PEER REVIEWED
Update on the Diagnosis and Treatment of CSC
Management of a potentially sight-threatening disease
ALANNA NATTIS, DO • ROBERT JOSEPHBERG, MD
Central serous chorioretinopathy (CSC) is an idiopathic, often bilateral (although asymmetric) condition characterized by the development of a well-circumscribed serous detachment of the sensory retina.1-3 The detachment results from altered barriers and deficient pumping function at the level of the retinal pigment epithelium, although the primary pathology may involve the choriocapillaris.1,3,4 Patients may develop acute or chronic CSC, the latter of which is characterized by lack of spontaneous resolution after four to six months, persistent macular leakage, diffuse accumulation of subretinal fluid, patchy RPE atrophy with pigmentary changes, frequent exacerbations, and poorer visual prognosis.1,2,5,6
Of eyes with acute CSC, 80% to 90% undergo spontaneous resorption of subretinal fluid within three to four months; visual recovery usually follows but may take up to one year.2,3 Mild metamorphopsia, faint scotomata, abnormalities in contrast sensitivity, and color deficits frequently persist.3 Some eyes have permanently reduced vision; 40% to 50% experience recurrence.1-3
Diffuse retinal pigment epitheliopathy (severe CSC) is rare but can occur. Some patients may have multifocal disease extending to the periphery or even subtotal serous bullous retinal detachments.3 Foveal attenuation, cystoid macular degeneration, and chronic damage to the photoreceptor layer can lead to vision loss.1
Chronic CSC is associated with choroidal neovascularization in 2% to 9% of patients.6,7 Development of CNV may stem from decompensation of the RPE with subsequent damage to Bruch’s membrane or alteration of the choroidal environment, secondary to chronic leakage from choroidal vessels and choriocapillaris inflammation.6,7 Duration of symptoms longer than five years and subretinal fibrosis have been identified as risk factors for marked reduction in vision.1
Alanna Nattis, DO, is chief ophthalmology resident, and Robert Josephberg, MD, is chief of the Retina Service at the New York Medical College Department of Ophthalmology. The authors report no conflicts of interest, financial or otherwise, in the publication of this article. Dr. Nattis can be reached via e-mail at asn516lu@gmail.com.
EPIDEMIOLOGY
CSC occurs most commonly in healthy men between 25 and 55 years old.1,2,3 The incidence of CSC is estimated to be one in 10,000; it is more common in whites, Asians, and Hispanics and rare in African Americans.3,8
Most patients are asymptomatic unless the macula is affected.3 Symptomatic patients complain of sudden onset of blurred/dim vision, micropsia, metamorphopsia, paracentral scotoma, decreased color vision, and rarely, migraine.3 Snellen visual acuity generally ranges from 20/20 to 20/200; the decreased acuity may be corrected with a hyperopic correction.3
Anecdotally, certain personality types have been associated with CSC, including the “type A” personality, as well as hypochondriasis, hysteria, and conversion neurosis.1,3,9 Stress has also been implicated as an etiologic factor.1,3,4
There are many theories arguing the underlying etiology/-ies and pathophysiology of CSC. Initial choroidal vascular compromise may lead to secondary dysfunction of the RPE.1,2,9,10 In the normal eye, there is constant elimination of fluid from the subretinal space, which helps to produce an adhesion force between the retina and RPE.11 If this adhesive functionality is lost, subretinal fluid accumulates, leading to CSC.1,10
Systemic associations with CSC include exogenous steroid use, endogenous hypercortisolism (eg, Cushing syndrome), organ transplantation, systemic lupus erythematosus, hypertension, sleep apnea, gastroesophageal reflux, use of psychopharmacologic medications, H. pylori infection, and pregnancy.2-4,9
Recent reports have emphasized the finding of increased choroidal thickness on optical coherence tomography, possibly indicating compromise of choroidal vessels as the cause.1,3,4,9 Leakage in the choroid may lead to serous RPE and neurosensory detachments (Figure).3,4,9
Figure. Spectral-domain OCT image of a patient with CSC, showing neurosensory retinal detachment.
