Central Serous Chorioretinopathy

Abstract

Central serous chorioretinopathy (CSC) is characterized by neurosensory retinal detachment and vision deterioration at the posterior pole mostly in working-age men. The exact molecular pathogenesis of CSC remains unclear. It is proposed that leakage into subretinal space is caused by increased permeability of choroidal vessels and outer blood-retinal barrier breakdown. The majority of CSC cases are self-limited for a few months with a good visual prognosis. However, if neuroretinal detachment persists longer than 4–6 months, the condition requires treatment because chronic disease induces progressive and irreversible photoreceptor and retinal pigment epithelium (RPE) damage leading to reduced visual acuity. Treatment of CSC aims at achieving a complete resolution of subretinal fluid, and preservation of photoreceptor and RPE. There have been a number of interventions proposed for CSC management. However, treatment of this disease is still a subject of controversy. The purpose of this chapter is to overview pathophysiological hypotheses, diagnosing, and current treatment options for CSC.

1. Introduction

Central serous chorioretinopathy (CSC) is a disease characterized by idiopathic serous detachment of the neurosensory retina occurring in the macula over one or more areas of leakage from the choroid through the defects in the retinal pigment epithelium (RPE) and may be associated with retinal pigment epithelium detachments (PED). CSC is the fourth most common maculopathy associated with fluid leakage after neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion. CSC has been known for a long time and likely this disease was described first by Albert Von Graefe in 1866 who called it “recurrent central retinitis”. CSC is usually unilateral and mainly affects young or middle-aged adults 30–60 years with the peak being in the age 35–45 years [1, 2]. It was found that men are affected 2–6 times more frequently than women [1, 2, 3, 4].

2. Risk factors

Certain predisposing factors were found to be associated with CSC. Strong risk factors are treatment with corticosteroids or endogenous hypercortisolism (Cushing’s disease) [1, 5, 6]. CSC, when related to exposure to exogenous glucocorticoids has a less prominent male predisposition, often bilateral, and manifests more frequently with a chronic form. Psychological stress, which is associated with increased levels of catecholamines, is also recognized as a significant risk factor for CSC development [7]. Type-A personality features such as sense of urgency, competitive behavior, impulsiveness, emotional instability, and aggressive nature were observed in patients suffering from CSC [8]. Type-A personality is characterized by increased basal production of catecholamines [9]. A high incidence of primary hyperaldosteronism was detected in patients with CSC, as well as RPE changes resembling findings typical for inactive CSC are often seen in patients with primary hyperaldosteronism. [10, 11]. This indicates that mineralocorticoid-dependent pathways might be involved in the pathogenesis of CSC. Genetic predisposition may play a role in the development of CSC, possibly via the complement factor H (CFH) gene [12, 13].

3. Pathogenesis

The primary molecular mechanism of CSC remains uncertain and seems to be multifactorial.

CSC is considered a pachychoroid spectrum disorder which includes features such as choroidal thickening, choroidal hyperpermeability, and RPE dysfunction [14, 15]. Choroid forms a rich vascular network plexus lying between the sclera and the retina, consisting of five layers starting from the sclera: suprachoroidea, three layers with vessels of decreasing size: Haller’s layer of large blood vessels, Sattler’s layer of medium and small size vasculature, and the choriocapillaris adjacent to the Bruch’s membrane [16, 17]. The basement membrane of capillary endothelial cells forms the outermost fibrous layer of Bruch’s membrane. The choriocapillaris is fenestrated and permeable to proteins that create a high oncotic pressure in the extravascular environment, which influences the movement of fluid from the retina to the choroid [18]. The choroidal circulation supplies oxygen and nutrients such as glucose and amino acid through the RPE to the outer retina [16, 19]. It has been proposed that abnormalities of choroidal vasculature such as dilation, congestion, and leakage lead to disruption of RPE barrier functions resulting in accumulation of subretinal fluid, PED, neurosensory retinal detachment, and RPE atrophy [20, 21, 22]. Intake of glucocorticoids is the most recognized risk factor for CSC development. It was suggested that mineralocorticoid receptor-dependent pathways are probably involved in the pathogenesis of CSC. Mineralocorticoid receptors (MRs) can bind both aldosterone and glucocorticoid hormones with similar high affinity [23]. MRs are expressed in the human RPE, in the choroidal endothelium, and also in the photoreceptors [24, 25]. It was shown that the overactivation of MRs mediates pathological effects such as oxidative stress, vascular inflammation, endothelial dysfunction, neovascularization, and fibrosis in the retina and other tissues [24, 26, 27]. Increased levels of glucocorticoid hormones induce excessive occupancy of MRs in choroidal vasculature and RPE that could mediate pathogenic effects leading to CSC. It was demonstrated in rats that intravitreal injection of aldosterone or high doses of glucocorticoids leads to choroidal vessel dilation and leakage due to upregulation of endothelial vasodilatory K channels KCa2.3 i [25]. Interestingly, low doses of glucocorticoids, widely used for intravitreal injections in ophthalmological practice, did not induce choroidal vasodilation [25]. Transgenic mice overexpressed the human MRs demonstrated dilatation of choroidal vessels, local alterations of the RPE, and outer blood barrier function disruption, resembling changes in retinal diseases of pachychoroid spectrum in humans [28]. Overactivation of MRs in RPE leads to up-regulation of CXCR4 and PTGER2 genes, inducing RPE migration and contraction leading to outer barrier structure malfunction and inhibition of rod outer segments phagocytosis by RPE cells [28]. On the other hand, MR-induced down-regulation of somatostatin (SST) and gap junction protein delta-2 (GJD2) genes could also cause destabilization of the RPE barrier [28]. Thereby, components of the outer retinal barrier were regulated towards disruption of its structure and function by overactivation of MRs.

