Central Serous Chorioretinopathy
|Central Serous Chorioretinopathy|
|Classification and external resources|
- 1 Disease Entity
- 2 Diagnosis
- 3 Management
- 3.1 Overview of Treatment
- 3.2 Medical Therapy
- 3.3 Surgical Management
- 4 Summary
- 5 Additional Resources
- 6 References
Central serous chorioretinopathy (CSCR) is the fourth most common retinopathy after age-related macular degeneration, diabetic retinopathy and branch retinal vein occlusion. CSCR typically occurs in males in their 20s to 50s who exhibit acute or sub-acute central vision loss or distortion. Other common complaints include micropsia, metamorphopsia, hyperopic or myopic shift, and reduced contrast sensitivity and color saturation. No underlying pathophysiologic mechanisms have been proven, but CSCR is thought to occur due to hyper-permeable choroidal capillaries, which, in association with retinal pigment dysfunction, cause a serous detachment of the neurosensory retina. Recurrence occurs in about 31% patients with CSCR.
The disease was first recognized by Albrecht von Graefe in 1866 and was named central recurrent retinitis. Since then it has been reported under a variety of names such as idiopathic flat detachment of the macula by Walsh et al, central angiospastic retinopathy by Gifford et al, and central serous retinopathy by Straatsma et al. The condition was named Idiopathic central serous chorioretinopathy by Gass et al in 1967.
CSR causes unilateral vision loss usually in males due to development of sub-retinal fluid, typically between the ages of 20 and 50 years old. The differential diagnosis for sub-retinal fluid is broad and encompass all disease entities that can cause macular neurosensory detachment. These entities include neovascular age related macular degeneration/polypoidal choroidal vasculopathy, myopic choroidal neovascular membrane, choroidal tumor, hypertensive choroidopathy, leukemic choroidal infiltration, choroidopathy due to multiple myeloma, retinal venous occlusion, unilateral acute idiopathic maculopathy, inflammatory conditions like posterior scleritis or Vogt-Koyanagi-Harada disease, optic nerve pit, and rhegmatogenous retinal detachment. Indeed, cases of bullous CSCR, where a significant amount of sub-retinal fluid is found, can be mistaken for rhegmatogenous retinal detachments. In both acute and chronic cases that have resolved, the only clue that may be present on examination is macular retinal pigment epithelium (RPE) mottling. By definition, the patient’s retinal detachment cannot be due to another primary process. If suspected, those diagnoses should be ruled out. A thorough history, detailed exam and appropriate imaging and laboratory tests can help delineate between these diagnoses.
Although exact mechanisms behind CSCR have not been elucidated, many associations have been found. Steroids, both endogenous and exogenous, have the strongest known association with CSR. Garg and colleagues found that patients with acute CSCR have higher levels of endogenous cortisol compared to age-matched controls. Other studies have shown that exogenous steroid use for treatment of unrelated conditions is also associated with CSCR.   In patients with CSCR, the odds ratio of systemic steroid use was found to be 37.1 (95% confidence interval (CI), 6.2–221.8). Exogenous hypercortisolism has been induced by any route: intravenous, cutaneous, or nasal spray. Furthermore, CSCR’s association with having a Type A personality seems logical given known increased glucocorticoid release with stress. It is therefore the only 'inflammatory' choroiditis, not proven to be associated with infection that is precipitated or worsened by glucocorticoids.
Increased choroidal vascular permeability is postulated to occur as a response to epinephrine mediated vasospasm that is potentiated by steroids, leading to choroidal ischemia and vascular hyper-permeability.  Oncotic pressure in the choroidal space, combined with RPE dysfunction, leads to accumulation of fluid in the sub-retinal space.   The currently theorized role of the RPE involves the increased hydrostatic pressure in the choroid causing “micro-rips or blowouts” in the RPE, jeopardizing its barrier function.
Other associations to CSCR have been described. Cotticelli determined that the odds ratio of Helicobacter pylori in CSCR patients is 4.6 (95% CI 1.28–16.9) and other prospective studies revealed that H. pylori infection was present in 53% and 69% of patients with CSCR. Rahbani-Nobar demonstrated that treating the H. pylori infection is associated with more rapid sub-retinal fluid resorption. Methylenedioxymethamphetamine (MDMA), also known as ecstasy, and sildenafil have also been associated with development of CSCR.