PATHOPHYSIOLOGY
Multiple reports have demonstrated a strong association of both acute and chronic CSC with states of hypercortisolism.1,2,4,5,9 Notably, Yannuzzi et al reported on 50 cases of acute CSC compared with appropriate selected and matched controls: in every patient with CSC associated with corticosteroid use, there was resolution of macular detachment with discontinuation of the drug.13 Bouzas et al found that patients with CSC had significantly higher levels of cortisol than controls.2
Additionally, corticosteroids may sensitize choroidal blood vessels and the RPE to endogenous catecholamines.1,14 Glucocorticoid excess may produce increased capillary fragility and hyperpermeability, causing choroidal decompensation and fluid leakage in the subretinal space.2 Glucocorticoids also affect the production of nitric oxide, prostaglandins, and free radicals — all of which are factors important to the regulation of choroidal blood flow.2,9 Additionally, some patients may have a genetic predisposition to a dysfunctional RPE so that under the influence of endogenous/exogenous glucocorticoids, CSC develops.2
It has also been hypothesized that cortisol may directly damage the RPE cells and their tight junctions, delaying any reparative process in damaged RPE cells by suppressing the synthesis of extracellular matrix components and inhibiting fibroblastic activity.2 Corticosteroids have been shown to modify the electrophysiologic parameters of RPE function in vivo and in vitro, consistent with the inhibitory effects of corticosteroids on RPE fluid absorption.1,15
Overaction of mineralocorticoids and the use of mineralocorticoid receptor antagonists as treatment for CSC have also been highlighted.8 Glucocorticoids bind to both glucocorticoid and mineralocorticoid receptors.8 It has been found that aldosterone, a mineralocorticoid receptor activator, induces choroidal vessel dilation and leakage.8 Mineralocorticoid receptor antagonists have been shown to reverse this effect, thus supporting the hypothesis that CSC may result from excessive occupancy of mineralocorticoid receptors by glucocorticoids.8
Also under investigation is the role of cytochrome-P450 (CYP450) enzymes in CSC. This role has recently been highlighted with positive responses of CSC to rifampin (Rifadin, Sanofi, Bridgewater, NJ), a potent CYP450 enzyme inducer.5,11,13
CYP450 enzymes are essential for the metabolism of many medications, and they modify production of cholesterol, steroids, prostacyclins, and thromboxane A2 and the detoxification of foreign chemicals.16,17 They are predominantly expressed in the liver but also exist in the lung, small intestine, placenta, eye, and kidneys.17
It has been demonstrated that the ciliary body and RPE have the highest levels of activity of CYP450-dependent mono-oxygenases in the eye.15 This specialized location of the CYP450 isoenzymes in ocular tissues may be related to the metabolism of endogenous steroid hormones, which have been implicated in the development of CSC.15
Additional work has suggested a role for prostaglandins in the development of CSC, particularly while studying NSAIDs as treatment options.14 Previous studies have established the presence of prostaglandin activity in the RPE cells and retinal vasculature, because they have been reported to affect both retinal and choroidal circulation.14
DIAGNOSIS
CSC is a clinical diagnosis.3 Differential diagnoses for CSC include polypoidal choroidal vasculopathy, CNV (most commonly type 1 CNV), cavitary optic disc anomalies (associated with chronic/recurrent serous retinal detachment), choroidal hemangioma (can present with serous retinal detachment with focal increased choroidal thickness), and dome-shaped macula (forward bulge of the macula protruding within a posterior pole staphyloma, occasionally associated with pinpoint leakage on fluorescein angiography and increased subfoveal choroidal thickness).7,18
A workup is usually not necessary in the typical demographic; however, in severe cases, clinicians may consider additional tests.2,3 FA, OCT, fundus autofluorescence (FAF), and indocyanine green (ICG) angiography may be used to confirm diagnosis.