Evidence suggests that patients with CSC may have functional changes in the regulation of choroidal blood flow which could be induced by emotional stress [29, 30, 31, 32]. Neural control, provided by sympathetic or parasympathetic nerve endings, is important for choroid [33]. Increased sympathetic stimulation may reduce blood flow in the choroid [34]. Thereby sympathetic dysregulation of choroidal blood vessels, possibly stress-related, might induce focal choroidal ischemia, which may cause RPE damage. Localized ischemia can also induce increased vessel exudation leading to serous PED, breakdown of the outer blood-retinal barrier, and finally detachment of the neurosensory retina [30, 35]. The choroid can regulate its blood flow by the release of nitric oxide (NO) [36, 37, 38]. The vasodilatory impact of NO can be regulated in part by prostaglandins [39, 40]. It was suggested that the choroidal vascular hyperpermeability seen in CSC might be induced partly by abnormalities in the autoregulation of the blood flow in the choroid. Corticosteroids influence the production of NO and prostaglandins and thereby may affect the autoregulation of blood flow in the choroid leading to vessels hyperpermeability [41].

4. Classification

CSC classically is divided into acute and chronic forms based on the duration of subretinal fluid and the structural changes visible on multimodal imaging. The threshold that differentiates acute CSC (aCSC) and chronic CSC (cCSC) is set between 4 and 6 months in most published studies. This time is critical because self-resolution of the disease is no longer expected and treatment intervention can be considered.

Acute CSC has been found to be self-resolved in most cases [42]. Recurrent CSC is characterized by several spontaneously resolving episodes, whereas patients with chronic form of CSC keep subretinal fluid for at least 4–6 months [43]. Recurrence of the disease was approximately 30–50% depending on the study and happened within a year of the first episode [44, 45, 46, 47]. Chronic CSC accounted for approximately 5% of all CSC cases [46]. General progression from aCSC to cCSC was established in around 16% of cases [48].

5. Diagnosis

5.1 Clinical presentation of CSC

Patients suffering from CSC usually complain of blurred vision or defects in the central visual field in the involved eye. Other symptoms could include metamorphopsia, micropsia, and mild dyschromatopsia. However, CSC can also be asymptomatic. The visual acuity of patients with aCSC decreases slightly or moderately and varies widely in cCSC. Amsler grid test reveals distortion of the straight lines in the majority of the cases of CSC [49]. Fundus ophthalmoscopic changes are characterized by around or oval-shaped focus of serous fluid under the neurosensory retina (Figure 1A) [50]. The area of the sensory retina detachment is described from less than 1 to more than 4 disc diameters [49]. The macula is affected in most cases, but the lesion can be located elsewhere, including the nasal retinal field [49]. Small pigment epithelium detachment (PED) can be seen behind the larger elevation of the sensory retina. PEDs are distinguishable by their grayish color. Subretinal precipitates are observed sometimes by biomicroscopy as multiple dot-like yellowish material under the neurosensory retina [51]. Fundoscopic examination shows focalized RPE mottling in aCSC. Persistence of serous neural retina detachment in cCSC is associated with more pronounced and diffused abnormalities in RPE including RPE hypertrophy, atrophy, and finally decompensation of RPE function and deterioration of vision [48, 52]. RPE defects can be observed as well in unaffected eyes.

Figure 1.

Acute central serous chorioretinopathy, multimodal imaging. Color fundus photography shows serous retina detachment in the macula (A). Fundus autofluorescence shows a gentle circular area of increased autofluorescence (B). There is a focal area of hyperfluorescent dye leakage which gradually increases on fluorescein angiography (C, D). Spectral-domain optical coherence tomography enhanced depth imaging (SD-OCT EDI) detected a high dome-shaped serous neuroretina detachment at the fovea, overlying a thick choroid (E).