The RAF/MEK/ERK pathway is an intracellular cell signaling pathway that is stimulated by growth factors and results in cell division. Medications that inhibit this pathway include sorafenib and vemurafenib. Sorafenib is used to treat hepatocellular carcinoma and renal cell carcinoma while vemurafenib is used to treat melanoma and non-Hodgkin’s lymphoma. Use of MEK/ERK inhibitors has been associated with acute CSCR that resolves with cessation of medication.
Central serous chorioretinopathy is associated with increased sympathetic activity, and obstructive sleep apnea is known to cause such increases. Yavas and colleagues showed in a prospective study that 61% of patients with CSCR had underling obstructive sleep apnea diagnosed with overnight polysomnography.
Epidemiology and Risk Factors
Most patients who present with CSCR are between the ages of 28 to 68 years with an average age of 43 years. Those who are over 50 years of age are more likely to have bilateral disease (50%) with RPE loss and choroidal neovascularization compared to those less than 50 years of age (28.4%). CSCR tends to affect males (9.9/100,000) about six times more than females (1.7/100,000).3 Similar prevalence of CSCR was noted in Caucasian, African American, and Asian populations. Studies have suggested that there may be a temporal predominance in spring months (March, April, May June) but the results were not statistically significant.
Weenink and colleague studied the family members of 27 patients with bilateral CSCR and found that in 52% of the families, at least one relative was affected. Of the studied family members, 27.5% suffered from chronic CSCR in at least one eye, suggesting a genetic predisposition to central serous chorioretinopathy. Most CSC cases are diagnosed in patients with no refractive error or mild hyperopia. Common risk factors, apart from the ones described in “etiology” include pregnancy, antibiotic use, alcohol use, untreated hypertension, and obstructive sleep apnea. Fok found that patients with psychiatric disorders such as depression are more likely to have a recurrence.
While no pathophysiologic cause of CSCR has been identified, epidemiology, hormonal studies, fluorescein angiography (FA), and optical coherence tomography (OCT) imaging have elucidated some of the pathologic manifestations.
While RPE dysfunction was thought to be the primary etiology of CSR in the past, recent studies along with the advent of new imaging suggests that RPE dysfunction may not be the cause but rather a sequelae of CSCR. Microscopic evaluation of iatrogenic CSCR in monkeys showed damage and defects endothelial cells of choriocapillaries with overlying degeneration of RPE cells and indocyanine green angiography studies in humans have demonstrated choroidal staining, suggesting increased capillary permeability to be the cause of CSCR.  Indocyanine green video-angiography shows choroidal hyperpermeability, irregular dilation of choroidal veins, and choroidal lobular ischemia.Foveal or peri-foveal leakage can be present in 50% of eyes. Prunte and Flammer demonstrated the presence of delayed arterial filling and ischemia followed by capillary and venous congestion in areas of the choroid affected by CSCR, either or both of which could be the mechanism for increased permeability. Auto-fluorescence studies show that in acute CSCR, there is increased auto-fluorescence in the area of leakage suggesting elevated metabolic activity of the RPE. However, in chronic CSCR, there is decreased or absent auto-fluorescence suggesting reduced metabolic activity of the RPE and secondary RPE damage. Hypofluorescent or hyperfluorescent fundus autofluorescence is attributed to changes in subretinal and RPE lipofuscin content. Enhanced depth imaging OCT of the choroid shows thickening of the choroid in patients with CSCR, which further supports the idea of vascular congestion and elevated hydrostatic pressure.
While pathophysiologic anatomy has been shown, the actual cause is still in speculation. Active CSCR has been correlated with elevated levels of endogenous and exogenous corticosteroids. Intravitreal injections of corticosteroids and aldosterone in rats leads to choroidal enlargement, suggesting that CSR associated vasculopathy may in part be due to activation of the mineralocorticoid receptor, which has more recently become a new target for treatment.  
Some mechanisms of action of steroids on the choroid and RPE include potentiation of adrenergic hormones, hypertension,  and altered ion transport in RPE cells. Glucocorticoids regulate the expression of adrenergic hormones and receptors, and therefore, said hormones may contribute to the pathophysiology of CSCR. A study showed that patients with CSCR have increased sympathetic activity and decreased parasympathetic activity based on tests of autonomic activity and reactivity. Other theoretical causes of choriocapillary hyper-permeability and RPE damage include epinephrine, ischemia, inflammatory including H. pylori infection, and hormonal causes. Epinephrine and norepinephrine has also been shown to be elevated in patients with active CSCR.
Foveal attenuation, chronic macular edema, and damage of the foveal photoreceptor layer have been reported as causes of visual loss in CSC.
