Central serous chorioretinopathy: Current update on management.

Central serous chorioretinopathy (CSC), the fourth most common nonsurgical retinopathy with a usual self-limiting course, is known to present with persistent or recurrent form with distressing visual loss. Evolution of newer mutimodal imaging techniques have revolutionized the understanding about the pathophysiology of CSC, and hence the diagnosis and management. Multifactorial etiopathology of CSC promotes the use of multiple treatment modalities. With advances in investigative options, treatment options including conventional focal laser, micropulse laser, photodynamic therapy, and transpupillary thermotherapy are also advancing and refining. Medical management for CSC is also under evaluation with a wide spectrum of new drugs in vogue. However, standard of treatment is yet to be established through randomized clinical trials. This review article discusses the current approach to multimodal treatment options for CSC including conventional as well as newer therapeutic modalities.

Introduction

Central serous chorioretinopathy (CSC) is the fourth most common nonsurgical retinopathy classically affecting middle-aged population.[1] Despite the availability of vast information about CSC in literature, the exact pathophysiology is still not very clear. With advancement in multimodal imaging techniques, our understanding about the pathophysiology and diagnosis of CSC is gradually refining, leading to revolution in the management of the condition. The management of CSC mainly depends on the stage of the disease, that is, acute or chronic.

Standard initial management of acute classic CSC is a careful observation with modification of various risk factors. Acute CSC has typically an excellent prognosis and self-resolving natural course with almost full visual recovery to the premorbid level. Active intervention should be considered in cases of CSC with persisting macular subretinal fluid (SRF) or reduced visual acuity. However, indications for early treatment include cases where untreated CSC resulted in a poor visual outcome in the fellow eye and also cases in which rapid recovery is needed due to occupational requirement or other reasons.[23] A recently performed angiography should be used as a reference to plan for active intervention. Laser treatment modalities including conventional laser, micropulse laser, transpupillary thermotherapy (TTT), and photodynamic therapy (PDT) constitute the most important part of active interventions for CSC. In general, conventional laser is directed to extrafoveal focal leaks, micropulse laser for juxtafoveal focal or diffuse leaks, and PDT to subfoveal leaks. These treatment modalities target choroidal vascular network and/or the retinal pigment epithelium (RPE) cells resulting in either accelerated absorption of SRF or decreased production and hence accumulation of fluid in the subretinal space.[3] Currently, many drugs are also being researched to find alternative to laser therapy.

This review article aims to discuss conventional as well as recent treatment options available for CSC. We reviewed the published data on management of CSC by searching Scopus, PubMed, and Web of Science to find relevant articles till December 2017, using the following combined search terms: “central serous chorioretinopathy,” “conventional laser,” “photodynamic therapy,” “transpupillary thermotherapy,” “micropulse laser,” “medical management,” “anti-vascular endothelial growth factor (anti-VEGF),” and “eplerenone.”

Conservative Management

Careful observation without any active intervention is advocated for 3 months in most cases of CSC in anticipation of spontaneous resolution of SRF. Optical coherence tomography (OCT) is repeated on every follow-up to compare SRF level with baseline scan. Decrease in SRF level indicates toward spontaneously closed leakage and such cases can be observed for more time. During the period of observation, however, risk factor modification constitutes an important part of initial conservative management. Corticosteroid use is the most common modifiable risk factor, and if practical, steroid intake in any form whether systemic (oral or intravenous) or local (e.g., skin creams, nasal sprays, joint injections) should be discontinued or tapered off after physician consultation.[2] Steroid-sparing agents may be of help in patients requiring long-term immunomodulation. As Type A personality has been associated with higher CSC incidence, patients should be advised to be involved in any activity which can reduce overall stress levels. Anxiolytic medicine could be prescribed in the initial days. Obstructive sleep apnea, if present, should be treated.[2] Other modifiable risk factors like phosphodiesterase inhibitor intake or smoking, if present, should be stopped.

Ophthalmologists have also been prescribing antioxidant supplementation as a part of initial conservative management. However, study by Ratanasukon et al. compared antioxidants to placebo, and no significant difference was found for mean change in best-corrected visual acuity (BCVA), recurrence rate, and mean change in central retinal thickness at 12 months.[4]

Conventional Laser Photocoagulation

Conventional laser treatment involves focal tissue coagulation at the RPE level, typically applied to areas of focal leakage identified on fundus fluorescein angiography (FFA), using a low-intensity green or yellow argon laser.[5] Although the mechanism of SRF resolution after focal laser treatment is not well understood, it is hypothesized that focal laser injury induces recruitment of healthy RPE cells as a healing response or the direct stimulation of RPE pumping function near treated area.[6]

