Abstract
Central serous chorioretinopathy (CSC) is a common disorder that predominantly affects males. Multimodal imaging has improved our understanding of the disease. However, the exact mechanisms of the disease pathology remain unclear. Acute CSC occurs following single or multifocal defects in the retinal pigment epithelium and is usually self-limiting and very rarely convert to chronic CSC. On the contrary, chronic CSC is associated with poor visual prognosis and presents as a diffuse retinal pigment epitheliopathy. There is no consensus on the best treatment option for chronic CSC.
Keywords
Central serous chorioretinopathy, Central serous retinopathy, Retinal pigment epithelium, Choroid, Photodynamic therapy, Laser, Epelernone
Central serous chorioretinopathy (CSC) is a disorder characterized by serous retinal detachment and/or retinal pigment epithelium (RPE) detachment. These changes are usually confined to the macula but may be multifocal and more widespread. It is the fourth most common retinal disorder and remains a priority research area due to lack of consensus in the etiology, pathogenesis, definition, diagnostic criteria, and management. This is reflected in the evolving terminologies used to describe the condition as progress is made in our understanding of the pathogenesis of the condition. Von Graefe first described it as “recurrent central retinitis” in 1866. Choroidal involvement was first suggested by Maumenee, who indicated that the choroid and RPE were the primary tissues involved based on angiographic findings. Since then, Gass confirmed these findings and coined the term CSC.
Epidemiology
CSC has always been thought to affect middle-aged men but with better characterization of the disease using more advanced imaging techniques, it is now established that the disease spectrum does involve older individuals including women. Male-to-female ratio in younger age groups ranges from 2.7:1 to 7:1 but the prevalence of the disease has an equal distribution in older age groups. The disease affects all ethnic groups.
The only confirmed risk factor for this condition is the use of any form of steroids (glucocorticoids). Elevated levels of endogenous corticosteroids, as in patients with Cushing’s syndrome or during the third trimester of pregnancy, can also cause CSC. Sympathomimetics are reported as a risk factor. However, corticosteroids and sympathomimetics may indeed have common properties that exacerbate choroidal vascular response. Steroids induce adrenergic receptor gene transcription, impair choroidal vascular autoregulation, potentiate vascular reactivity, and have prothrombotic effects. In addition, steroids may affect the Bruch’s membrane by inhibiting collagen synthesis. Steroids can also reduce the barrier properties of the RPE cells. A sympathetic overdrive may explain other stress-related associations of CSC that include type A personality, use of psychotropic medication, systemic hypertension, gastroesophageal reflux disease, and sleep apnea. Despite the multitude of ways steroids can adversely affect the RPE-choroid complex, intraocular and periocular steroids only infrequently trigger CSC. Helicobacter pylori infection may also cause CSC. An immune-mediated damage to choroidal endothelial cells resulting from molecular mimicry is one proposed mechanism.
Interest on complement-induced inflammatory pathology in CSC has also gained momentum recently with at least three independent reports of genomic variations in complement factor H (CFH) that confer genetic susceptibility to CSC. CFH is a critical negative regulator of the alternative pathway of the complement system. de Jong also showed an association of chronic CSC with genetic variants in ARMS2 and CFH but the alleles in ARMS2 and CFH that confer risk of AMD may be protective for chronic CSC and vice versa. In CSC, the binding of CFH to adrenomedullin may be of relevance as it induces choroidal vasodilation affecting choroidal blood flow. However, no increase in aqueous cytokines has been reported to date. Schubert C. et al . observed that variations in a cell–cell adhesion molecule, cadherin (CDH5), is more prevalent in males with CSC than controls and suggested that corticosteroids may downregulate this adhesion molecule in the choroidal vasculature.
Clinical Classification of CSC
Broadly, this condition is usually classified into acute or chronic forms based on duration of signs and symptoms. However, the onset of subretinal fluid and the associated symptoms do not usually correlate. This distinction between acute and chronic CSC is important as chronicity usually signifies the need for intervention.
CSC may be accurately defined as
- 1.
Acute CSC when the patient presents with symptoms of blurred central vision, metamorphopsia, micropsia, or impaired contrast sensitivity due to a localized circular area of subretinal fluid at the macula with or without a small pigment epithelial detachment (PED) ( Fig. 9.1 ). There is usually no evidence of retinal pigmentary changes suggestive of previous CSC in either eye at this stage. A fundus fluorescein angiography (FA) shows the presence of one or multiple leaks. Most reports suggest that acute CSC may last up to 4–6 months with complete resolution of subretinal fluid. However, patients may complain that persistent decrease in contrast sensitivity and multifocal electroretinogram (ERG) in an area of resolved subretinal fluid may continue to show lower amplitudes compared to neighboring previously uninvolved retina.
