Central Serous Chorioretinopathy: Current Treatments
Central serous chorioretinopathy (CSCR) is one of the common posterior segment disorders in the United States after Age Related Macular Degeneration, Diabetic Retinopathy, Hypertensive Retinopathy, and Retinal Vein Occlusion. Unlike other common retinopathies, acute CSCR tends to affect younger populations, with the mean age of onset at 45 years old. Although the etiology and pathogenesis of CSCR is not well understood, it has been proposed that an inciting event may trigger increased permeability of the choriocapillaris and dysfunction of retinal pigment epithelium (RPE) This allows for exudative fluid to accumulate beneath the retinal pigment epithelium and neurosensory retina, which manifests as pigment epithelial detachment (PED) and sub-retinal fluid (SRF). Common visual disturbances include moderate decline in visual acuity, central scotomas, and metamorphopsia. The initial management continues to be control of risk factors and observation for resolution. Upwards of 80% of patients with CSCR will have spontaneous resolution of their symptoms within 3 months, but several treatment options have been explored to manage patients with persistent symptoms.
Risk Factors and Risk Factor Modification
Exogenous steroids of any route (oral, intramuscular, intranasal, etc.) have been strongly linked to an increased risk of CSCR  , even at doses as low as 10mg per day. Discontinuation of steroids is highly recommended; however, if patients must remain on steroids, reductions in steroid dose have been shown to increase the speed of CSCR resolution. Systemic steroid can cause bullous exudative retinal detachment or multiple serous pigment epithelial detachment.
While there are several other risk factors that have been associated with CSCR, modification strategies have not yielded consistent results like discontinuation of exogenous steroids. For example, H. pylori has been linked to CSCR; its atherosclerosis-inducing cytotoxins are believed to lead to choroidal vessels damage. Several studies investigated the effects of screening and treating H. pylori in patients with CSCR, but resulted in discordant results on SRF reabsorption and VA improvement. Similarly, long-standing hypertension has been associated with CSCR; however, treatment with anti-hypertensive agents such as propranolol and metoprolol has yielded no beneficial effects.
Patients that show persistent visual defects or lack of improvement on imaging after a few months may require alternative therapies. One option is laser photocoagulation, including focal argon laser and micropulse diode laser photocoagulation. Both rely on angiography to identify focal targets based on hyperfluorescence at sites of RPE detachment/disruption. It is hypothesized that destruction of these detached sites allow scarring that re-attaches the retina . During this process, healthy surrounding RPE cells are able to pump SRF back into the choroid and expedite healing .
For patients with focal RPE detachments not involving the fovea, focal argon laser photocoagulation may be considered. It has been shown to reduce the duration of CSCR up to two months, with complete resolution of RPE detachment and increased speed of improvement of VA. However, long term benefits of focal argon laser photocoagulation remain unclear. Several studies showed significantly decreased rates of CSCR recurrence in treatment groups vs placebo groups after 9 to 18 months of follow-up . Others have concluded there was no difference in CSCR recurrence rates between groups after 1 to 12 years of follow-up. Although focal argon laser photocoagulation may lead to more rapid resorption of SRF and recovery of VA, patients should be made aware of its potential side effects. Because the laser destroys targeted retinal tissue, patients may develop symptomatic scotomas corresponding to these sites. Choroidal neovascularization (CNV) and further vision loss can result if Bruch’s membrane is ruptured by the laser, requiring additional therapy. Due to these potential complications, patients treated with focal argon laser photocoagulation should have regular ophthalmology follow-up.
Micropulse diode (MPD) laser photocoagulation has been investigated as an alternative to focal argon laser. The pulsations allow for less heat damage, resulting in reduced retinal destruction and decreased symptomatic scotoma formation. Furthermore, MPD results in deeper laser penetration than argon laser, allowing therapy to reach the choroid. MPD demonstrated greater VA improvement compared to argon laser treatment at 4 weeks; however, at 8 weeks, there was no significant differences in VA between groups. Although CNV is a potential side effect, no study to date has found CNV in patients treated with MPD photocoagulation. While MPD may be a favorable alternative to argon laser, the long-term safety data of this treatment modality is limited due to lack of access and standardized protocol.
