Central Serous Chorioretinopathy: Multimodal Imaging and Management Options

Central serous chorioretinopathy (CSCR) is an idiopathic maculopathy characterized by thickened choroid, retinal pigment epithelial detachment, and variable subretinal fluid. CSCR predominantly affects young men, with risk factors including corticosteroid use, the type A behavior pattern, and psychological stress. While usually self-limited with a good visual prognosis, recurrent and persistent CSCR can lead to outer retinal and/or retinal pigment epithelial atrophy, choroidal neovascularization, and visual loss. This article reviews current multimodal imaging and treatment options, which include observation, mineralocorticoid receptor antagonists, thermal laser photocoagulation, and off-label photodynamic therapy with verteporfin.


Introduction
Central serous chorioretinopathy (CSCR) is a macular disorder thought to be due to alterations of the choroidal vasculature that overwhelm the ability of the retinal pigment epithelial (RPE) to dehydrate the subretinal space, with consequent accumulation of subretinal fluid. [1][2][3] Thickened choroid, RPE detachments, and variable subretinal fluid are cardinal features of CSCR. Patients may be asymptomatic or may complain of central scotoma, metamorphopsia, dyschromatopsia, and micropsia [4][5][6].

Clinical Features
Patients with acute CSCR typically present with clear and well-demarcated subretinal fluid. There is typically a smooth pigment epithelial detachment (PED) underlying the subretinal fluid, although the PED can be small and challenging to identify with biomicroscopy alone. The clinical course of CSCR is usually self-limited, with spontaneous resolution of subretinal fluid and restoration of visual acuity by three months [20]. The presence of turbid subretinal fluid and/or blood should alert the physician to the possibility of another diagnosis, including idiopathic choroidal neovascularization (CNV), exudative age-related macular degeneration, or polypoidal choroidal vasculopathy. Some patients with CSCR will have a persistent or recurrent course beyond three months. Chronic CSCR can involve multifocal or diffuse RPE disruption and atrophy throughout the posterior pole, potentially causing severe visual loss [8]. RPE atrophy, along with outer retinal atrophy, secondary CNV, cystoid macular edema (CME), and choriocapillaris atrophy are causes of permanent visual loss [20] [21].
Chronic CSCR may show multiple areas of mottled hyperfluorescence, indicating widespread patchy RPE dysfunction and/or atrophy [23]. FA can also detect the presence of secondary CNV.
3.2. Indocyanine Green Angiography. Indocyanine green angiography (ICGA) is another dye-based test that can detect   [26,27]. FAF patterns in acute CSCR may include confluent or granular hypoautofluorescence signifying loss of RPE cells and hyperautofluorescence representing accumulation of unphagocytized photoreceptor outer segments [28]. In chronic CSCR, there is multifocal or diffuse mottled hypoautofluorescence representing atrophy of the RPE. There can be areas of hyperautofluorescence. Descending tracts, also known as "guttering", ( Figure 3) with increased and decreased autofluorescence may be seen [28,29].
3.4. Optical Coherence Tomography. Optical coherence tomography (OCT) allows for rapid noninvasive identification of PED, CME, subretinal fluid, and other structural abnormalities ( Figure 4). In addition, enhanced depth imaging OCT can detect increased choroidal thickness, which is characteristic of CSCR [30] ( Figure 5). CSCR can be described in the spectrum of pachychoroid diseases, which share similar features of choroidal thickening and retinal pigment epithelial changes. [21,[31][32][33] The exact clinical significance of the different pachychoroid disorders with respect to treatment outcomes is uncertain and still under investigation [34].    Occasionally, treatment can be initiated sooner for patients requiring more rapid improvement in vision for occupational or other needs.

Thermal Laser Photocoagulation.
Thermal laser photocoagulation is a well-established option for treating CSCR by directly applying argon laser to a leaking site seen on FA and/or ICGA (Figures 8 and 9). Thermal laser photocoagulation has been reported to decrease subretinal fluid and improve visual acuity [38]. However, long-term visual outcomes have not been reported to improve significantly with argon laser treatment [39,40]. While most studies reported no differences in recurrence rates associated with laser photocoagulation, there are a few studies that reported lower rates of recurrence in laser-treated patients [41][42][43][44]. Complications of thermal laser photocoagulation include scar formation and secondary CNV. Given the potential for scarring, argon laser is most appropriate for extrafoveal leaking sites [42].
Subthreshold micropulse laser was initially described by Bandello and colleagues. In their pilot study, five patients with chronic CSCR were treated and had complete subretinal fluid resorption without recurrence; follow-up data and subsequent case studies have been promising [45][46][47].