There are three characteristic FA patterns observed in CSC.3 The expansile dot pattern of hyperfluorescence is the most common: here, a focal hyperfluorescent leak appears early in the study and increases in size and intensity as the study progresses.3
The smokestack pattern refers to fluorescein leakage, in which there is an initial central spot of hyperfluorescence that spreads vertically and laterally in a shape resembling a plume of smoke.3 Although characteristic, this pattern is found in only 10% of cases.3 Rarely, there is a diffuse pattern, without a prominent leakage point.3
OCT is an excellent, noninvasive method to diagnose and monitor the resolution of subretinal fluid and pigment epithelial detachments in CSC.3 OCT can highlight subtle fluid accumulation beneath the sensory retina and RPE not evident on clinical exam or FA. Increased choroidal thickness may be well visualized using enhanced depth imaging OCT, as well as foveal thinning and cystoid macular degeneration.3,18
In addition, hyper-reflective dots may be seen in the retina and in the subretinal space; the number of dots (possibly composed of proteinaceous compounds, lipid, or fibrin) tends to increase with disease duration and is correlated with worse final VA.18
Disruption of the ellipsoid zone (junction between the inner and outer segments of photoreceptors) and thinning of the outer nuclear layer have been demonstrated in CSC; these developments also portend a poor visual prognosis.18
FAF is an imaging modality that exploits the naturally fluorescent properties of parts of the retina and RPE.3 In CSC, short-wave FAF shows hypoautofluorescence corresponding to the site of focal RPE leakage depicted on FA; central macular autofluorescence patterns are correlated with RPE abnormalities.3,9,18 Hyperautofluorescent material on the outer surface of the elevated retina has been hypothesized to represent the accumulation of shed photoreceptor outer segment.3,9
ICG angiography can show choroidal vascular abnormalities.3,9 In the early phase of the study, hypofluorescent areas are seen as a result of decreased filling of the choriocapillaris, which persists in the midphase and late phase.18
During the midphase, dilation of large choroidal veins is seen, which is correlated with atrophic or elevated areas of RPE.18 Geographic areas of hyperfluorescence with blurred contours appear, secondary to hyperpermeability of choroidal vasculature.18
In the late phase of the study, the previously seen hyperfluorescent areas evolve into persistent hyperfluorescent spots, wash out, or form hyperfluorescent rings secondary to centrifugal displacement of the hyperfluorescence.18
TREATMENT
Despite extensive advances made in the treatment of various macular disorders, ophthalmologists are still without an FDA-approved treatment for CSC.12,19,20 CSC is a difficult disease to investigate, especially because it typically resolves spontaneously.3
Thus, even if treated, it is difficult to be completely certain whether it was treatment or observation alone that caused resolution.3,12 Lack of understanding of the etiology and pathophysiology makes it unclear what the treatment target should be.12
Current treatment guidelines recommend observation in most cases.3 If fluid persists, treatment may be indicated, especially if serous detachment persists for more than three to six months, if there is recurrence in eyes with visual deficits from prior episodes, if there is a permanent visual deficit, if chronic signs develop, or if occupational/patient needs require prompt restoration of vision, stereopsis, or both.3
Multiple treatment modalities have been attempted for CSC, including laser photocoagulation, oral acetazolamide, topical NSAIDs, methotrexate, eplerenone, spironolactone, nadolol, H. pylori treatment, verteporfin photodynamic therapy (PDT; Visudyne, Bausch + Lomb, Rochester, NY), intravitreal injections of anti-VEGF agents, aspirin, antiglucocorticoid agents, and rifampin.1,3,5,9,12,18,19,21,22
Laser photocoagulation to extrafoveal sites of leakage can induce rapid remission; resorption of subretinal fluid may occur within several weeks of therapy.1,3,23 Watzke et al showed significantly more rapid resolution of subretinal fluid in treated vs untreated eyes; however, there was no improvement in VA in either group despite shorter disease duration (nor was there evidence that treatment altered recurrence rate).3,23 Patients should be counseled about possible adverse effects, such as induction of scotoma, increased risk of late CNV, and ineffectiveness in cases with diffuse RPE decompensation.12
Multiple studies have demonstrated success of both standard-fluence (600 mW/cm2) and low-fluence (300 mW/cm2) PDT, with resolution of subretinal fluid and visual improvement.1,2,3,9,13 Verteporfin is thought to release free radicals into the choroidal circulation, leading to vessel occlusion from endothelial vascular damage.18
Short-term choriocapillaris hypoperfusion and choroidal vascular remodeling decrease choroidal congestion, vascular hyperpermeability, and extravascular leakage.18 However, PDT is not benign — it may be associated with pigmentary change, RPE atrophy, choroidal ischemia, and secondary CNV.1,12
VEGF release from ischemic retinal and choroidal cells causes increased vascular permeability and edema.24 The rationale argued for using intravitreal anti-VEGF agents (eg, bevacizumab [Avastin, Genentech, South San Francisco, CA]), is that the drug penetrates to the retina and choroid, thus reducing active fluid leakage from both sites.1,9,24 However, there have been variable results published on the efficacy of bevacizumab for CSC.1,9
Several systemic medications have been studied for the treatment of CSC. Multiple case reports exist, but no large, randomized, controlled trials have been executed to evaluate a particular medication’s effect on CSC.
