Central Serous Chorioretinopathy


Background

Central serous chorioretinopathy (CSCR) is a disease in which a serous detachment of the neurosensory retina occurs over an area of leakage from the choriocapillaris through the retinal pigment epithelium (RPE). It is a self-limited macular disease marked by distortion, blurry vision, and metamorphopsia. Other causes for RPE leaks, such as choroidal neovascularization, inflammation, or tumors, should be ruled out to make the diagnosis. Choroidal neovascularization is also an uncommon complication of CSCR.

CSCR may be divided into 2 distinct clinical presentations. Classically, CSCR is caused by one or more discrete isolated leaks at the level of the RPE as seen on fluorescein angiography (FA). However, it is now recognized that CSCR may present with diffuse retinal pigment epithelial dysfunction (eg, diffuse retinal pigment epitheliopathy, chronic CSCR, decompensated RPE) characterized by neurosensory retinal detachment overlying areas of RPE atrophy and pigment mottling. Broad areas of granular hyperfluorescence that contain one or many subtle leaks are seen using FA.

CSCR most commonly occurs in males and is associated with psychosocial factors such as stress and type A personality and with corticosteroid exposure. It has a high rate of recurrence.

Treatment consists of observation, focal laser, reduced fluence photodynamic therapy, and mineralocorticoid antagonists.

Pathophysiology

Previous hypotheses for the pathophysiology have included abnormal ion transport across the RPE and focal choroidal vasculopathy. The advent of indocyanine green (ICG) angiography has highlighted the importance of the choroidal circulation to the pathogenesis of CSCR. ICG angiography has demonstrated both multifocal choroidal hyperpermeability and hypofluorescent areas suggestive of focal choroidal vascular compromise. Some investigators believe that initial choroidal vascular compromise subsequently leads to secondary dysfunction of the overlying RPE. [12]

Studies using multifocal electroretinography have demonstrated bilateral diffuse retinal dysfunction even when CSCR was active only in one eye. [3These studies support the belief of diffuse systemic effect on the choroidal vasculature.

Corticosteroids have a direct influence on the expression of adrenergic receptor genes and, thus, contribute to the overall effect of catecholamines on the pathogenesis of CSCR. Consequently, multiple studies have conclusively implicated the effect of corticosteroids in the development of CSCR. Carvalho-Recchia et al showed in a series that 52% of patients with CSCR had used exogenous steroids within 1 month of presentation as compared with 18% of control subjects. [4]

Daruich et al examined the role of the mineralocorticoid pathway in the pathophysiology of CSCR. Study in a rodent model led to the observation that overexpression of a mineralocorticoid receptor expressed in vascular endothelial cells can result in up-regulation of calcium-dependent potassium channel, which is associated with vasodilation. [5This association may suggest the therapeutic mechanism underlying treatment with mineralocorticoid antagonists.

Type A personalities, systemic hypertension, and obstructive sleep apnea may be associated with CSCR. [6The pathogenesis here is thought to be elevated circulating cortisol and epinephrine, which affect the autoregulation of the choroidal circulation. Furthermore, Tewari et al demonstrated that patients with CSCR showed impaired autonomic response with significantly decreased parasympathetic activity and significantly increased sympathetic activity. [7]

Helicobacter pylori infection has also been implicated in the pathogenesis of CSCR. Cotticelli et al showed an association between H pylori infection and CSCR. [8The prevalence of H pylori infection was 78% in patients with CSCR compared with a prevalence of 43.5% in the control group. The authors proposed that H pylori infection may represent a risk factor in CSCR. While still controversial, other groups have continued to pursue this hypothesis based on case series. [910Zavoloka et al also reported that treatment of H pylori infection decreased the duration and symptoms associated with CSCR. [11Can et al demonstrated that choroidal thickness increases with H pylori infection and then normalizes after treatment. [12However, others have found no association with choroidal thickness and H pylori infection. [13]

Epidemiology

Frequency

United States

Kitzmann et al reviewed the incidence of CSCR in Olmsted County, Minnesota. They evaluated the period from 1980-2002. They found the mean annual age-adjusted incidence of CSCR to be 9.9 cases per 100,000 population for men and 1.7 cases per 100,000 population for women. [14]