Photodynamic Therapy.
Off-label photodynamic therapy (PDT) with verteporfin (Visudyne, Bausch + Lomb, Bridgewater, NJ) was first described in a case series of 15 patients with chronic CSCR. Complete resolution of subretinal fluid occurred in 12 of the 15 patients [48]. PDT has been reported effective in resolving subretinal fluid and improving visual acuity [48][49][50]. Complications associated with PDT include secondary CNV, choriocapillaris hypoperfusion, and RPE damage [51]. In an effort to reduce complications, low dose verteporfin and lower fluence PDT have been reported effective with lower risks of adverse effects [52,53]. Half-dose PDT has been reported to reduce subretinal fluid compared to argon laser in CSCR; however, visual acuity outcomes were similar in both groups [40] (Figures 10-12). The authors are anecdotally aware of, but have no personal experience with, the use of PDT in pediatric patients.

Eplerenone and Spironolactone.
Eplerenone and spironolactone are two mineralocorticoid receptor (MR) antagonists that are increasingly used in the off-label treatment of CSCR. One hypothesis for the etiology of CSCR is inappropriate activation of MR by glucocorticoids; of note, corticosterone induces choroidal dilation,   Case Reports in Ophthalmological Medicine hyperpermeability, and egress of fluid across the RPE into the subretinal space [54]. Spironolactone is a nonselective antagonist of the aldosterone receptor. Its effects of blocking the aldosterone receptor are hypothesized to decrease choroidal hyperpermeability from off-target binding of corticosteroids. Spironolactone has multiple effects on estrogens and androgens that can result in unwanted side effects in male patients such as gynecomastia, decreased libido, and erectile dysfunction [55][56][57].
Eplerenone is a newer, more selective aldosterone antagonist that binds to the MR and less to the other steroid receptors. Eplerenone has a 10-to 20-fold lower affinity to MR, and a 100-to 1000-fold lower affinity to the other steroid receptors than spironolactone, resulting in fewer side effects [57,58]. In general, both MR antagonists are prone to hyperkalemia and potassium levels should be monitored [55]. The authors have no personal experience with the use of MR antagonists in pregnancy or in pediatric patients.
Bousquet et al. conducted a prospective, nonrandomized study of 13 patients with CSCR symptomatic for at least four months. These patients were treated with 25 mg of oral eplerenone daily for one week, followed by 50 mg daily for 1-3 months. Treatment with eplerenone was associated with significant improvements in central macular thickness, subretinal fluid, and visual acuity [59]. The authors followed up with a prospective, randomized, double-masked, placebo-controlled study of 16 patients randomized to receive 50 mg of spironolactone or placebo daily for 30 days. There was a significant reduction of subretinal fluid and subfoveal thickness in the treatment arm compared to placebo; however, no significant changes in best-corrected visual acuity were reported [60]. Herold et al. reported another prospective, nonrandomized study in 18 patients with chronic CSCR evaluating spironolactone 25 mg twice daily for 12 weeks. They reported improvements in subretinal fluid, central macular thickness, and visual acuity [61] (Figure 13).  Case Reports in Ophthalmological Medicine 4.5. Anti-vascular Endothelial Growth Factor Therapy. Antivascular endothelial growth factor (anti-VEGF) therapy is mainly used for chronic CSCR with secondary CNV (Figures 14 and 15). In cases without CNV, there is no evidence of elevated VEGF levels in plasma or aqueous, suggesting that anti-VEGF agents would be ineffective for the treatment of acute or chronic CSCR [62]. However, a few case series have reported variable efficacy using anti-VEGF agents for patients with chronic CSCR and no apparent CNV [63][64][65].

Conclusions
Acute CSCR is often self-limiting, so treatment of CSCR is generally not indicated except when symptoms persist for more than about 3 months. Some patients, especially monocular patients or patients with specific occupational needs, may benefit from earlier intervention. Chronic, nonresolving CSCR has no widely accepted and definitive treatment, due to the paucity of head-to-head clinical trials. In such cases, the authors prefer to use combined

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FA and ICGA to identify extrafoveal sites of leakage that might be amenable to thermal photocoagulation, which is safe to use in almost all patients, including pregnant patients and in pediatric patients.
If there is no focal extrafoveal leak on angiography, options other than thermal photocoagulation include reduced fluence PDT and/or MR antagonists. This is typically an individualized decision. Some patients may be more willing to take a long-term systemic medication rather than undergo PDT with its required period of sunlight avoidance; other patients may prefer the reverse. Figure 16 summarizes the treatment options in CSCR.

Conflicts of Interest
None of the authors have any conflicts of interest.  14 Case Reports in Ophthalmological Medicine