Albert & Jakobiec's Principles & Practice of Ophthalmology, 3rd Edition

CHAPTER 142 - Central Serous Chorioretinopathy

Catherine B. Meyerle,
Richard F. Spaide

DEFINITION

Central serous chorioretinopathy (CSC) is characterized by an idiopathic circumscribed serous retinal detachment, usually confined to the central macula, caused by leakage of fluid through the retinal pigment epithelium (RPE) as defined by fluorescein angiography. Eyes with CSC do not have signs of intraocular inflammation, accelerated hypertension, infiltration or infarction of the choroid or RPE. Serous detachments of the RPE are frequently present. Although most cases are acute with minimal sequela, some patients have a more chronic version of the disease with poorer visual prognosis.

 

 

HISTORICAL BACKGROUND

CSC has a long history of changing names reflective of the previous uncertainty about the etiology of the pathological process. von Graefe first described it as a recurrent central retinitis.[1] Horniker[2] agreed that the pathology was localized to the retina but thought these patients had an underlying angioneurosis causing angiospasm and exudation. He used the name capillarospastic central retinitis. Gifford and Marquardt[3] shared Horniker's view and coined the term central angiospastic retinopathy. Bennet also localized the disease to the retina and applied the name central serous retinopathy.[4] Through fluorescein angiography, Maumenee[5] changed the concept of the primary tissue affected by describing the leak occurring at the level of the RPE. Gass[6] expanded on this view with his description of the fluorescein angiographic findings and named the condition idiopathic central serous choroidopathy. Today, since we understand that hyperpermeability at the choroid causes a leak through the RPE resulting in a neurosensory retinal detachment, CSC is the preferred term.

 

 

DEMOGRAPHICS

CSC has certain common demographic features.[1-11] Historically the mean patient age was reported as 20-45 years, but more recent studies have not substantiated these numbers and actually report an older mean age. In a 1996 study of 130 patients with CSC, the mean age was 51 years.[11] Two recent large retrospective case control studies concur with this older mean age. A study of 230 patients found the mean age to be 51 years[12] and another study of 312 patients revealed a mean age of 45 years.[13] If diagnosed in a patient older than 50 years of age, however, one must carefully assess for macular degeneration or choroidal neovascularization (CNV) before making the diagnosis of CSC. CSC is very rare in patients less than 20 years old. Although CSC in a 7-year-old girl has been reported, this patient may actually have had posterior scleritis.[14]

In terms of gender, there is a male predilection with the reported male:female ratio ranging from 6:1 in older studies[1-10] and less than 3:1 in more recent literature.[12,13] Race also plays a role in CSC, with more whites, Hispanics, and Asians affected. CSC has been reported as uncommon in blacks, but some authors refute this point.[15] The disease may run a more severe course in Hispanics and Asians with extensive bullous changes. Refractive error is significant with hyperopic or emmetropic patients affected more in Western nations.[16] This association, however, does not hold for those in Asian regions with a high prevalence of myopia such as in Japan.

Corticosteroids have been implicated in CSC by multiple studies. Tittl and associates, in a retrospective case-control study of 230 patients, found that corticosteroids (used by 9.1% of patients) are risk factors in addition to psychotropic medications and hypertension.[12] Haimovici and co-workers[13] also reported an association of CSC with corticosteroids (used by 14.4% of patients) in a retrospective case-control study of 312 patients. Other risk factors, according to Haimovici[13], included pregnancy, antibiotics, alcohol, untreated hypertension, and allergic respiratory disease, with the pregnancy association also reported by Gass.[17] Karadimas eventually confirmed that corticosteroids are a risk factor for CSC in a smaller, but prospective, case-control study.[18] Systemic corticosteroid treatment in organ transplant patients has been associated with aggressive CSC.[19,20] More recent studies have shown that fundus changes previously attributed to organ transplantation[21] were in fact most likely due to corticosteroid-induced CSC, as patients who never had organ transplantation but were on corticosteroids had similar findings.[22] Inhaled, intranasal, intramuscular, and topical dermatological[23-26] corticosteroids have also been implicated in CSC pathogenesis. There have even been isolated case reports of CSC following vitrectomy with intravitreal triamcinolone acetonide for diabetic macular edema[27] and CSC after a periocular steroid injection for HLA-B27-associated iritis.[28] Our associates, however, have performed hundreds of intravitreal triamcinolone acetonide injections and have not yet observed a case of CSC. Endogenous corticosteroids are also thought to contribute to the pathogenesis of disease as many CSC patients have elevated 24-h urine corticosteroids.[29] Repeated injections of intramuscular prednisolone in combination with intravenous epinephrine in a cynomolgus monkey (Macaca irus) resulted in CSC after the thirty-second injection.[30] Some question the validity of this animal model, however, based on the histopathology. Ultrastructural findings of RPE degeneration with underlying damaged endothelial cells within the inner surface of the choriocapillaris[31] may be more consistent with infarction seen in malignant hypertension. Yoshioka defends his CSC animal model by pointing out that the monkeys in his study did not have any Elsching's spots or retinal vasculature changes consistent with hypertension.[30]