International

Liew et al reviewed the epidemiology of CSCR in Australia. They found an incidence rate of 10 cases per 100,000 population in men. The rate of CSCR in this study was 6-fold higher in men than in women. [10In the population-based Beijing Eye Study 2011, the estimated prevalence of CSCR in the Chinese population older than 50 years was 0.14%. [15]

Mortality/Morbidity

Serous retinal detachments typically resolve spontaneously in most patients, with most patients (80-90%) returning to 20/25 or better vision. Even with return of good central visual acuity, many of these patients still notice dyschromatopsia, loss of contrast sensitivity, metamorphopsia, or, rarely, nyctalopia.

Patients with classic CSCR (characterized by focal leaks) have a 40-50% risk of recurrence in the same eye.

Risk of choroidal neovascularization from previous CSCR is considered small (< 5%) but has an increasing frequency in older patients diagnosed with CSCR. [1617]

A subset of patients (5-10%) may fail to recover 20/30 or better visual acuity. These patients often have recurrent or chronic serous retinal detachments, resulting in progressive RPE atrophy and permanent visual loss to 20/200 or worse. The final clinical picture represents diffuse retinal pigment epitheliopathy.

Otsuka et al reviewed a subset of patients who presented with a severe variant of CSCR over a mean follow-up period of 10.6 years. [18These patients were characterized by multifocal lesions and bullous retinal detachments with shifting fluid and fibrin deposition. During the follow-up period, 52% of patients experienced recurrences of CSCR ranging from 1-5 episodes. However, 80.4% of eyes (n=46) returned to a visual acuity of better than 20/40 and 52% returned to a visual acuity of 20/20 or better. Eventually, patients reached a state of quiescent disease.

Tsai et al reviewed a population-based cohort of CSCR patients from the Taiwan national health insurance research database from 2000-2007. They identified CSCR as an independent risk factor for ischemic stroke. After adjusting for age, sex, and comorbidities, CSCR had a 1.56-fold increased risk of stroke compared with controls. [19Using this same database, patients with CSCR were also found to be at increased risk for rhegmatogenous retinal detachment (7.85 times) and central retinal vein occlusions (3.15 times). [2021]

Race

CSCR appears uncommon among African Americans but may be particularly severe among Hispanics and Asians. However, one study suggests that CSCR is underdiagnosed in African Americans, underestimating its prevalence in this group of patients. [22]

Sex

Classically, CSCR is most common in male patients aged 20-55 years with type A personality. This condition affects men 6-10 times more often than it affects women. However, as society has shifted, the prevalence of CSCR in women has increased. Spaide et al reported a male-to-female ratio of 2.6:1. [23]

Age

Patients may present with a later age of onset (>50 y). Spaide et al reviewed 130 consecutive patients with CSCR and found the age range at first diagnosis to be 22.2-82.9 years, with a mean age of 49.8 years. [23]

Changes in the presentation and demographics of CSCR are observed with increasing age at first diagnosis. Classically, patients tend to be male and present with focal, isolated RPE leaks in one eye.

Patients diagnosed at age 50 years or older are sometimes found to have bilateral disease, demonstrate a decreased male predominance (2.6:1), and show more diffuse RPE changes. Furthermore, these patients are more likely to have systemic hypertension or a history of corticosteroid use. [24These older patients are more likely to have choroidal neovascularization.

Prognosis

The overall prognosis of CSCR is relatively good. Up to 90% of patients return to 20/25 or better vision after a single bout of CSCR, though with mild residual symptoms. However, with multiple recurrent episodes and RPE decompensation, visual acuity changes. [18Development of choroidal neovascularization can also adversely affect the visual prognosis, although this is rare. [1617]

Serous retinal detachments typically resolve spontaneously in most patients, with most patients (80-90%) returning to 20/25 or better vision. [252627]

Patients with classic CSCR (characterized by focal leaks) have a 40-50% risk of recurrence in the same eye. [252728]

Even with return of good central visual acuity, many of these patients still notice dyschromatopsia, loss of contrast sensitivity, metamorphopsia, or nyctalopia. [25]

These patients often have recurrent or chronic serous retinal detachments, resulting in progressive RPE atrophy and permanent visual loss to 20/200 or worse. The final clinical picture represents diffuse retinal pigment epitheliopathy.