Typically, patients complain of central vision loss or distortion with a possible central scotoma. Other common complaints include micropsia, hyperopic or myopic shift, and reduced contrast sensitivity and color saturation. Patients are generally healthy, however hypercortisolism should be ruled out, especially in chronic cases. Type A personality, abdominal pain from H. pylori, and pregnancy, MDMA use, and sildenafil use may be associated as described above.
On refractive exam, best corrected visual acuity (BCVA) can range from 20/20 to 20/200.1 Visual loss can partly be attributed to a hyperopic shift caused by the anterior displacement of the macular photoreceptors. Folk recorded that patients with CSCR can have minimal afferent pupillary defects and reduced critical flicker-fusion thresholds, both of which are the first to improve with resolution of the CSCR episode. Ophthalmoscopy typically discloses a round or oval serous macular detachment without hemorrhage, with small, yellow sub-retinal deposits in the area of neurosensory detachment. At times, the sub-retinal fluid may contain grey-white serofibrinous exudate. A RPE detachment may be seen on OCT in up to 63% of eyes and if it encircles the detachment, a “halo” may be seen around the detachment. Macular RPE mottling can be found in cases of recurrent or chronic CSCR. Ophthalmoscopy may show a range from mono- or paucifocal RPE lesions with prominent elevation of the neurosensory retina by clear fluid - typical of cases of recent onset - to shallow detachments overlying large patches of irregularly depigmented RPE.
Diagnostic Procedures and Tests
The diagnosis of CSCR can be made clinically but diagnostic tests such as FA and OCT are often performed to rule out other differential diagnoses and guide treatment. Typical fluorescein angiography include the ink blot appearance (31%), smokestack pattern (12%), and minimally enlarging spot (7%). Fluorescein angiography is also used to rule out sub-retinal neovascularization.
OCT can be helpful in cases of CSCR that show equivocal signs on clinical exam, and can show detailed findings not appreciable on exam such as small PEDs and hyper-reflective, fibrinous sub-retinal fluid. Furthermore, OCT can be helpful in following chronic CSCR patients to track resolution. Enhanced depth imaging OCT technology has been able to identify choroidal thickening bilaterally, even in patients with unilateral CSCR.
Fundus autofluorescence (FAF) photography (488nm) provides functional images of the fundus by employing the stimulated emission of light from endogenous fluorophores, the most significant being lipofuscin. In the case of RPE cells, the buildup of lipofuscin is related in large part to the phagocytosis of damaged photoreceptor outer segments and altered molecules retained within lysosomes, which eventually become lipofuscin . Moreover, near infrared fundus autofluorescence (NIA) imaging (787nm) is able to study the RPE, the choriocapillaris, and choroid, by determining melanin fluorescence .
Natural Progression and Prognosis
Acute CSCR is a self-limited condition with resolution of neurosensory retinal detachment and generally good recovery of visual acuity within three months. Of note, recurrences of CSCR have been documented in up to 50% of patients within one year. Fifteen percent of patients may exhibit symptoms and show persistent sub-retinal fluid for greater than 6 months and thus, are diagnosed with chronic CSCR. Limited studies investigating prognostic markers found that outer nuclear layer thickness at the fovea correlates with BCVA in patients with resolved CSCR and that total foveal thickness correlates with BCVA in patients with chronic CSCR with symptoms for 21.8 (7-36) months.
Overview of Treatment
As CSCR usually resolves spontaneously within 2 to 3 months, observation is currently standard of care for newly presenting cases. Risk factors should always be addressed. If present, exogenous steroid use should be discontinued or limited and endogenous hypercortisolism should be managed. Patients with Type A personality should be addressed by lifestyle modification and stress management, however there is no high quality data to support this. The presence of H. pylori infections should be investigated and treated as needed. For chronic CSCR, recurrent CSCR, and acute CSCR in functionally monocular patients, treatment should be discussed.
As mineralocorticoid receptor action has been implicated in the pathogenesis of CSCR, Zhao and Bousquet treated patients with eplerenone, a mineralocorticoid antagonist, for five weeks and found a significant and rapid improvement of retinal detachment with improvement in mean central macular thickness, sub-retinal fluid height, and visual acuity that persisted at five month follow up. Similar studies have supported this potential treatment and have shown greater efficacy in patients with chronic CSCR. Spironolactone, another anti-corticosteroid, has been shown to decrease sub-retinal fluid, decrease central retinal thickness, and increase BCVA in patients with chronic CSCR. A prospective, randomized, double-blind, and placebo-controlled study with a crossover design showed a reduction in sub-retinal fluid and sub-foveal choroidal thickness. A prospective, randomized, placebo controlled trial studying the use of eplerenone for chronic CSCR found modest gains in BCVA and improvement in sub-retinal fluid height (in press).