Figure 9.1
Acute CSR RE. (A) FAF showing hypoautofluorescence corresponding to the area of SRF on OCT. (B) IR photograph and corresponding OCT scan (green arrow) indicating detachment of the neurosensory retina at the macula and fluid accumulation in the subretinal space. RE , right eye; FAF , fundus autofluorescence; SRF , subretinal fluid; OCT , optical coherence tomography; IR , infrared.
- 2.
Recurrent CSC is diagnosed when the subretinal fluid recurs after evidence of complete resolution of an acute CSC. This recurrence may be in the same area of previous detachment or at a new location. There may be evidence of localized pigmentary changes of previous CSC in the same or the contralateral eye. The FA may show leak(s) from the same area or elsewhere. These eyes may also present with no evidence of subretinal fluid but will have telltale evidence of focal RPE changes of previous CSC. At this point, they may be termed as inactive CSC. Approximately 30% of patients may already have evidence of focal RPE changes due to past CSC in the contralateral eye ( Fig. 9.2 ). Therefore, although it may be the first episode in one eye, the focal RPE changes in the other eye would ideally place these patients into the recurrent CSC group.
Figure 9.2
(A) FAF of recurrent CSR in the RE. The hyperautofluorescent dots correspond to punctate precipitates observed on clinical exam. (B) IR showing a well demarcated hyporeflective area, corresponding to the SRF. (C) Corresponding OCT scan (green arrow) showing an accumulation at the level of the RPE and irregularities of the photoreceptor layer.
- 3.
Persistent CSC is defined as persistent subretinal fluid from acute or recurrent CSC of more than 4 months duration with or without RPE changes. The elongated outer segments may be seen as an area of hyperautofluorescence at this stage.
- 4.
Chronic CSC is characterized by diffuse RPE changes with or without subretinal fluid ( Fig. 9.3 ). The subretinal detachment is usually narrow and may cover a wider area of the fundus. There may be tracks of subretinal fluid from the macula or the optic disc. The retinal pigment epitheliopathy may be widespread and may show areas of both hyper- and hypoautofluorescence as the RPE cells progress from lipofuscin-laden cells to atrophy. The visual impairment is more profound at this stage. These eyes may become so chronic that they may present with cystoid macular edema, bullous retinal detachments or fibrinous subretinal fluid. They may also have multifocal PEDs.
Figure 9.3
Chronic CSR with RPE changes. (A) FAF. Diffuse RPE damage originating from the optic disc with coexisting hyperautofluorescence and granular hypoautofluorescence. (B) The IR image shows an irregular background at the macular level, and OCT scan illustrates SRF and hyperreflective intraretinal dots.
Evolution of CSC
The most frequent outcome of acute CSC is complete resolution of the subretinal fluid without any RPE changes. However, a proportion of acute CSC may progress to persistent or recurrent CSC. Progression of a single episode of acute CSC to the chronic form of diffuse epitheliopathy is rare.
Diagnosis
Ocular Symptoms
Fovea-involving serous detachment is usually symptomatic. Patients may complain of a central blur, micropsia, or difficulty with reading using current spectacle refraction.
Multimodal Imaging of CSC
Our understanding of CSC has increased with the availability of multimodal imaging. Previously, we defined CSC into acute and chronic based on the presence or absence of leak on FA. However, the availability of optical coherence tomography (OCT) and fundus autofluorescence (FAF) and serial examinations with these noninvasive tests have enabled us to understand the natural history and evolution of the subtypes of CSC. In addition, indocyanine-green (ICG) angiography and OCT have also changed our focus on the pathogenesis of CSC from the RPE to the choroid as the area of primary insult. Multimodal imaging is also very useful in assessing treatment response and diagnosis and management of complications such as polypoidal choroid vasculopathy (PCV) or choroidal neovascularization (CNV) ( Fig. 9.4 ).
OCT is the most commonly used diagnostic tool. Acute CSC is typically seen as a well defined serous retinal detachment and may be associated with a PED. The elongated outer segments of the photoreceptors are evidence of healthy photoreceptors attempting to shed their outer segments to the RPE. RPE microrip in the location of a fluorescein leakage may be seen in some patients. Small RPE bumps may be seen in raster spectral domain OCT (SD-OCT) scans that may be sign of early RPE decompensation. These changes may also be seen in fellow eyes. In more chronic cases, SD-OCT may also show small hyperreflective foci in and around the neuroretinal detachment and the choroid. These are postulated to shed photoreceptor outer segments in the subretinal space, accumulations of fibrin or lipid, or macrophages. In the choroid, these foci may represent chronicity and an inflammatory response to the diseased or dead RPE cells. In chronic cases, the amount of subretinal fluid is also limited to a shorter height of the neuroretinal detachment compared to eyes with acute CSC and the outer retinal layers may be disrupted or even absent. The disruptions of the ellipsoid zone correlate with visual acuity outcomes. In addition, both higher and lower subfoveal retinal thickness compared to control eyes is associated with poor visual prognosis.