Risk of choroidal neovascularization from previous CSCR is considered small (< 5%) but has an increasing frequency in older patients diagnosed with CSCR. [1628 These patients can be treated with intravitreal injection of anti-VEGF agents, including aflibercept, ranibizumab, or bevacizumab.

Patient Education

Because of the concomitant risk of CSCR recurrence of and the small risk of choroidal neovascularization, patients with CSCR must be educated regarding the risk of choroidal neovascularization, which requires prompt intervention.

If possible, patients should avoid stressful situations. Patient participation in stress-reducing activities (eg, exercise, meditation, yoga) is recommended.

Recent evidence associates systemic hypertension with CSCR, but it is unknown as to whether careful control of systemic hypertension will reduce the incidence of CSCR.



History

Patients with central serous chorioretinopathy (CSCR) typically present with acute symptoms of visual loss and metamorphopsia (especially micropsia) in one eye. Other symptoms include decreased central vision and a positive scotoma.

The decreased vision usually is improved by a small hyperopic correction.

Other clinical signs include a delayed retinal recovery time following photostress, loss of color saturation, and loss of contrast sensitivity.

Physical

Clinical examination shows a serous retinal detachment but no subretinal blood. The neurosensory retinal detachment may be very subtle, requiring contact lens examination for detection. [28]

Pigment epithelial detachments, RPE mottling and atrophy, subretinal fibrin, and, rarely, subretinal lipid or lipofuscinoid flecks also may be seen. [29Choroidal neovascularization may develop after multiple episodes of CSCR.

Causes

Previous hypotheses for the pathophysiology have included abnormal ion transport across the RPE and focal choroidal vasculopathy. The advent of ICG angiography has highlighted the importance of the choroidal circulation to the pathogenesis of CSCR.

ICG angiography has demonstrated both multifocal choroidal hyperpermeability and hypofluorescent areas suggestive of focal choroidal vascular compromise. Some investigators believe that initial choroidal vascular compromise subsequently leads to secondary dysfunction of the overlying RPE. [30]

Type A personalities and systemic hypertension may be associated with CSCR, presumably because of elevated circulating cortisol and epinephrine, which affect the autoregulation of the choroidal circulation. [3132]

Studies using multifocal electroretinography have demonstrated bilateral diffuse retinal dysfunction even when CSCR was active only in one eye. This supports the belief of diffuse systemic effect on the choroidal vasculature. [3]

Allibhai et al reported an association with sildenafil citrate and CSCR. [33Fraunfelder and Fraunfelder further evaluated the association of CSCR with sildenafil. [34The authors reviewed 1500 cases of sildenafil associated ocular side effects. Eleven of these cases described men with CSCR. The symptoms resolved following cessation of sildenafil in 8 of 11 patients but recurred in 3 of these patients upon restarting sildenafil. They determined that a causal relationship could not be determined as a result of the cyclic nature of CSCR though patients with refractory CSCR should consider cessation of sildenafil use.

Another hypothesis involves activation of the mineralocorticoid pathway. Inappropriate or over-activation of mineralocorticoid pathways in ocular tissues could lead to vasodilation in the choroid. This pathway would also link CSCR to co-morbidities such as systemic hypertension and psychological stress. Animal models stimulated by aldosterone demonstrate clinical findings similar to acute CSCR. [35]

The complement cascade has also been implicated in chronic CSCR. Certain polymorphisms of complement factor H and variants in the C4B have been associated with chronic CSCR in certain populations. [3637]

Systemic associations of CSCR include organ transplantation, exogenous steroid use, endogenous hypercortisolism (Cushing syndrome), systemic hypertension, sleep apnea, systemic lupus erythematosus, pregnancy, gastroesophageal reflux disease, and use of psychopharmacologic medications. [38393240641Carvalho-Recchia et al showed in a series that 52% of patients with CSCR had used exogenous steroids within 1 month of presentation as compared with 18% of control subjects. [4​ Haimovici et al evaluated systemic risk factors for CSCR in 312 patients and 312 control subjects. [42Systemic steroid use (odds ratio [OR], 37.1) and pregnancy (OR, 7.1) were most strongly associated with CSCR. Other risk factors included antibiotic use, alcohol use, untreated hypertension, and allergic respiratory disorders.




