Central Serous Chorioretinopathy: Update on Pathophysiology and Treatment

Abstract

Recent technological advances—new pathophysiological insights, new imaging techniques for diagnosis and management, and new treatments—have led to an improved understanding of central serous chorioretinopathy (CSC). The primary role of the choroid has become more widely accepted with widespread use of indocyanine green angiography. Optical coherence tomography (OCT), and particularly enhanced depth imaging OCT, demonstrate a thickened and engorged choroid. Adaptive optics, fundus autofluorescence, multifocal electroretinography, microperimetry, and contrast sensitivity testing reveal that patients with even a mild course suffer previously undetected anatomic and functional loss. Although focal laser and photodynamic therapy are the current standard of care for persistent subretinal fluid in CSC, they are not appropriate in all cases, and the optimal timing of intervention remains unclear.

Introduction

Central serous chorioretinopathy (CSC) is a disorder characterized by serous retinal detachment and/or retinal pigment epithelial (RPE) detachment, changes most often confined to the macula, and associated with leakage of fluid through the RPE into the subretinal space. CSC is seen frequently in most retina practices, classically in young male patients with no associated systemic conditions. CSC has been known by many names since the original description by von Graefe in 1866,²¹⁹ and these names reflect the course of progress in our understanding of the pathogenesis of the disease. von Graefe described the disease as a recurrent central retinitis, and Horniker in 1922 called it capillarospastic central retinitis to reflect his belief that vasospasm was the mechanism.⁷⁷ Other names used in the 20th century include central angiospastic retinopathy and central serous retinopathy.¹³⁷ Maumenee described fluorescein angiographic (FA) characteristics; fluorescein leakage at the level of the RPE revealed that the choroid and RPE were the primary tissues involved.¹³⁵ Gass further characterized the angiographic findings and coined the term central serous chorioretinopathy.⁵⁸ Because we now understand that hyperpermeability of the choroid causes leakage through the RPE, resulting in a neurosensory retinal detachment, CSC is the preferred term.¹³⁷

CSC has historically been viewed as primarily affecting men in their third and fourth decades, but the average age reported in recent large studies has ranged from 45⁷³ to 51¹⁹⁸ years. Spaide and colleagues reported a mean of 51 years, but they observed that older patients were more likely to present with diffuse RPE loss and secondary choroidal neovascularization (CNV),¹⁹⁸ suggesting that the onset of disease occurred years before presentation. Some patients are initially asymptomatic and may not be diagnosed until they develop more advanced disease. Likewise, the large retrospective case control series published by Haimovici and colleagues in 2004 included patients with evidence of chronic disease.⁷³ They reported a mean age of 45 years. Kitzmann and colleagues (2008) assessed for age of onset and reported a mean of 41 years.⁹⁷ Age-related macular degeneration (AMD) with CNV may resemble CSC, and this must be ruled out in patients over 50.

The lone population-based study of CSC reported an annual incidence of 9.9 cases per 100,000 men and 1.7 per 100,000 women in Olmstead County, Minnesota.⁹⁷ Reported male:female ratios range from 2.7:1²¹⁴ to 7:1.²⁰⁴ CSC is thought to be less common in African Americans than in Caucasians, Hispanics, and Asians,²³² although this has been disputed.⁴⁴

Numerous risk factors for CSC have been reported, but the most consistent is the use of glucocorticoids. This association was suspected as early as 1966 by Jain and Singh,⁸⁶ but was first reported in detail in the mid 1980s by Wakakura and Ishikawa and Harada and Harada.20, 74, 221 Haimovici et al reported an odds ratio of 10.3 (95% confidence interval [CI], 4.0–26.4) for corticosteroid use in their case control study of 312 patients with CSC.⁷³ Tittl and colleagues reported an odds ratio of 3.17 (95% CI, 1.3–7.7) in their 230 patients.²¹⁴ A smaller prospective study (38 cases) also supports the association.⁸⁸ CSC appears to be associated with elevated levels of endogenous corticosteroids, as in patients with Cushing’s syndrome.¹⁹ Glucocorticosteroids have at times been used to treat CSC,91, 119, 161 but given the strong association between CSC and steroid use, they should be avoided whenever possible. Furthermore, patients with CSC should be questioned exhaustively about all forms of steroid use to eliminate the possibility that a skin cream, joint injection, nasal spray, inhalant, or other commonly overlooked form of glucocorticoid could be a contributing factor.