For many patients with CSCR involving the fovea, or CSCR with diffuse leak, photodynamic therapy (PDT) is a favored treatment modality. Photodynamic therapy, similar to laser photocoagulation, begins with angiography to map out RPE disruptions. Verteporfin is then intravenously infused and triggers local oxidative damage upon activation by light of a specific wavelength. It has been proposed that PDT treats CSCR by decreasing choroidal permeability through narrowing of the choriocapillaris. Although the exact mechanism of PDT in CSCR is still unclear, it has been shown that PDT works best in CSCR with diffuse hyperfluorescence on angiography  and tends not to be successful in highly localized types of CSCR.
Resolution of RPE detachment can be seen within 1 month of PDT treatment. Furthermore, at 1 month, a greater proportion of PDT treated patients showed complete SRF reabsorption compared to patients treated with laser photocoagulation. However, there was no significant differences in VA in PDT vs laser treatment groups at 6 months.
Concerns surrounding pigment loss, choroidal hypoperfusion, and reactive RPE changes has led to reductions in dose and fluence of PDT. Half dose PDT (3 mg/m2) has been shown to increase VA, significantly increase SRF re-absorption, and significantly decrease choroid thickness compared to placebo . Half-fluence PDT (25J/cm2) was also shown to be as effective and safer than full-fluence PDT (50J/cm2) in terms of SRF re-absorption and choroidal hypoperfusion.
Therapies Under Investigation: Mineralcorticoid Antagonists, Anti-VEGF
Recent research has aimed to find alternatives to PDT and laser therapy. Glucocorticoids (GC) have been known to cross react with mineralocorticoid receptors, especially at higher concentrations. It has been hypothesized that GC associated CSCR pathogenesis may involve GC interactions with mineralocorticoid receptors in the choroid , leading to abnormal fluid and ion flow. This hypothesis is further supported in mice studies that showed an intravitreal injection of high dose GCs induced an increased expression of ion and water channels in the eye.
Although there have only been a handful of studies examining the effects of mineralocorticoid antagonists in CSCR, the results appear promising. Studies using spironolactone have shown significant reduction in RPE detachment and in choroid thickness in treatment groups vs. placebo groups after 1 month of treatment. In a recent clinical trial, it was found that spironolactone significantly improved VA in patients with prolonged CSCR after 1 month of treatment versus placebo or eplerenone. Furthermore, this study also demonstrated that both spironolactone and eplerenone significantly reduced SRF in comparison to placebo. While research has suggested a role for mineralocorticoid antagonist treatment in CSCR, safety studies for both drugs are still needed as spironolactone has been known to cause gynecomastia, erectile dysfunction, and menstrual irregularities.
The role of anti vascular endothelial growth factor (anti-VEGF) in the treatment of CSCR remains controversial. Since VEGF is known to increase vessel permeability and increase risk of edema, it has been proposed that reducing the effects of VEGF could reduce the abnormal hyperpermeability seen in CSCR. Despite several studies on the effects of intravitreal anti-VEGF agents on CSCR, the results remain inconclusive at this time, with some studies finding no difference compared to placeboand others finding significant benefit with anti-VEGF agents.
Mifepristone, rifampicin, melatonin have also been tried with success in chronic CSCR (http://eyewiki.aao.org/Central_Serous_Chorioretinopathy)
Conclusion and Summary of Recommendations
With advancements in CSCR research, patients now have more treatment options. Due to the high likelihood of spontaneous resolution, first line therapy for first time CSCR remains risk factor modification and observation. For CSCR that persists, there are several treatment modalities to choose from. For patients with focal lesions not involving the fovea, focal laser photocoagulation with argon laser may be suitable. In patients with foveal involvement, photodynamic therapy or micropulse diode laser would spare central vision. As our understanding of the mechanism of CSCR grows, new therapies, such as a spironolactone or eplerenone, may develop along the way.
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