To the Editor:

Recently, we read a thought-provoking clinical trial entitled “Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomized, double-blind, placebo-controlled trial” [1]. However, the authors did not observe any significant benefit of eplerenone regarding best-corrected visual acuity (BCVA), subretinal fluid (SRF), central subfield thickness, and recurrence in patients with central serous chorioretinopathy (CSCR) compared with placebo. The study also did not explain these observations using possible mechanisms [1].

In contrast, Petkovsek et al. reported anatomical improvement, including central subfield thickness, macular cube volume, maximum SRF height and diameter achieved within the first year of eplerenone treatment [2]. In another recent study, BCVA was significantly improved and SRF and macular thickness decreased significantly in patients with CSCR treated with oral eplerenone, especially in those under stress [3]. Additionally, it is known that elevated levels of cortisol and endogenous mineralocorticoid dysfunction [4] in patients with CSCR contribute to choroidal vasodilation, and the inhibition of this pathway may prevent aldosterone-induced choroidal thickening [5].

To understand these dissimilar results, we should remember that the presence of a focal leakage point on indocyanine green angiography (ICGA) in the absence of choroidal neovascularization (CNV) signals on optical coherence tomography angiography (OCTA) serve as predictive factors for the complete resolution of SRF after oral eplerenone [6]. However, the presence of widespread changes in retinal pigment epithelium (usually in elderly patients) may hinder the favorable outcome of eplerenone treatment. With this in mind, we noticed that the participants’ age included in the VICI study was between 18 and 60 years [1]. Importantly, CSCR in elderly patients is usually complicated with type I CNV with or without aneurysmal changes [7], especially for refractory and recurrent cases, some of which can be only visualized in OCTA other than dye angiographies [8]. Neovascular CSCR is associated with a worse visual acuity outcome compared to non-neovascular CSCR [9]. We used OCTA to detect CNV secondary to CSCR (Fig. 1). In particular, swept source-OCTA provides a promising CNV detection rate [4]. However, the methodology to exclude CNV is the combination of ICGA and fluorescein angiography in the VICI study [10], which is failed to detect tiny CNVs in some cases. OCTA was not used in this clinical trial to rule out this type of CNV, which would increase the bias of therapeutic outcomes. In fact, CSCR with CNV might benefit from anti-VEGF treatment [6].

Fig. 1: Choroidal neovascularization in a 47-year-old male patient with central serous chorioretinopathy.
figure 1

A Fluorescein angiography showed macular leakage in his left eye (left image); indocyanine green angiography showed choroidal hyperpermeability in his left eye (right image). B En face optical coherence tomography angiography (OCTA) visualized choroidal neovascularization in the area of choroidal hyperpermeability (upper image); B-scan OCTA visualized the increased choriocapillary flow correspondingly (lower image). C OCTA demonstrated subretinal fluid, double layer sign of retinal pigment epithelium and increased thickness of choroidal vessels; the subretinal choroidal thickness was 525 μm.

Current evidence indicates that CSCR can be understood as a subtype of pachychoroid disease characterized by the presence of pachyvessels [7]. Therefore, both retinal and choroidal recovery may be considered desirable treatment outcomes In our previous study, SRF completely resolved 2–3 weeks after photodynamic therapy (PDT), but both mean and subfoveal choroidal thicknesses returned to normal 2–3 months after PDT [11]. Therefore, the premature interruption of treatment may contribute to the relapse of CSCR. For this reason, further studies and a profound reappraisal of published evidence are necessary before changes in current clinical practice are justified.