Similar to corticosteroids, both exogenous and endogenous sympathomimetic agents have been implicated in CSC. Excessive use of sympathomimetic compounds has been associated with CSC.[32]Endogenous plasma concentrations of epinephrine and norepinephrine were found to be higher among CSC patients than in controls in one study.[33] Repeated injections of intravenous epinephrine alone in a Japanese monkey model (Macaca fuscatus) resulted in CSC after 39 injections.[30]

Personality traits are thought to play a role in CSC. Patients with CSC commonly are stressed by multiple events in their life.[34] Based on the the Jenkins Activity Survey, Yannuzzi showed that these patients are more likely to have type A personality characteristics when compared with controls.[35] Werry and Arends,[36] using the Minnesota Multiphasic Personality Inventory Test, showed that CSC patients are more likely to show hypochondria or hysteria and have a conversional neurosis.

 

 

OCULAR SYMPTOMS

Common symptoms of CSC are decreased vision with distortions including metamorphopsia, micropsia, scotomas, chromatopsia, and prolonged after-images. The visual acuity, somewhat improvable with mild hyperopic correction, is usually reduced to between 20/30 and 20/60 but can decline to worse than 20/200 in severe or recurrent disease. Superior field defects can occur in patients with inferior detachments from gravitating fluid. Younger CSC patients usually have unilateral involvement, while older patients are more likely to have bilateral involvement.

 

 

OCULAR FINDINGS OF CLASSIC CSC

CSC can present in three different ways: classic acute chorioretinopathy, chronic diffuse retinal pigment epitheliopathy (DRPE), and bullous retinal detachment. Classic or acute CSC is the most common form, consisting of a solitary, localized neurosensory detachment in the posterior pole. A round to oval, well-delineated, shallow serous retinal detachment elevates the macula and blunts the normal foveal reflex (Fig. 142.1). This blister of clear fluid has a characteristic halo formed by light reflexes where the sloping retina reflects light back to the observer. The size of the detachment can vary considerably, but the average size is 2 disk diameters. Serous retinal pigment epithelial detachments (PEDs) are also commonly seen in association with CSC (Fig. 142.2). On biomicroscopy, a PED appears as a well-circumscribed, orange-colored elevation with a slightly darker rim that can illuminate with a slit beam aimed from the side. A PED forms when the RPE cells, and their associated basement membrane, separate from the underlying Bruch's membrane. These detachments are often less than 0.25 disk diameter, but can be larger. Prominent PEDs are found in two other conditions besides CSC: CNV, particularly occult CNV, and polypoidal choroidal vasculopathy, a variant of CNV. Therefore, if turbid fluid or subretinal blood is noted, the macular pathology is most likely not CSC and is rather secondary to CNV.

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FIGURE 142.1  (a) Red-free photography shows a trace amount of fluid. (b) OCT better illustrates the presence of both subretinal fluid (asterisk) and a small pigment epithelial detachment (arrow).

 

 

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FIGURE 142.2  (a) Red-free photograph illustrates a classic pigment epithelial detachment. (b and c) ICG angiography shows the typical early hyperfluorescence and late hypofluorescence of the pigment epithelial detachment.

 

 

Some patients may have the deposition of subretinal fibrin. The subretinal fibrin is a grayish-white sheet overlying prominent leaks. Frequently, there may be a concomitant underlying PED with the fibrin accumulating radially around the top of the PED making a ring appearance.