Significant focus has been recently placed on enhanced depth imaging (EDI) scans that characteristically show a thickened choroid in this condition. Studies with swept-source OCT (SS-OCT) have shown a thickening of deeper choroidal layers composed by the larger vessels and a thinning of the inner choroidal layers. However, other conditions that mimic CSC such as PCV, pachychoroid, and even vitelliform maculopathy may also present with thickened choroid, and so multimodal imaging should be done to confirm the diagnosis ( Table 9.1 ).
| Acute CSR | Chronic CSR | Polypoidal Choroidal Vasculopathy | Pachychoroid Neovasculopathy | Vitelliform Maculopathy | |
|---|---|---|---|---|---|
| Gender | M>F | M=F | F>M | Not known | M>F |
| Fundus | Serous detachment | Retinal pigmentary changes with or without subretinal fluid, tracts | Orange nodules, hemorrhage, exudative detachment of retina and RPE | No tessellation of fundus, no drusen | Bilateral, gray-yellowish round-oval shaped lesion, central pigmented spot, laminar drusen, exudative macular detachment mildly elevated, 1/3–1/2 DD |
| SD-OCT | Subretinal detachment with or without pigment epithelial detachment; subretinal deposists; thick choroid | Outer retinal disruption; subretinal fluid, pigment epithelial detachment; double layer sign; thick choroid | Subretinal fluid; cysts, lipid deposits, PED, double layer sign, choroidal vessel dilation (focal or diffuse) | Subretinal fluid | Yellowish material under sensory retina, above RPE, foveal thinning |
| Fluorescein angiography | Focal or multifocal points of leakage; smoke-stack or ink-blot; pooling in PED | Window defects with or without point leaks | Discrete hyperfluorescence | Ill-defined late hyperfluorescence easily mistaken for choroidal neovascular complex | Early hypofluorescence, late hyperfluorescence ring |
| Indocyanine angiography | Hyperpermeability of choroidal vessels | Hyperpermeability of choroidal vessels | Early nodular hyperfluorescence, late nodular hyperfluorescence, and punctate hyperfluorescence | Hyperpermeable choroidal vessels | No changes |
FA characteristically shows a single pinpoint leak at the level of the RPE in acute CSC. Some patients may present with multiple pinpoint leaks or a smokestack fluorescein pattern. Window defects on FA are very useful signs of previous asymptomatic CSC in the fellow eye or in the same eye. In chronic CSC, diffuse epitheliopathy shows up as window defects interspersed with pinpoint leaks. In addition, RPE pigment clumping and tracts of subretinal fluid either originating in the macula or the optic disc are evidence of chronicity.
ICG adds significant input on the extent of choroidal hyperpermeability. In mid-phase, there are often plaques of hyperfluorescent inner choroidal staining in both the posterior pole and the periphery. In addition, delayed choroidal filling and venous dilation have been reported.
CNV may present as a complication of CSC and should be suspected if CSC is associated with hemorrhage, exudates, and/or intraretinal cystoid spaces. These features may also be seen in PCV, and these polypoidal changes may coexist in eyes with chronic CSC. Cystoid spaces may also suggest chronicity of CSC. Both FA and ICG should be performed to assist the diagnosis of these cases.
FAF is a useful imaging tool for the diagnosis of chronicity of CSC. In acute CSC, FAF may be normal or show hypoautofluorescence, outlining the area of subretinal fluid ( Fig. 9.1 ). A darker area of hypoautofluorescence within the CSC correlates with the pinpoint RPE leak seen on FA. A homogenous hyperautofluorescence characteristically develops within the area of subretinal fluid over months, accumulating along the borders of the detachment and usually disappears with resolution of subretinal fluid in acute CSC. Sometimes, the hyperautofluorescent area may be stippled with punctate hyperautofluorescence that corresponds to punctate precipitates observed on clinical exam. In chronic CSC, hypoautofluorescence abnormalities reflect areas of chronic RPE damage or areas of active serous detachment and may present with both a granular or confluent hypoautofluorescence. Most phenotypes of chronic CSC show both hypoautofluorescence and hyperautofluorescence corresponding to areas with different degrees of RPE damage ( Figs. 9.3 and 9.4 ).