Mineralocorticoid antagonists may raise serum potassium level, especially in patients with congestive heart failure and chronic kidney disease. Hyperkalemia can manifest as fatigue, muscle weakness, palpitations, and arrhythmias. Prior to starting a medication in this class, reviewing medical history and discussing with the primary care doctor is recommended. Baseline serum potassium levels and renal function should be established, such as with a basic metabolic panel. Initiation of medication should be postponed or avoided if serum potassium concentration is >5.5 mEq/L, creatinine clearance is <50 mL/min, or serum creatinine is >2 mg/dL in men and >1.8 mg/dL in women. Other anti-corticosteroid treatments have also been studied. Finasteride, a 5a-reductase inhibitor with anti-androgenic properties, was shown to improve central macular thickness (CMT) and sub-retinal volume in a study of five patients but these findings reversed when the drug was discontinued. Mifepristone, an anti-progesterone and anti-glucocorticoid agent, was shown in a study of 16 patients to improve Snellen visual acuity. Rifampin, an anti-tuberculous drug and cytochrome P450 3A4 inducer, accelerates the metabolism of steroids and has been shown to benefit patients with CSCR. A case study of patient with multifocal CSCR with persistent SRF of two years who was treated with rifampin showed complete resolution of SRF in one month. Side effects of rifampin include orange-colored body fluids, anorexia, and hepatotoxicity.
Melotonin is an endogenous neuromodulator that has been linked to circadian cycles and sleep regulation, aging, and neuroprotection via an antioxidant mechanism.61 Melotonin also has an inhibitory effect on corticosteroids and has a minimal side effect profile, making it a target for CSCR treatment. A study of eight patients showed significant improvements in CMT (87.5%) and BCVA (100%) compared to controls. Furthermore, no side effects were observed.
Mineralocorticoid antagonists may raise serum potassium level, especially in patients with congestive heart failure and chronic kidney disease. Hyperkalemia can manifest as fatigue, muscle weakness, palpitations, and arrhythmias. Prior to starting a medication in this class, reviewing medical history and discussing with the primary care doctor is recommended. Baseline serum potassium levels and renal function should be established, such as with a basic metabolic panel. Initiation of medication should be postponed or avoided if serum potassium concentration is >5.5 mEq/L, creatinine clearance is <50 mL/min, or serum creatinine is >2 mg/dL in men and >1.8 mg/dL in women.
Low-dose aspirin has been explored in treating CSCR. Elevated levels of plasminogen activator inhibitor 1 (PAI 1), a marker of platelet aggregation, have been linked to steroid use and have been measured in patients with CSCR.A prospective study of 113 eyes with CSCR showed faster improvement in BCVA compared to control.
Helicobacter pylori treatment
A randomized control trial (RCT) of patients tested positive for H. pylori studied the effect of treatment of H. pylori treatment of chronic CSCR. This study found that patients treated for H. pylori infection has faster resolution of sub-retinal fluid (9 weeks) versus control (11 weeks) but no change in BCVA. A case series of treated biopsy positive H. pylori patients showed resolution of SRF in 14 of 15 patients. However, another RCT tested the same hypothesis and found no statistical change in resolution of SRF and BCVA. Dang and colleagues did find a statistically significant improvement in foveal sensitivity in the H. pylori treatment group. These studies with contradictory results indicate that larger RCTs are needed to elucidate the clinical significance of H. pylori treatment on resolution of CSCR.
The role of anti-adrenergic therapy for CSCR is unclear. A small case series in 1993 described 6 patients with CSCR treated with metoprolol, a non-selective beta-blocker, who improved symptomatically and had partial or complete resolution of retinal detachment. Other studies have shown that both metipranolol (non-selective beta blocker) and metoprolol tartrate (selective beta-1 blocker) both induced remission of CSCR. In contrast, a randomized controlled double blind study examining the impact of beta-blockade with metipranolol over the course of acute CSCR found no difference in the course of acute CSCR between the beta-blocker group and control group. Since this RCT examined patients with acute CSCR, the conclusions are not readily applicable to patients with chronic CSCR. Although anti-adrenergic agents have been shown to be beneficial in CSCR in some studies, this therapy has not been widely implemented in treatment.