Pregnancy is another recognized risk factor for CSC. Plasma cortisol levels are elevated during pregnancy, particularly during the third trimester.⁴² Haimovici and colleagues had 18 pregnant patients among their 312 cases (versus just 2/312 age and sex-matched controls, p < 0.0001) and calculated an odds ratio of 9.3 (95% CI, 2.1–40.6).⁷³ Chumbley and Frank describe an otherwise healthy young woman who developed active CSC during each of four successive pregnancies, with spontaneous resolution after giving birth.⁴⁰ Pregnancy-associated CSC occurs most often in the third trimester, tends to present with distinctive white subretinal exudation, and usually resolves spontaneously after delivery.²⁰

The historic association between CSC and type A personality is controversial. Although this is a challenging relationship to study, Yannuzzi’s study of CSC and personality types supports the association.²³² His study relied on a comparison of personality surveys of CSC patients with matched controls that predominantly had diabetic retinopathy, rhegmatogenous retinal detachment, and refractive error. Others have found use of psychotropic medication to be a risk factor, which may suggest that psychological stresses are associated with CSC.²¹⁴ Additional associations including systemic hypertension,73, 214 gastroesophageal reflux disease,¹²³ and use of alcohol⁷³ or sympathomimetic agents138, 207, 239 require further confirmation. Kitzmann et al’s small (74 eyes) case control series failed to confirm any of the above associations with CSC, including corticosteroid use.⁹⁷

CSC can occur in an acute or chronic form. The designation of chronicity in CSC is somewhat arbitrary. Some authors have defined chronicity as persistent fluid for at least 6 months,²³⁶ whereas recent clinical trials have used 3 months with persistent fluid.36, 170, 189 Although the acute form can sometimes be recurrent, it generally resolves spontaneously with minimal sequelae. Chronic CSC, however, can result in widespread RPE damage, sometimes referred to as diffuse retinal pigment epitheliopathy (DRPE). These patients have longstanding subretinal fluid that cannot be reabsorbed efficiently because of choroidal disease and extensive dysfunction and loss of RPE. The presence of chronic fluid leads to photoreceptor death and may result in permanent visual loss. Furthermore, chronic CSC is more likely to be complicated by CNV that can cause severe visual loss. Not all patients with acute CSC go on to develop chronic disease, and the reasons for the varied courses are not well understood. There may be additional unknown differences in the pathophysiology of acute and chronic CSC.

A newer classification scheme based on the status of the retinal pigment epithelium uses the terms classic CSC and DRPE. Classic cases have minimal focal RPE damage and discrete leaks at the level of the RPE, and DRPE cases have extensive RPE damage and diffuse leakage.¹⁹⁸ Additionally, a minority of patients develop the bullous variant which occurs when inferiorly gravitating fluid results in a bullous serous retinal detachment.⁵⁹

The hallmark of CSC is the presence of a serous detachment of the neurosensory retina in the posterior pole, sometimes associated with a serous RPE detachment. These findings are usually apparent on slit-lamp biomicroscopy, and they are easily detected and quantified with optical coherence tomography (OCT). In long-standing CSC, some eyes will develop intraretinal fluid and cystoid edema (Fig. 1). The most common FA pattern in CSC is a single pinpoint leak at the level of the RPE (Fig. 2). Some patients will present with multiple pinpoint leaks or a smokestack fluorescein pattern (Fig. 3). FA may show evidence of CSC episodes limited to the extramacular area (Fig. 4) that typically go undetected as they are asymptomatic. Those presenting with DRPE have extensive RPE disease and diffuse fluorescein leakage. In long-standing CSC, findings may include RPE atrophy that exposes underlying choroidal vascular patterns, areas of RPE pigment clumping, and even bone spicules. Other important imaging findings include evidence of gravity-driven descending tracts of subretinal fluid on fluorescein angiography or fundus autofluorescence (FAF) (Fig. 5). These tracts are typically hyperautofluorescent when the fluid first occurs, but then become increasingly hypoautofluorescent as RPE cells are damaged in the pathway of the fluid. On mid-phase indocyanine green (ICG) angiography, there are often plaques of hyperfluorescent inner choroidal staining both in the posterior pole and in the periphery. As shown in Fig. 6, CSC often extends beyond the macula.²⁰¹ Hence, CSC can be regarded as a disorder of the posterior pole rather than purely a maculopathy. Enhanced depth imaging (EDI) reveals a thickened choroid.⁸⁰ These imaging findings are discussed further subsequently.