Acetazolamide was shown to have encouraging short-term results but no long-term benefit.1 Kurup et al studied the efficacy of methotrexate for CSC and found that 83% of patients treated had total resolution of subretinal fluid and associated visual improvement.1,21
Bousquet et al hypothesized that CSC was the result of overactivation of the mineralocorticoid receptor pathway in choroidal blood vessels.22 They found that the use of the mineralocorticoid receptor antagonist eplerenone (Inspra, Pfizer, New York, NY) effectively decreased subretinal fluid and improved vision in a small patient population.22 Similarly, Kapoor et al found that use of spironolactone (Aldactone, Pfizer) significantly decreased subretinal fluid in the majority of patients with CSC.10
Use of these medications requires careful monitoring because they may be associated with undesired progestational and antiandrogenic effects, such as gynecomastia, abnormal menses, impotence, changes in blood pressure, and electrolyte imbalances.8,18
Because glucocorticoids have been implicated in the development of CSC, inhibition of glucocorticoid activity has been suggested as potential treatment modality.5,11 Mifepristone (RU-486) is a glucocorticoid and progesterone receptor antagonist that inhibits cortisol-induced peripheral vasoconstriction.1,9 In a small study, it demonstrated a positive treatment response for patients with chronic CSC.1,9 This is not a standard treatment due to potential adverse effects, such as gastrointestinal upset, hypotension, vaginal bleeding, and syncope.1,9,25
Rifampin, an antibiotic, is a CYP450 (3A4) enzyme inducer and is believed to favorably alter the metabolism of endogenous steroids, leading to improvement in CSC manifestations.5,9,11,16,19,20 Packo et al demonstrated that rifampin therapy led to rapid resolution of subretinal fluid and improved vision in the majority of treated cases of CSC.11,20 Steinle et al found similar results within one month of treatment.5 Additionally, in a study published by Nattis et al, it was demonstrated that oral rifampin had 100% efficacy in reducing subretinal fluid and improving vision in patients with chronic CSC.16
It may thus be hypothesized that induction of the CYP450 (3A4) enzyme by rifampin increases the metabolism of endogenous steroids, leading to improvement of CSC manifestations and possibly improving the ability of the RPE function to pump out excessive subretinal fluid.5 However, it is important to monitor for potential adverse medication effects, such as rash, gastrointestinal upset, elevated liver enzymes, and hematologic abnormalities.19
CONCLUSION
The etiology and pathogenesis of CSC appear to be multifactorial and to result from a complex interaction of environmental and genetic factors.1,19 Although several studies have demonstrated promising treatment options, none thus far have been definitive.
If we are able to determine the role of different chemicals, hormones, and medications in the function of the RPE and the modulation of choroidal blood flow, we would have a better understanding of how to accurately and effectively design a treatment and to identify treatment targets for both chronic and acute CSC. As we continue investigation, the treatment of CSC may change from watchful waiting and late intervention to immediate and definitive medical therapy. RP
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