The tracts are typically hyperautofluorescent when the fluid first occurs ( Fig. 9.5 ), but then become increasingly hypoautofluorescent due to RPE atrophy.
Visual Functions in CSC
In acute CSC, despite being symptomatic, visual acuity may remain at Snellen 20/20. Both microperimetry and multifocal ERG are more sensitive tools and show good correlation between visual function deficit and the anatomical location of subretinal fluid. Most studies evaluating visual function show that complete recovery to normal levels of retinal sensitivity is slow. These observations are consistent with the reports on fewer cones per square millimeter in resolved acute CSC than in controls in adaptive optics even in eyes with a single acute episode and preserved ellipsoid layer.
Pathophysiology
The pathophysiology of CSC remains poorly understood. However, advances in imaging have pointed us in the direction of the choroid as being the primary tissue involved in CSC. A thickened choroid on EDI scans and hyperpermeable choroidal vessels on mid-phase ICG have paved the way to the concept that CSC is a choroidal disease with secondary RPE changes. Hyperpermeable choroidal vessels are thought to produce increased tissue hydrostatic pressure that may consequently result in the formation of PED and RPE pinpoint leaks (microrips or RPE blowout) that result in the accumulation of subretinal fluid. The wider involvement of the choroidal hyperpermeability compared to the focal leaks on FA support other theories such as choroidal lobular ischemia. A thrombotic mechanism has also been reported based on elevated serum levels of plasminogen activator inhibitor-1, an inhibitor of physiologic fibrinolysis. Studies on choroidal blood flow indicate greater pulsation amplitudes with laser inferometer and increased subfoveal choroidal blood flow in chronic CSC eyes compared to controls.
The RPE changes seen in CSC are more visible with imaging techniques, and so the RPE was previously thought to be the area of primary pathology. However, it is becoming increasingly clear that the changes in RPE are sequelae of the choroidal hyperpermeability. The incompetence of the RPE may extend from pinpoint leaks due to focal RPE pump failure or loss of RPE cell polarity to large areas of window defects and pigmentary changes induced by chronic subretinal fluid accumulation. However, formes frustes of primary RPE defects may explain some cases where de novo CSC is associated with choroid of normal thickness. In these cases, laser photocoagulation of RPE pinpoint leaks results in total resolution of subretinal fluid. Focal RPE apoptosis due to epinephrine, steroids, or inflammation have also been suggested as possible explanations for this rare variant of CSC.
Treatment
To date, there has been no consensus regarding the optimal treatment option and the timing of treatment for CSC. Acute CSC is a self-limiting disease, and visual acuity usually returns to normal after the first episode. Therefore, despite the observations that cone numbers are reduced after acute CSC, treatment of acute CSC is deferred to at least 4 months since onset of symptoms of CSC to allow for the spontaneous resolution of the disease. Most imaging studies also suggest that 4-month timeline is quite accurate as that is when signs of chronicity become evident on imaging. Earlier treatment is only offered to individuals when rapid recovery is needed such as in cases with a history of poor visual acuity in the fellow eye and in recurrent cases. Recurrences occur in 15–50% of acute CSC cases within 2–13 years of follow-up. Subretinal fluid may also contain subretinal deposits. These deposits may also be observed after fluid resolution and is a poor visual prognostic indicator (worse than 20/40).
Advice to modify lifestyle aspects to limit the amount of stress faced by these individuals is advocated. Discontinuation of any corticosteroid treatment or switching to steroid-sparing agents, as well as management of endogenous hypercortisolism can improve visual symptoms and prompt the resolution of subretinal fluid and the response to treatment. Drugs that may trigger the development of CSC such as Sildenafil and other sympathomimetic drugs should be avoided. The treatment of H. pylori -positive cases may also be useful.
The challenge in the treatment of CSC lies in the correct balance between the risks and benefits of every treatment offered as patients frequently show good visual acuity despite persistent symptoms of poor contrast or color vision. To date, several treatments with different levels of evidence have been proposed and are reserved for chronic and recurrent cases of CSC, history of CSC in the fellow eye with poor visual acuity, and when rapid recovery is needed. However, eyes with chronic diffuse epitheliopathy with loss of ellipsoid layer are unlikely to benefit from any of the treatment options discussed below.