Diagnostic Considerations

CSCR may have a broad range of manifestations considering its presentation from acute to chronic CSCR. Sahoo et al described CSCR as a "great mimicker and...one of the commonest causes of referral." [43444546]

Ozkaya et al found that, in a series of patients with suspected pattern dystrophy, 55% of eyes were misdiagnosed and actually had age-related macular degeneration or CSCR as the underlying disease. [46]

Differential Diagnoses


Laboratory Studies

Laboratory tests, in general, are not helpful in the diagnosis of central serous chorioretinopathy (CSCR), although a recent case report identified an elevated level of plasminogen activator inhibitor 1 in the serum of patients with CSCR.

Imaging Studies

Optical coherence tomography (OCT) reveals many aspects of the pathophysiology of CSCR, ranging from subretinal fluid, pigment epithelial detachments, and retinal atrophy following chronic disease. OCT is especially helpful in identifying subtle, even subclinical, neurosensory macular detachments. Spaide correlated lipofuscinoid deposition of material in CSCR that might mimic vitelliform lesions in pattern dystrophies. [47OCT showed accumulation of this material on the outer surface of the retina in neurosensory detachments.

A 45-year-old man presented with micropsia and bluA 45-year-old man presented with micropsia and blurry vision OS. His visual acuity was 20/15 OD and 20/30 OS. The OCT shows subretinal fluid localized under the foveal center. Six weeks later, the subretinal fluid had resolved and his vision had recovered to 20/15 OU.

FA of classic CSCR shows one or more focal leaks at the level of the RPE. The classic "smokestack" appearance of the fluorescein leak is seen only in 10-15% of cases. FA of diffuse retinal pigment epitheliopathy demonstrates focal granular hyperfluorescence corresponding to window defects and blockage caused by RPE atrophy and clumping with one or more areas of subtle continued leakage. [28]

Fluorescein angiography in the early recirculationFluorescein angiography in the early recirculation phase of a patient with a localized neurosensory detachment in the macula from central serous chorioretinopathy. Note the focal hyperfluorescence.
Fluorescein angiography in the late recirculation Fluorescein angiography in the late recirculation phase of the same patient as in the image above. Note the distribution of leakage of fluorescein dye within the neurosensory detachment.

ICG angiography has shown hypofluorescent areas early in the angiogram followed by late hyperfluorescence and leakage in choroidal vasculature. Often, multiple areas of leakage are seen on ICG angiography that are not evident clinically or on FA. According to some researchers, characteristic mid phase findings on ICG angiography allow differentiation from occult choroidal neovascularization in older individuals. Multiple patches of hyperfluorescence presumably are due to choroidal hyperpermeability, which, in later phases, results in silhouetting or negative staining of larger choroidal vessels.

Newer technology to evaluate the retina is available. Ooto et al showed that adaptive optics scanning laser ophthalmoscopy is useful in evaluating cone abnormalities associated with visual acuity loss in eyes with CSCR. [48]

Other Tests

Multifocal electroretinography has been used to identify focal regions of decreased retinal function, even in asymptomatic or clinically inactive eyes. Chappelow and Marmor first described the persistently reduced focal electrical responses on multifocal electroretinography in eyes with resolved CSCR. [49Furthermore, investigators, including Lai et al, are using multifocal electroretinography as a means of assessing the efficacy and safety of new treatment modalities for CSCR. [50]

Microperimetry (using the Nidek MP-1 microperimeter) has also shown that, despite clinical resolution of CSCR, there is lower retinal sensitivity in the macula even once visual acuity returned to 20/20. Ojima et al showed that areas of reduced sensitivity were typically focal and localized to clinically apparent regions of irregular RPE. Fixation studies showed stability of central fixation


Medical Care

Efficacy of tranquilizers or beta-blockers is unknown. Furthermore, an evaluation of 230 consecutive patients with central serous chorioretinopathy (CSCR) found that use of psychopharmacologic agents (eg, anxiolytics, antidepressants) was a risk factor for CSCR. Use of corticosteroids in the treatment of CSCR should be avoided because it may result in exacerbation of serous detachments already present.