 

 

FLUORESCEIN ANGIOGRAPHIC FINDINGS OF 'CLASSIC' CSC

Fluorescein angiography in acute cases of classic CSC demonstrates one or several hyperfluorescent leaks at the level of the RPE. Early in the angiogram, there is a focal dot-like hyperfluorescence representing the leakage of dye from the choroid through the RPE. Later, dye accumulates beneath the sensory retinal detachment but does not extend outside the borders of the detachment. Two patterns of leakage occur. First, the classic smokestack leak described by Shimizu and Tobari in 1971[37] occurs in the minority of cases (10%), but has a dramatic appearance. The leakage first arises superiorly, resembling a smokestack, and then plumes out laterally. This pattern is thought to be related to convection currents and a protein gradient, with protein concentration increasing in the fluid accumulating under the neurosensory detachment.[38] Smokestack leaks are usually associated with larger areas of retinal detachment. The second and more common pattern of dye leakage, occurring in up to 90% of cases, is manifested as a small dot leak with a uniform filling pattern within the detachment (Fig. 142.3).

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FIGURE 142.3  (a) The typical pinpoint leak is present on fluorescein angiogram. (b) Magnified view of the macula shows a pigment epithelial detachment resulting from the leak.

 

 

In both types of leakage patterns, focal leaks are somewhat more common nasally than temporally, superiorly than inferiorly.[9,39] Most leaking points are in a ring 1 mm wide, starting 0.5 mm from the center of the fovea, but can occur further than 3 mm from the foveal avascular zone in 11.8% of cases. The leakage point occurs in the fovea in less than 10% of cases and within the papillomacular bundle in 20-25% of cases. If a leakage point is not readily apparent on fluorescein angiography, the superior extramacular area should be inspected carefully as gravity might cause a detachment below the leak. In some cases, a leakage point will not be found because the leak has healed. In these cases, the detachment will usually resolve in days to weeks. Finally, other conditions such as exudative age-related macular degeneration (AMD) may mimic CSC clinically, and thus a leakage point will not be found.

 

 

INDOCYANINE GREEN ANGIOGRAPHIC FINDINGS OF 'CLASSIC' CSC

Indocyanine green (ICG) angiography demonstrates multifocal areas of choroidal vascular hyperpermeability (Fig. 142.4).[40-42] These areas are best seen in the mid-phases of the angiogram, and appear localized within the inner choroid. With time the liver removes the ICG from the circulation, and the dye that has leaked into the choroid appears to disperse somewhat, particularly into the deeper layers of the choroid.[42] This produces a characteristic appearance of larger but less prominent hyperfluorescent patches in the choroid with silhouetting of the larger choroidal vessels in the later phases of the ICG angiographic evaluation. Patients with CSC can actually present with no fluorescein leakage during a quiescent phase, but will still have areas of underlying choroidal vascular hyperpermeability that serves as a marker of the disease. Younger patients may have PEDs as a forme fruste of CSC in that underlying choroidal hyperpermeability may cause elevations of the RPE without creating breakthrough leaks.

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FIGURE 142.4  (a) Early phase; (b) mid phase; (c) late phase of ICG. ICG angiography demonstrates multiple patchy areas of choroidal hyperpermeability, best seen in mid phase (b). These hyperpermeability regions may persist in chronic central serous even when there is no active leakage on fluorescein angiography.

 

 

 

 

AUTOFLUORESCENCE PATTERNS OF CLASSIC CSC

Autofluorescence photography is a noninvasive test that provides functional images of the fundus based on stimulated emission of light from lipofuscin and related molecules. Lipofuscin, found within the RPE, is a cellular waste product containing lipid, protein, and fluorophores such as A2E. Additional sources of autofluorescence are the precursors to A2E that accumulate in the outer retina prior to phagocytosis. These A2E precursors increase in number if the outer segments are not being phagocytized.

Autofluorescence images can be generated by excitation of the fluorophores with light centered at 580 nm, detection above 695 nm with a barrier filter and recording by a Topcon 50× fundus camera. The filter combination ensures that autofluorescence from the natural crystalline lens is bypassed. Alternatively, a Heidelberg retina angiograph (HRA) can be used with excitation at 488 nm and detection above 500 nm. HRA is based on confocal imaging. The advantage of the confocal aspect is that it allows the HRA system to reject lens autofluorescence. The disadvantage of the confocal imaging is that it collects light only from the RPE. If there is a retinal detachment, as in CSC, the HRA does not record the light coming from the retina. With a fundus camera, however, it is possible to see the autofluorescence from the RPE and outer retina simultaneously. The resulting autofluorescence photograph obtained with the fundus camera, therefore, is a summation of the autofluorescence from the retina and underlying RPE. Visualization of the autofluorescent signal depends on the distribution pattern of the fluorophore-containing lipofuscin and A2E precursors. Autofluorescence photography is important in CSC because it provides a noninvasive technique to study the status of both the RPE and outer retina and to assess atrophic changes.