Intravitreal anti-VEGF therapy
The use of anti-vascular endothelial growth factor (VEGF) agents are based on the idea that VEGF levels may be elevated due to the choroidal pathology. However, studies have shown that VEGF levels are similar between CSCR patients and control patients.A meta-analysis of four controlled studies with patients treated with intravitreal bevacizumab (IVB) compared to control showed no improvement in BCVA or CMT at six months.73 Of note, patients with coexisting choroidal neovascularization and CSCR (confirmed on FA or OCT-angiography) do benefit from anti-VEGF therapy.
Argon focal laser photocoagulation provides utility in patients with a defined leakage point on fluorescein angiography that is not foveal or perifoveal. Due to its destructive nature, side effects include permanent scotoma, scar formation, and laser induced choroidal neovascularization Several studies have shown more rapid reabsorption of sub-retinal fluid in eyes with CSCR, but this does not appear to affect final visual acuity or risk of recurrence.
Photodynamic therapy (PDT) with verteporfin, a photosensitizer that accumulates in vessels and helps target therapy, causes endothelial damage and vascular hypoperfusion to inhibit the choroidal hyperpermeability seen in CSCR. Several reports and studies have demonstrated that PDT can be used in chronic CSCR patients to decrease SRF and improve BCVA. Unfavorable side effects, which include choroidal ischemia, RPE atrophy, RPE rip, retinal thinning, and secondary choroidal neovascular membrane (CNVM) have led to the development of safer versions of PDT, which are reduced-dose PDT and reduced-fluence PDT. Bae demonstrated that reduced-fluence PDT was superior to intravitreal ranibizumab in a RCT for improving BCVA and central retinal thickness. Half dose PDT versus half fluence PDT was compared in eyes with chronic CSCR, demonstrating that half dose PDT treatment allowed for faster SRF resolution and decreased recurrence compared to half-fluence PDT. Further studies titrating dosage of verteporfin and laser fluence are needed to more precisely compare safety profiles and efficacy. PDT necessitates the avoidance of physical activity after treatment.
Subthreshold Micropulse Laser Photocoagulation
The traditional argon laser is thought to work by activating the RPE cells at the periphery of the laser burn that are affected but not destroyed by thermal energy. Subthreshold micropulse laser (SML), also known as “high density, low-intensity” laser, uses subthreshold energy that that selectively targets RPE cells without inducing chorioretinal damage or scaring. This allows exposure to a large area of RPE cells, which then down-regulate cytokine production and inflammation. The laser is applied in pulses in a frequency that allows heat dissipation to prevent structural heat damage to the retina. Unlike conventional laser, SML can be safely applied to the fovea. Fluorescein angiography and indocyanine green (ICG) angiography can be supplemented to determine areas of treatment. Several wavelengths of pulse lasers including green 532 nm laser, yellow 577 nm laser, and infrared 810 nm laser have been used to target different cells in the retina. For example, the 577 nm yellow laser has the highest hemoglobin to melanin ratio making it the best SML for vascular structures. Furthermore, the 577 nm laser allows for more concentrated light with a lower power compared to the 810 nm laser. Several uncontrolled studies have shown the effectiveness of 810 nm and 577 nm SML therapy. In a RCT, chronic CSCR patients treated with 810 nm SML showed significantly better BCVA, lack of scotoma, and improved contrast sensitivity compared to patients treated with argon laser photocoagulation. A study comparing 577 nm SML with PDT in the treatment of chronic CSCR showed a better treatment response in the SML group and greater improvement in central retinal thickness in the SML group. In addition to the superior outcomes with SML over PDT, SML avoids the potential side effects of PDT such as RPE atrophy, choroidal neovascularization, choriocapillary ischemia, and transient reduction of macular function. Similar to PDT, there is no visible tissue response during treatment, which is why SML treatment guidelines for optimal laser, energy, and duty cycle parameters is a much needed area of investigation.
CSCR is a multifactorial disease without a known mechanism of action. It is most strongly associated with hypercortisolism and is hypothesized to occur because of choroidal hyperpermeability and secondary RPE dysfunction leading to serous retinal detachment. While acute CSCR can be observed and is self-resolving in most cases, progression to chronic CSCR warrants treatment. The mainstay of treatment is currently photodynamic therapy, however treatment with SML or mineralocorticoid antagonists such as eplerenone are gaining momentum.
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