Tatham and Macfarlane described a case series of patients who were treated with propranolol for CSCR. [53They suggested that beta-blockade had a hypothetical mechanism in treating CSCR. Further evidence is needed to substantiate this potential treatment.

Nielsen et al proposed the use of mifepristone in the treatment of chronic CSCR in a case report. [54]

Forooghian et al evaluated the safety and efficacy of finasteride, an inhibitor of dihydrotestosterone synthesis, in 5 patients for chronic CSCR. Macular thickness and subretinal fluid decreased while treated and recurred immediately upon planned cessation of the medication. [55]

Steinle et al reported a single patient successfully treated with oral rifampin after having chronic subretinal fluid for more than 2 years’ duration. The fluid resorbed after 1 month of rifampin therapy. [56Shulman et al conducted a prospective pilot study on 12 patients with chronic CSCR and concluded that oral rifampin may be a treatment option in patients with longstanding chronic CSCR. [57However, a case of rifampin-induced hepatotoxicity has also been reported during treatment of CSCR. [58]

Kurup et al reported a retrospective series of 9 patients who were treated with low-dose oral methotrexate with resolution of subretinal fluid without any apparent complications. [59]

Chin et al reported a series of 120 patients who had some response to mineralocorticoid antagonists, eplerenone or spironolactone. They specifically evaluated patients with recalcitrant disease and found a positive effect in half of the patients treated. [60Other authors have also demonstrated the potential for mineralocorticoid antagonists in the treatment of CSCR. [6162]

Intravitreal bevacizumab (Avastin) has been used to successfully treat the complication of choroidal neovascularization following CSCR. [636465Multiple studies have evaluated intravitreal bevacizumab in the treatment of CSCR uncomplicated by choroidal neovascularization. Despite multiple studies suggesting a trend toward benefit, other studies show that bevacizumab does not significantly affect the course of CSCR. [6667]

Other anti-VEGF agents such as aflibercept (Eylea) and ranibizumab (Lucentis) are also being used to treat the neurosensory detachment of CSCR, both in the presence and in the absence of choroidal neovascularization. Bae et al conducted a prospective randomized study comparing intravitreal ranibizumab to low-fluence photodynamic therapy in chronic CSCR. At 6 months, they concluded that the anatomic outcomes with ranibizumab injections were “not promising” compared with low-fluence photodynamic therapy. [68Semeraro et al compared intravitreal bevacizumab to low-fluence photodynamic therapy for treatment of chronic CSCR. The series was limited to 22 patients total and no statistical significant difference could be identified between the two groups. [69]

Surgical Care

Laser photocoagulation

Laser photocoagulation should be considered under the following circumstances: (1) persistence of a serous retinal detachment for more than 4 months, (2) recurrence in an eye with visual deficit from previous CSCR, (3) presence of visual deficits in opposite eye from previous episodes of CSCR, and (4) occupational or other patient need requiring prompt recovery of vision. Laser treatment also may be considered in patients with recurrent episodes of serous detachment with a leak located more than 300 µm from the center of the fovea. [7071Laser treatment shortens the course of the disease and decreases the risk of recurrence for CSCR, but it does not appear to improve the final visual prognosis. [7273Some evidence suggests that patients with chronic CSCR (diffuse retinal pigment epitheliopathy) may have better prognosis with laser treatment.

Photodynamic therapy

Photodynamic therapy (PDT) in the treatment of chronic CSCR was first reported in 2003. PDT is known to have a direct effect on the choroidal circulation but was limited by potential adverse effects, such as macular ischemia. Authors, such as Lai et al, are now describing reduced dosing of verteporfin, while the use of reduced fluence has been shown to be therapeutically effective in age-related macular degeneration. The rates of adverse events have decreased significantly with these modifications. [745075Subsequent studies, using PDT protocols established by the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study, have reported case series that support the use of PDT, especially in the setting of chronic CSCR with neurosensory detachments. PDT is believed to hasten both fluid resorption and visual recovery. Yannuzzi et al described using ICG angiography to first identify areas of choroidal hyperpermeability that were then targeted with PDT. [75]