Von Ruckman and Bird reported abnormalities of fundus autofluorescence in a prospective study of 69 eyes with CSC.[43] In this study, acute CSC was defined by a focal leak on angiography with serous retinal detachment or pigment epithelial detachment. In the acute CSC eyes, increased autofluorescence noted at the leakage site and in the area of retinal detachment was attributed to increased metabolic activity of the RPE. In longstanding lesions of acute or classic CSC patients, decreased or absent autofluorescence was reported to indicate reduced metabolic activity of the RPE due to photoreceptor cell loss.

A retrospective German study of 85 patients evaluated autofluorescence changes in both acute and chronic CSC patients, with acute defined as less than 6 weeks.[44] The findings for the acute patients were that 72% had decreased autofluorescence at the leakage site and 77% had decreased autofluorescence in the area of the neurosensory detachment. The authors suggest that the hypoautofluorescence in the acute stage is due to blockage caused by edema.

Our group's case series evaluating autofluorescence in 58 eyes with CSC expanded on these previous studies by including optical coherence tomography (OCT) analysis and statistical measurement of autofluorescence values.[45] The acute leaks of classic CSC, if imaged within the first month, showed no apparent abnormal autofluorescence other than a serous detachment of the macula. Beyond 1 month, however, the area of detachment showed increased autofluorescence in a diffuse pattern with some subretinal granular deposits. OCT analysis demonstrated that the hyperautofluorescent areas had material on the outer surface of the retina. The thickness of the outer retinal material was proportional to the amount of hyperautofluorescence. We hypothesize that the material on the outer surface of the retina represents accumulated photoreceptor outer segments secondary to lack of direct apposition and phagocytosis by the RPE. Autofluorescence, therefore, is not limited to RPE cells but can include outer retina as well. Our study also indicated that measurement of autofluorescence of the central macula is highly correlated with visual acuity. While a healthy macula has a relatively uniform distribution of autofluorescence, an unhealthy macula has more variance related to cell injury and accumulation of abnormal amount of fluorophores.

Autofluorescence photography, therefore, provides a noninvasive assessment of the status of the RPE and outer retina in CSC patients. This imaging technique will not only scientifically help us better understand the pathogenesis of CSC, but will also clinically guide us in management of individual patients.

 

 

DIFFUSE RETINAL PIGMENT EPITHELIOPATHY

A second principal presentation of CSC shows widespread alteration of pigmentation of the decompensating RPE in the posterior pole that appears to be related to the chronic presence of subretinal fluid. This variant of CSC has been termed 'DRPE' or 'chronic CSC'.[42] Just as CSC has had many names during its history, so has this more chronic variant. DRPE is related to not only a past history of CSC, but also to the age of the patient at the time of diagnosis.[11] Patients with DRPE generally have a more pronounced loss of visual acuity, and may have permanent loss of visual acuity to the level of legal blindness.

 

 

OCULAR FINDINGS OF DRPE

Patients with DRPE have widespread disease. Close examination of the retina by slit-lamp biomicroscopy may show thinning of the retina and possible cystic changes within the retina. There are often RPE alterations that are manifest in three different ways. First, the RPE can show atrophy where there is a loss of pigmentation and increased visibility of the underlying larger choroidal vessels. This atrophy is readily seen with autofluorescence photography. Second, the RPE can have areas of focal hyperpigmentation. Finally, some patients may have RPE hyperplasia to the point where they develop bone spicules. Within the detachment, the subretinal fluid is clear, but sometimes has flecks of subretinal lipid. This feature may suggest the presence of occult CNV when in fact the diagnosis is CSC. Because CNV has a different course and treatment, great care must be made in establishing the diagnosis of CSC in an older patient with subretinal lipid. Broad areas of detachment in the posterior pole are present and tracts of fluid may descend inferiorly toward the equator. Yannuzzi and colleagues[7] described 25 patients with extramacular inferior hemispheric RPE atrophic tracts related to an antecedent retinal detachment. Five of these patients actually had a peripheral retinal detachment.

 

 

ANGIOGRAPHIC FINDINGS OF DRPE

The various diffuse areas of altered RPE are readily apparent on fluorescein angiography. These areas have a granular hyperfluorescence due to relative atrophy of the involved RPE and associated subtle, indistinct leaks (Fig. 142.5). There may be dependent retinal detachments into the inferior fundus with associated atrophic tracts of the RPE.[7] Capillary telangiectasis, capillary nonperfusion,[46] and secondary neovascularization associated with the chronic detachments may occur. Because of the widespread pigmentary alterations and chronically reduced visual acuity, these patients are sometimes misdiagnosed as having an inherited retinal or macular dystrophy. ICG angiography of DRPE shows the same type of widespread choroidal vascular hyperpermeability as patients with typical CSC have, except the number and area of hyperpermeability seems to be greater in patients with DRPE.