5.2 Multimodal images

Spectral-domain optical coherence tomography (SD-OCT) confirms serous detachment of neurosensory retina which usually presents as dome-shaped in aCSC (Figure 1E) and tends to be shallower in cCSC (Figure 2D, E) [50].

Figure 2.

Chronic central serous chorioretinopathy, multimodal imaging. Color fundus photography shows mild pigmentary abnormalities, which correspond to the areas of neuroretinal detachment and leakage (A). Fundus autofluorescence showing areas of speckled hyperautofluorescence suggesting chronic retinal pigment epithelium changes and the presence of subretinal fluid (B). Clear areas of focal leakage (inkblot pattern of leakage) can be seen on fluorescein angiography (C on the left). Indocyanine green angiography shows a similar leakage pattern with additional hyperfluorescent areas of choroidal vascular hyperpermeability (C on the right). Spectral-domain optical coherence tomography enhanced depth scan (SD-OCT EDI) showing the presence of subretinal fluid (including the fovea) and increased choroidal thickness (D, E).

In aCSC the outer retinal layers are usually well-observed and preserved. Sometimes protrusion of outer segments of detached photoreceptors and focal defects in the RPE at the leaking point can be noticed [53]. In contrast, in cCSC, SD-OCT demonstrates thinning of the outer retinal layers with poor visualization of the ellipsoid zone referring to photoreceptor inner segments which are tightly packed with mitochondria and therefore are very important for the photoreceptor health and function [54]. In cCSC cystoid macular degeneration can be developed. Serous retinal detachment can be associated with different types of PEDs including, dome-shaped, flat, and irregular PEDs [55, 56]. Spectral-domain enhanced depth imaging OCT (SD-OCT EDI) technique, which provides a deeper insight into the choroidal morphology, demonstrates an increased choroidal thickness in patients with CSC (Figure 1E on the right; Figure 2D, E). Interestingly, thick choroid is often seen in both eyes, even if the disease was developed in one eye [57].

Fluorescein angiography (FAG) allows to observe leakage of fluid into the subretinal space through the defects in RPE [58]. In CSC, usually, two types of patterns can be seen. Pinpoint hyperfluorescence appears in the early stage and subsequently increases in size and intensity into a large dot within the site of neuroretinal detachment called inkblot type (Figures 1C,D and 2C). A smokestack pattern with dye rising superiorly within the subretinal space is thought to be related to the higher concentration of proteins in the subretinal fluid and was found in approximately 10–20% of cases. Acute CSC usually presents with one or a few focal leaks (so-called hot spots) which induce an isolated dome-shaped neuroretinal detachment. Chronic CSC is associated with multifocal leakage. If subretinal fluid persists, it tends to move toward the lower part of the macula inducing gravitational dystrophy of the RPE (Figure 2C on the left). Focal or geographic RPE window defects referring to past episodes of neurosensory retina detachment may also be observed.

Indocyanine green angiography (ICGA) shows hypofluorescent areas in early transit followed by late hyperfluorescence and pooling of indocyanine green which corresponds to atrophic and elevated RPE areas or leakage points on FAG (Figure 2C on the right) [35, 59].

Spectral-domain optical coherence tomography angiography (OCTA) and swept-source optical coherence tomography angiography (SS-OCTA) are advanced non-invasive imaging technologies that enable imaging, segmentations, and quantifications of blood flow in the retina and choroid. Some studies focused on comparisons between ICGA and OCTA imaging of CSC and found that abnormalities in the choroidal vasculature visible on OCTA correspond to ICGA changes in CSC [59, 60]. Therefore, OCTA is a promising noninvasive tool for visualization and follow-up quantifications of the choroidal vasculature in patients with CSC.

Fundus autofluorescence (FAF) helps in the diagnosis of CSC. RPE lipofuscin produces short-wavelength autofluorescence thereby FAF indicates structural and metabolic condition of the RPE cells in the macula.

Regions of granular hyper- and hypo-autofluorescence are visualized in CSC. Circumferential areas of hyperautofluorescence can be seen reflecting the presence of subretinal fluid (Figure 1B). Multiple gravitational tracks are seen as granular areas of hyper- and hypo-autofluorescence and are distinguishable for cCSC (Figure 2B).

6. Treatment

The treatment of CSC is a subject of controversy. Large prospective, randomized, controlled trials are particularly important to elicit the most effective treatment methods for CSC because of the relatively high percentage of spontaneous resolution of this disease which can be taken for treatment success in small, retrospective studies.