Focal laser photocoagulation fastens the SRF resolution in both acute and chronic CSC, however, results about the final visual outcome and rate of recurrences have been variable in various studies.[7891011] In a randomized controlled trial including 70 eyes with acute CSC, Leaver and Williams reported a faster resolution of SRF (6 vs. 16 weeks, P < 0.01) in eyes treated with focal argon laser to the leakage site.[7] Ficker et al. studied the 44 eyes, with a follow-up ranged from 6.4 years to 12.1 years, for long-term analysis, and found similar recurrence rate, final visual acuity, and color discrimination.[10] Brancato and Bandello and Gilbert et al. also found similar results with no difference in long-term outcomes after laser compared to natural course of CSC.[911] In a nonrandomized study of laser versus observation in 45 eyes, Burumcek et al. found a faster fluid resolution, fewer recurrences, and better visual acuity after 5 years of follow-up in eyes treated with focal laser compared to observation.[12]

When planning focal laser for acute or chronic CSC, focal leakage should be present, at least 375 μm from the fovea, in recently performed FFA. A setting of low intensity, longer duration, and moderate spot size (100–200 μ) should be used to reduce the risk of rupture of Bruch's membrane and subsequent choroidal neovascular membrane (CNVM) development and development of progressive RPE atrophy.

Micropulse Diode Laser Photocoagulation

Micropulse diode laser treatment for CSC involves a series of repetitive ultrashort (810 nm) laser pulses broadly targeting the RPE cells with little thermal damage to collateral tissues because of the relatively small amounts of energy delivered.[1314] The use of micropulse laser is increasing in the treatment of chronic CSC cases with diffuse epitheliopathy or juxtafoveal point leak.

In a randomized controlled trial by Verma et al., the outcomes of micropulse laser (810 nm) treatment and argon laser (514 nm) treatment, randomized to 30 cases of CSC with single focal leak, were compared at 12 weeks. Complete resolution of fluid and similar final BCVA was noted in both the groups. However, a significantly better final contrast sensitivity was noted in diode laser group, which improved from mean absolute value of contrast sensitivity (Cambridge low contrast gratings) of 98.4 to final mean value of 306.0 in diode group compared to improvement from baseline value of 130.66 to final value of 215.33 in argon laser group. Furthermore, no persistent scotoma was noted in diode group compared to 20% cases with persistent scotoma in argon laser group.[15] In another series of 26 eyes treated with diode laser, Chen et al. noted complete fluid resolution in 14 of 15 eyes with focal leaks, while only 5 of 11 eyes with diffuse leakage showed complete fluid resolution.[16]

One of the challenges of micropulse diode laser is that it is difficult to confirm visually the laser uptake as it does not induce visible laser burn. To overcome this difficulty, Ricci et al. described the indocyanine green (ICG)-assisted technique of micropulse diode laser, which resulted in fluid-free retina in all seven eyes at 1-year posttreatment. They suggested that RPE uptake of ICG molecule with an absorption peak at 805–810 nm allows a more targeted treatment with 810 nm diode laser as well as confirmation of laser burn at desired area by postlaser examination with ICG filter.[17]

Subthreshold micropulse yellow laser photocoagulation is a recently described treatment modality using 577 nm yellow laser. The yellow (577 nm) laser wavelength occurs outside the absorption spectrum of retinal xanthophylls, potentially allowing for treatment of juxtafoveal lesions. The combined absorption by both melanin and oxymelanin of 577 nm causes lesser scatter compared to other yellow (532/561/568 nm) laser, leading to energy concentration to smaller volume allowing the use of lower powers and shorter pulse durations. Yadav et al. treated 15 eyes with CSC, persisting for more than 3 months, with 577 nm yellow laser in micropulse emission mode using setting of 100 μm spot size, 0.2 s exposure, 10% duty cycle with half the power titrated to cause mild retinal whitening. They noted significant reduction in fluid height (average 79%) in all eyes, improvement of one line in median BCVA on Snellen's visual acuity chart, improvement in the threshold sensitivity values in 75% eyes examined with microperimetry, and no evidence of RPE or retinal damage on spectral domain OCT, FFA or fundus autofluorescence.[18]

Recently, studies have compared the effect of subthreshold micropulse laser and half-dose PDT in management of chronic CSC and found that both are effective treatment modalities for chronic CSC.[1920] However, in a comparative study, Scholz et al. found that though both the half-dose PDT and subthreshold micropulse laser are potent treatment modalities for chronic CSC, more patients showed treatment response and greater decrease in central retinal thickness in the subthreshold micropulse laser group.[20] Because of the good efficacy and nondamaging effect on retina, subthreshold micropulse laser is emerging as a good therapeutic option for chronic CSC. However, better standardization of treatment criteria as well as laser settings is needed through larger prospective studies.

