR. This meta-analysis identified 20 papers with records of baseline and follow-up BCVA and CMT and the proportion of SRF resolution after treatment with IVR, IVB and IVA (online supplemental table 1).37
Although all three anti-VEGF agents have a similar mechanism of action, some therapies may be more theoretically advantageous compared with others. For example, ranibizumab has a smaller molecular size, higher binding affinity to VEGF and deeper penetration to choroidal vascular hyperpermeability lesions compared with bevacizumab.40 Aflibercept is a recombinant fusion protein unlike ranibizumab and bevacizumab, which are both full-length humanised monoclonal antibodies.34 Aflibercept also binds VEGF-B which is critical for blood vessel survival and has a higher binding affinity to VEGF compared with both bevacizumab and ranibizumab.38 41 There were limited studies which analysed ranibizumab (n=4) and aflibercept (n=2); therefore, it is challenging to draw conclusions regarding the comparative efficacy of anti-VEGF agents; however, Tekin et al35 did not report a significant difference in CMT measurements between IVB and IVR up to 1 year post-injection.35
Dosage and frequency also pose a challenge. For example, 15 studies investigated the efficacy of IVB but varied in their dosage and dosing schedule protocol (online supplemental table 4).37 Eleven studies administered 1.25 mg IVB and the remaining administered either 1.5 mg (n=1) or 2.5 mg IVB (n=3). Out of 11 studies which used the lowest dose of IVB, 5 papers recorded a significant improvement in BCVA and reduction in CMT.
Most studies in this meta-analysis incorporated treatment-naïve patients and excluded patients who had prior vitreoretinal treatments including lasers, intravitreal injections and vitreoretinal surgeries. Studies were also eliminated which studied the results of a combined regimen of anti-VEGF and PDT. Despite several studies reporting patients with persistent SRF, only four studies documented subsequent rescue treatment with alternative therapies such as PDT. These successful results demonstrate that PDT may be an appropriate treatment with persistent SRF after a trial of anti-VEGF injection. However, it is unclear how long anti-VEGF treatment should be maintained before resorting to rescue therapy. Likewise, anti-VEGF treatment may be trialled in cases recalcitrant to PDT; therefore, it is difficult to ascertain the true efficacy of anti-VEGF agents based on the results of this meta-analysis.
Some studies in this analysis did not account for biases in their experimental design. For example, Koss et al did not randomise their patient population; rather, patients elected if they would prefer laser treatment, IVB or observation.4 Control groups are highly recommended in studies testing efficacy of a new treatment; otherwise, it is challenging to determine if the improvement in visual and anatomical outcomes was due to time or pharmacotherapy, given the natural course of CSR. Only three studies compared results with a control group of patients who were observed.4 22 35 Additionally, 5 out of 20 studies were case reports or case series which limited generalisability of findings.
The safety profile for these pharmaceuticals is an important consideration for use in patients with CSR. There are known risks involved with long-term use of anti-VEGF, such as choriocapillaris damage, RPE atrophy, damage to the ganglion cells and most significantly endophthalmitis.26 However, none of the studies in this meta-analysis reported any adverse events other than minor side effects such as ocular pain and subconjunctival haemorrhage.
Limitations of our paper include the following: (1) searching for studies only using the PubMed database; (2) this study was not registered prior to conducting the meta-analysis; and (3) finally, bias assessment was not performed with two researchers independently using the Newcastle–Ottawa Scale.
Based on the pooled statistics presented here, anti-VEGF treatment demonstrated significantly decreased macular thickness and a high proportion of SRF resolution in the treatment of chronic CSR without significant BCVA improvement. This may be because persistent SRF can cause irreversible damage to retinal photoreceptors. Thus, despite resolution of SRF after anti-VEGF treatment, BCVA may remain low. This study suggests that anti-VEGF treatment has the potential to become a secondary treatment option for patients with chronic CSR. We recommend anti-VEGF treatment in patients with chronic CSR if (1) PDT is unavailable, or access is limited, or contraindicated, (2) there is secondary choroidal neovascularisation, or (3) they have failed conventional treatment with PDT and have persistent SRF. Further research in the form of adequately powered randomised controlled trials involving treatment-naïve patients with chronic CSR is essential, which could enable determination of optimal treatment regimen with anti-VEGF therapy. Additionally, where possible, modifiable risk factors should be optimised, such as cessation of corticosteroids.
Data availability statement
Data are available in a public, open access repository.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
References
Supplementary material
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors MP, MM and AS performed literature review, collected data and interpreted the results. AS performed statistics. MP, MM, AS and FA prepared the manuscript. Guarantor, FA.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.