Lai et al described the use of half-dose verteporfin in the treatment of CSCR. [50Of the eyes treated, 85% showed complete resolution of the neurosensory retinal detachment and/or pigment epithelial detachment by 1 month after treatment. Reibaldi et al evaluated the treatment efficacy of standard-fluence PDT versus low-fluence PDT using microperimetry. The study found improvement of macular sensitivity following treatment along with greater efficacy in treatment overall using low-fluence PDT. [76Bae et al compared low fluence PDT to intravitreal ranibizumab in a prospective randomized trial. Although only 8 eyes were randomized to each group, ranibizumab did not appear promising when compared with low fluence PDT. After a single treatment, 6 of the 8 eyes in the PDT group had resolution of subretinal fluid whereas 4 of the 8 eyes in the ranibizumab group ultimately required PDT rescue treatment. [77Multiple authors have also begun to use PDT as a first-line therapy for acute focal leaks from CSCR with reported success. Most papers describe resolution of subretinal fluid within 1 month of treatment.

Chan et al demonstrated that there is evidence of choroidal vascular changes on ICG with regard to choroidal permeability and vascular remodeling. [78ICG mediated photothrombosis is a technique using a low-intensity laser combined with ICG dye infusion to treat focal areas of hyperpermeability in the choroid. Like PDT, it addresses treatment to the level of the choroidal vasculature. [79An 810-nm laser is applied after infusion of ICG dye. Without prior ICG dye, investigators have also used the 810-nm laser as transpupillary thermotherapy (TTT) with moderate anecdotal success. [8081However, Penha et al described severe retinal thermal injury in a 31-year-old man following this treatment modality and recommended caution for this adverse event following ICG mediated TTT treatment. [82]

Activity

At one time, stress reduction was considered a mainstay of controlling recurrences and duration of CSCR. Potentially, patient participation in stress-reducing activities (eg, exercise, meditation, yoga) can still be recommended.

Complications

A small minority of patients develops choroidal neovascularization at the site of leakage and laser treatments. A retrospective review of cases shows that one half of these patients may have had signs of occult choroidal neovascularization at the time of treatment. In the other patients, the risk of choroidal neovascularization may have been increased by the laser treatment. [1773]

Acute bullous retinal detachment may occur in otherwise healthy patients with CSCR. This appearance may mimic Vogt-Koyanagi-Harada disease, rhegmatogenous retinal detachment, or uveal effusion. A case report also has implicated the use of corticosteroids in CSCR as a factor increasing the likelihood of subretinal fibrin formation. Reducing the corticosteroid dose frequently will lead to resolution of the serous retinal detachment.

RPE decompensation from recurrent attacks leads to RPE atrophy and subsequent retinal atrophy. RPE decompensation is a manifestation of CSCR but may also be considered as a long-term complication. [26]

Long-Term Monitoring

Most patients with CSCR receive follow-up care for 2 months to determine whether the fluid resolves spontaneously. Even following resolution of symptoms, patients should be cautioned about the high likelihood of recurrence and the potential for development of choroidal neovascularization.



Medication Summary

Currently, the use of mineralocorticoid antagonists such as aldosterone or eplerenone for the treatment of chronic and recurrent central serous chorioretinopathy (CSCR) is rising among retinal specialists worldwide. Eplerenone is administered at 25-50 mg orally each day. Multiple clinical trials have evaluated and supported the efficacy of mineralocorticoid antagonist use.  Coordination with the patient's primary care provider is recommended, and, in many instances, the primary care provider will substitute one of the patient's existing antihypertensive medications with the mineralocorticoid antagonist. Other case reports and series have evaluated a range of potential medical treatments for CSCR, such as rifampin. Currently, only case series and reports support the use of other medications.

Tatham and Macfarlane described a case series of patients who were treated with propranolol for CSCR. [53 They suggested that beta-blockade had a hypothetical mechanism in treating CSCR. Further evidence is needed to substantiate this potential treatment.

Nielsen et al proposed the use of mifepristone in the treatment of chronic CSCR in a case report. [54]

Intravitreal bevacizumab (Avastin) has been used to successfully treat the rare complication of choroidal neovascularization following CSCR.