Photodynamic Therapy

PDT using verteporfin (Visudyne, Novartis) is thought to act by short-term choriocapillaris hypoperfusion and long-term choroidal vascular remodeling to negate choroidal hyperpermeability which is consistently found in CSC cases.[2122] Current indication for PDT typically includes persistent CSC with subfoveal or juxtafoveal focal leaks or diffuse RPE leakage. In a largest series, 82 eyes with chronic CSC were treated with standard PDT, which resulted in complete SRF resolution in all the eyes. However, 13 patients needed repeated PDT, and two eyes developed CNVM and nine eyes developed RPE hyperplasia at the site of treatment.[23] These dose-dependent complications such as progression of RPE atrophy, foveal injury, RPE rip, and CNVM development raised the concerns about safety of standard PDT.[24] These treatment-related risks that portends a significant threat to visual outcome, promoted safety enhanced treatment alternatives by reducing the dose, or fluence of PDT to reduce the risk of complications while maintaining the potential treatment benefit.[25]

Low-dose PDT is performed using half dose of verteporfin (3 mg/m2) and has been shown to be effective in treating CSC both anatomically as well as functionally.[22] Half-dose PDT has also shown to facilitate an earlier resolution of SRF and visual recovery when compared to focal laser.[26] The lowest safe and effective dose of verteporfin has been proposed to be 30% of the standard dose in treating acute CSC.[27]

Low-fluence PDT (LF-PDT) has also shown to be effective in achieving prompt resolution. LF-PDT is performed by infusing 6 mg/m2 of verteporfin over 10 min, followed by delivery of diode laser at 689 nm, about 15 min after the start of infusion with a fluence of 25 J/cm2, a light dose rate of 300 mW/cm2 and a photosensitization time of 83 s. LF-PDT may perhaps be safer by preventing excessive activation of verteporfin and limiting generation of singlet oxygen by activated verteporfin in the treated area, thereby decreasing the choroidal hypoperfusion and CNVM associated with PDT.[28] On comparing low-fluence and half-dose PDT, half-dose PDT induced faster resolution of SRF with a longer effective duration than low-fluence PDT, and safety was also found to be at par.[29]

Transpupillary Thermotherapy

TTT is cheaper and effective treatment option for chronic CSC that causes temperature-based closure of the choriocapillaris which leads to stasis of blood flow and stops leakage using an 810 nm long-pulse low-energy diode laser.[3031] Among the handful of TTT-based studies, Shukla et al. investigated TTT in 25 eyes of chronic CSC and found complete resolution of SRF and focal leakage in 84% at 1 month and in 96% patients at 3 months. Visual acuity improvement was noted in 92% of cases compared to 33% cases of control group. One patient developed CNVM.[32]

Concern of producing a foveal burn and collateral damage promoted the evolution of the safety-enhanced graded subthreshold TTT.[33] In graded subthreshold TTT, a starting power at 40% of the threshold extramacular test burn (reducing 60% from the threshold power), for a foveal laser treatment is planned. If an inadequate response is observed at 6 weeks after treatment, retreatment is done with a 20% increase in power, thus grading the desired response by producing invisible burns and limiting adverse events.[33]

Medical Management

Medical management for CSC is under evaluation with a wide spectrum of new drugs in vogue. The systemic medications could be more beneficial in bilateral and/or chronic cases of CSC as the treatment targets the entire retina rather than specific areas.[34] However, long-term randomized controlled trials are warranted to establish safety and effectiveness of the following drugs.

Antisteroidal drugs

Owing to possible role of excessive glucocorticoid -dependent choroidal mineralocorticoid receptor in the pathogenesis of CSC, many studies have evaluated role of various drugs with anti-steroidal property in the management of CSC.[343536373839] This group includes ketoconazole, mifepristone, rifampicin, finasteride, spironolactone, and eplerenone.

Ketoconazole, an antifungal agent of imidazole group, has additional antiglucocorticoid effects by blocking the conversion of 11-deoxycortisol to cortisol and hence endogenous glucocorticoid production.[25] Because of this inhibition, use of ketoconazole in CSC was believed to be a rational treatment approach.[4041] It has, however, not been able to demonstrate significantly better outcomes.[36]

Mifepristone (RU-486) is a high-affinity glucocorticoid and progesterone receptor antagonist and hence has been tried in the management of chronic CSC.[42] Nielsen and Jampol administered mifepristone in a dose of 200 mg up to 12 weeks in chronic CSC and noticed beneficial effects in some cases.[37]

Rifampicin, an antitubercular drug, facilitates catabolism of endogenous steroids. It induces proliferation of the smooth endoplasmic reticulum and an increase in the cytochrome P-450 content in the liver, thus affecting the metabolism and bioavailability of endogenous corticosteroids, and hence aiding in resolution of CSC.[3843] It, however, brings with it a significant risk for hepatotoxicity and development of drug resistance to the bacteria while being treated for CSC.