Acute CSC is essentially a benign disorder and in most cases, observation without treatment is generally recommended as initial management because subretinal fluid can resolve spontaneously within six months and visual acuity usually returns to normal [49]. However, small clinical sequelae can remain due to pre-existing irreversible retinal damage, including RPE alterations, complaints of darkening of the central visual field, color vision changes, metamorphopsia, and micropsia. Chronic and severe recurrent variants of CSC are associated with progressive vision loss [52]. The treatment aim for CSH is to achieve full resolution of neuroretinal detachment in order to restore normal anatomical and functional photoreceptor-RPE interactions because even a small amount of persisting subretinal fluid induces damage to photoreceptors [61, 62]. Treatment targets for CSC are the choroidal vascular network and RPE. Available treatment methods are aimed at accelerating the ability of RPE to absorb subretinal fluid, reducing leakage from the choroidal vasculature, and decreasing the flow of fluid through the RPE barrier into the subretinal space. Traditionally, continuous-wave thermal laser has been a treatment choice for CSC [63]. This method of laser treatment is directed to the site of fluorescein dye leakage and attempts to seal the focal defects in the outer blood-retinal barrier. Other benefits could be due to the migration of adjacent healthy RPE cells after injury and stimulation of the pumping function of RPE near the treated sites. Laser photocoagulation should be limited to extrafoveal leakage points because subjective scotoma can develop in the treated area. The long-term prospective randomized study compared argon laser photocoagulation with no treatment in the management of CSC revealed that direct photocoagulation reduces the duration of retinal detachment, however found no evidence that this treatment can significantly improve best corrected visual acuity (BCVA) and reduce a recurrence rate [44]. Robertson and Ilstrup demonstrated that laser photocoagulation shortened the duration of CSC and decreased the rate of recurrences at the site of treatment as compared with sham treatment [63]. Navigated laser photocoagulation of the focal leakage point on FAG showed accuracy and effectiveness of subretinal fluid resolution [64]. Adverse events observed with laser photocoagulation include subretinal neovascularization and the development of progressive atrophy over time at the treatment site [63, 65].

Two commonly performed treatments for CSC are high-density subthreshold micropulse laser (HSML) and photodynamic therapy (PDT) with verteporfin (Visudyne (Novartis, Basel, Switzerland). HSML energy is delivered to the retina in a series of extremely short (microseconds) repetitive pulses allowing dissemination of the heart between the pulses and keeping the temperature below the threshold for denaturation of tissue proteins. Therefore, no laser-visible thermal damage to neural retina and choroid is induced. Subthreshold micropulse laser energy is absorbed mostly by melanin of RPE. It is proposed that HSML treatment increases the expression of heat shock proteins in targeted cells, which could activate endogenous protective mechanisms, decrease injury, and improve RPE functions [66]. It was demonstrated the effectiveness of HSML for CSC treatment, especially presented with point source leakage, in terms of resolution of subretinal fluid and improvement of BCVA [67, 68]. Another option available for CSC management is photodynamic therapy (PDT). The rationale for applying verteporfin PDT is a photochemical mechanism that induces occlusion of choriocapillaris leading to vascular remodeling and reduction of choroidal hyperpermeability [69, 70, 71] However, PDT can induce complications such as RPE atrophy and CNV [72, 73]. The PLACE trial is a large, prospective multicentre randomized controlled study comparing 810 nm HSML with half-dose PDT in patients with cCSC [74]. In this trial, half-dose PDT was superior to HSML in terms of complete resolution of SRF and improvement of BCVA. Measuring the value of HSML for CSC treatment is significantly complicated by the wide range of treatment regimens and laser wavelengths that have been reported [75]. Treatment with MR antagonists such as eplerenone and spironolactone has been associated with complete resolution of subretinal fluid and improved BCVA [76, 77, 78]. Eplerenone passes an increased MR selectivity compared to spironolactone and therefore has less antiandrogenic activity. Spectra trial is a prospective multicentre randomized controlled study designed to compare half-dose PDT with eplerenone in cCSC treatment regarding achieving complete resolution of SRF and improving the BCVA. In this study, PDT was found to be superior to eplerenone treatment in patients with cCSC [79]. VICI trial is a large randomized placebo-controlled double-blinded trial designed to assess the efficacy of eplerenone in cCSC [80]. VICI trial showed that eplerenone was not superior to placebo for the treatment of cCSC. Interestingly, the selective MR antagonist eplerenone has not demonstrated expected effect in the treatment of CSC in large trials. Efficiency of spironolactone was not assessed in large prospective randomized trials. Clinical and experimental evidence suggests that anti-VEGF agents could be used for CSC treatment due to their anti-hyperpermeability effect on the choroidal endothelial cells and ability to reduce choroidal blood flow [81, 82]. However, the use of anti-VEGF compounds for CSC treatment is generally off-label [75].

7. Conclusion

CSC is an enigmatic disease. Despite the fact that CSC has been known for more than 150 years, primary molecular pathogenesis and clear treatment strategy for this condition remain to be elucidated.