Laser photocoagulation targets the extrafoveal well defined focal angiographic RPE leaks, sealing its disruption, using the continuous or micropulse mode of yellow (577 nm) or green (514 nm) light. This treatment usually results in rapid resolution of subretinal fluid ( Fig. 9.6 A and B). However, the effect on visual acuity may not be significant. The mechanism of subretinal fluid resolution after laser photocoagulation remains unclear. The postulated mechanisms suggest that laser photocoagulation may seal focal defects in the RPE monolayer, promote a healing response and recruitment of healthy RPE cells, or directly stimulate pumping function of RPE cells near the leak. Laser photocoagulation does not influence the recurrence rates either, as it has no effect on the choroidal hyperpermeability. Reported side effects of laser treatment are iatrogenic CNV, paracentral scotoma, and laser scar enlargement.
Photodynamic therapy (PDT) with Verteporfin (Visudyne; Novartis, Switzerland) is frequently offered as a treatment in chronic and recurrent CSC because of its effects on the choroidal circulation. When stimulated by a wavelength of 693 nm in the presence of oxygen, Verteporfin releases free radicals in blood circulation that induce vascular narrowing, choriocapillaris hypoperfusion, and long-term reduction of choroidal congestion and leakage ( Fig. 9.7 ). It is also hypothesized that PDT tightens the outer retinal barrier.
The approved standard PDT dose of 6 mg/m² with a fluence of 50 J/cm² has been used in chronic CSC with subretinal fluid. ICG angiography after the treatment demonstrates a reduction in extravascular leakage from the choroid and a reduction of the choroidal thickness of 9–19% at 1 month and 12–21% at 3 months. Long-term complications following this treatment include choroidal nonperfusion, RPE atrophy, RPE rip, secondary CNV, and visual loss. The side effects of choroidal nonperfusion with standard PDT have encouraged the development of modified PDT regimens with a more acceptable safety profile in CSC.
Half-dose PDT (3 mg/m²) induces subretinal fluid resolution at 12 months with no side effects. In a recent meta-analysis of nine studies including 63 eyes with acute CSC and 256 eyes with chronic CSC, half-dose PDT improved best corrected visual acuity (BCVA), prompted central macular thickness reduction and subretinal fluid resolution at 12 months when compared to placebo. One-third-dose PDT (2 mg/m²) is not as effective as half-dose PDT in reducing subretinal fluid in chronic CSC.
Similarly to half-dose PDT, lower-fluence PDT (25 J/cm²) decreases subretinal fluid at 12 months with a safer profile compared to standard PDT. In the same meta-analysis reported above, half-fluence PDT is as effective as standard-fluence PDT, and both are superior anatomically when compared to intravitreal bevacizumab at 3 months, although no significant difference in visual acuity change is reported. In chronic CSC, half-fluence PDT significantly reduces risk of choriocapillaris ischemia compared to standard PDT.
Long-term results from large randomized controlled trials are needed to assess the effectiveness and safety of the different regimens of PDT in CSC and the comparative efficacy of half-fluence or half-dose PDT with micropulse laser.
Antivascular endothelial growth factor (VEGF) agents have been evaluated for chronic CSC based on the hypothesis of increased VEGF expression due to choroidal hyperpermeability, even though increased VEGF ocular levels have not been detected. In a recent meta-analysis in acute and chronic CSC, intravitreal bevacizumab did not significantly improve visual acuity and central macular thickness reduction at 6 months when compared to observation, PDT, or laser photocoagulation. Ranibizumab and aflibercept have both been used in the treatment of this condition, but the results remain uncertain and further evidence is needed to support the evidence of their efficacy. Anti-VEGF therapy is a well established treatment for CNV secondary to CSC.
The influence of raised endogenous cortisol levels and the role of corticosteroids in the development of the disease have prompted the role of steroid antagonists in the management of CSC. Glucocorticoids have an affinity for mineralocorticoid receptors, and CSC may be caused by an overexpression of these mineralocorticoid receptors. Intravitreal injection of aldosterone or high dose of glucocorticoid shows an increased expression of ion and water channels on the outer limiting membrane in animal models and human Müller glial cell lines and the accumulation of fluid in the subretinal space. These changes were associated with vasodilation and leakage of the choroidal vasculature and increased choroidal thickness. Blocking aldosterone upregulated potassium channels in the choroidal endothelial cells and prevented aldosterone-induced choroidal thickening.
Spironolactone and eplerenone are both aldosterone antagonist agents that are approved by the Food and Drug Administration for heart failure. Spironolactone has higher binding effect to mineralocorticoid receptors but also possesses more antiandrogen effects compared to eplerenone. Both agents have been investigated in nonresolving CSC and have been found to be effective in reducing subretinal fluid, macular thickness, and choroidal thickness in small studies in the short term ( Fig. 9.8 ). However, further evidence is required to assess the role of mineralocorticoid receptor antagonist as a target for CSC therapy.