Finasteride, a 5-alfa reductase inhibitor, prevents conversion of testosterone to dihydrotestosterone, the latter of which has a higher affinity to androgen receptor.[44] Some studies have implicated the role of androgen in the pathophysiology of CSC.[3545] This is the rationale for the use of finasteride in the management of CSC cases.

Eplerenone and spironolactone, aldosterone receptor antagonists, inhibit binding of both aldosterone and glucocorticoids to mineralocorticoid receptors. An experimental study in rats showed that retinal and choroidal vasculature expresses glucocorticoid and mineralocorticoid receptors.[46] Eplerenone has excellent selectivity for mineralocorticoid receptors, while spironolactone has additional antiandrogenic properties.[47] Based on these findings, a number of studies have used eplerenone and spironolactone for treatment of chronic CSC cases and have noted decrease in mean macular thickness as well as SRF.[3439]

Owing to the excellent selectivity, eplerenone is being evaluated as a promising therapeutic agent in the management of chronic CSC in various studies.[4849] In a randomized, double-blind, placebo-controlled pilot study including 15 patients, oral eplerenone was given as 25 mg daily for 1 week followed by 50 mg daily for 8 weeks in cases of chronic CSC. The therapy was found safe and potentially effective, resulting in improvement in maximum SRF height, maximum subfoveal fluid height, central subfield thickness, and BCVA.[49] However, in another randomized controlled double-blind study, eplerenone was not found to be superior to placebo in treatment of chronic CSC in 19 eyes of 17 patients.[50]

Along with different treatment results noted in various studies, dose and duration of oral eplerenone therapy is also not well defined and varies from study to study. Hence, large multicentric prospective randomized placebo-controlled double-blind studies are needed for better evaluation of eplerenone and to define the dose and duration of this treatment in cases of chronic CSC.

Carbonic anhydrase inhibitor

Acetazolamide, a carbonic anhydrase inhibitor, is used off-label to treat CSC by ophthalmologists. Inhibition of carbonic anhydrase IV in the RPE to promote resorption of SRF and retinal adhesion seems to form basis for the use of acetazolamide in these cases.[51] The only clinical study to date showed faster subjective improvement and SRF resolution among patients treated with acetazolamide compared to controls, with no difference in the final BCVA or recurrence rate.[52] Topical carbonic anhydrase inhibitor, brinzolamide, was used in a study to treat acute CSC, and recurrence rate and persistence of fluid were less frequent compared to placebo group after 6-month follow-up.[53]

Anti-Helicobacter pylori treatment

Several studies have shown that CSC cases may have a higher incidence of serum anti- Helicobacter pylori antibodies, probably due to molecular mimicry of host proteins of the choroidal vasculature and RPE with antigens of H. pylori.[5455] Comparative studies have shown slightly better visual outcomes and lesser persistent CSC in anti-H. pylori treatment group than in placebo group.[5657]

Anti-vascular endothelial growth factor therapy

Although anti-VEGF agents are not considered as first-line treatment modality for CSC, recently a number of studies have evaluated the role of these agents. The use of anti-VEGF in CSC is based on the hypothesis that hypoxic conditions in choroid or RPE can cause compartmentalized VEGF expression.[2] Results have been variable with studies suggesting that response was either similar to control group or inferior to the response to other treatment modalities like PDT,[5859] while few other uncontrolled studies showed favorable results for intravitreal anti-VEGF.[6061] A recently published meta-analysis including 266 eyes from 14 studies found that for acute CSC, anti-VEGF treatment was not superior to observation in terms of both final anatomical and functional outcomes; while in chronic cases, a significant difference was observed in central macular thickness reduction but not in final visual acuity between anti-VEGF treatment and observation groups.[62] Hence, the exact role of anti-VEGF in CSC cases is questionable and ill-defined currently.

Conclusion

Although natural history of CSC shows a self-limiting course, patients are known to present with persistent, recurrent, or even bilateral CSC with distressing visual loss indicating the need for treatment. Multifactorial etiopathology of CSC promotes the use of multiple treatment modalities for regression of CSC. While focal laser and PDT are the current standard of care for persistent CSC, these treatment options are not appropriate in all cases and the optimal timing of intervention with these modalities also remains unclear. Recent studies have shown promising results with the use of new drugs in management of acute as well as chronic CSC and can be developed as treatment modalities alternative to lasers and PDT. With a number of established treatment modalities as well as upcoming therapeutic agents such as subthreshold micropulse laser and eplerenone, standard of treatment needs to be redefined through long-term randomized controlled trials culminating to achieve the treatment of choice for CSC.

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Conflicts of interest

There are no conflicts of interest.