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FIGURE 142.5  (a and b). As CSC becomes chronic, the hyperfluorescence on fluorescein angiography loses its pinpoint character and becomes more diffuse.

 

 

 

 

AUTOFLUORESCENCE PATTERNS OF DRPE

Autofluorescence imaging of DRPE patients varies according to the degree of cellular injury. Von Ruckman and Bird[43] concluded in their study that decreased or absent autofluorescence within longstanding lesions indicates reduced metabolic activity of the RPE due to photoreceptor cell loss. A German study[44] reported that the irregular and increased autofluorescence changes observed among their chronic patients is reflective of RPE reactive changes.

Our study of 58 eyes[45] helps explain the varying patterns of hyper- and hypo-autofluorescence seen in chronic CSC. The descending atrophic tracts often seen in DRPE have characteristic patterns. Tracts of more recent origin and the outer edge of more chronic descending tracts exhibit hyperautofluorescence, reflecting the increased lipofuscin within the RPE and A2E products within the outer retina. Patients with a history of CSC that has been quiescent for many years have only hypoautofluorescent areas, indicative of the RPE atrophy. Autofluorescence photography, therefore, provides a noninvasive tool to monitor cellular function in CSC patients and indirectly determine visual prognosis (Figs 142.6 and 142.7).

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FIGURE 142.6  This autofluorescence photograph taken with a Topcon 50× camera illustrates the diffuse decompensation of the RPE seen in chronic CSC.

 

 

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FIGURE 142.7  This autofluorescence photograph taken with a Topcon 50× camera shows dark hypoautofluorescent descending tracts reflecting the atrophic patterns resulting from inferiorly gravitating fluid.

 

 

 

 

BULLOUS DETACHMENT OF THE RETINA SECONDARY TO CSC

There is an additional, but rare, form of CSC that causes bullous retinal detachments. Although most patients with CSC have one to three leaks seen during fluorescein angiography, some patients in an unusually severe variant have numerous exuberant leaks, multiple PEDs, and bullous retinal detachments that extend into the inferior periphery of the fundus.[47] These detachments are often associated with subretinal fibrinous exudates and shifting subretinal fluid. Several reports of this condition originated in Japan, where this variant seems more common.[41,46,48] Bullous serous retinal detachments also have been reported in organ transplant patients.[49] Patients with bullous detachment have the same findings during ICG angiography as the patients with classic CSC and DRPE, except the number and size of choroidal hyperpermeability areas are greater.

An observational case series of 25 patients showed that this severe variant can occur in both healthy patients (21/25) and patients treated with corticosteroids for metabolic or autoimmune disease (4/25).[50]Bilaterality is the norm (84%). While some of the patients initially presented with bullous changes, others converted from classic CSC (36%). The conversion time ranged from 7 months to 9 years after onset. Recurrence rate was as high as 52% in this study, but 80.4% recovered central visual acuity of 20/40 or better. Those patients who experienced visual loss greater than 20/40 had macular damage.

 

 

SUBRETINAL DEPOSITS

Patients with CSC, of any variety, may have deposition of subretinal material that occurs in four forms:[17,51] fibrin (see section on Ocular Findings of Classic CSC), lipid, macrophages, and outer photoreceptor segments. Subretinal lipid is usually found in chronic CSC in older patients and appears as discrete, hard-edged, subretinal accumulations typically at the borders of a neurosensory detachment. This older age group is at risk for CNV, which is a more common disorder causing subretinal lipid. Because CNV has a different course and treatment, great care must be exercised in establishing the diagnosis of CSC in an older patient with subretinal lipid.

Diffuse deposition of macrophages and outer photoreceptor segments gives the appearance of outer retinal small dots on ophthalmoscopy. This can be seen in almost every patient with CSC lasting more than a few months. Pronounced accumulation of material may even produce the appearance of diffuse yellow flecks in some patients. Because of the subretinal deposits, some of these patients have been initially suspected of having retinitis, choroidal tumors, or CNV. Based on autofluorescence studies,[45] the material on the outer surface of the elevated retina may perhaps represent an accumulation of photoreceptor outer segments secondary to lack of phagocytosis, given that the RPE in these cases is not in direct apposition with the retina. Interestingly, the granular dots may vary in number, but do not vary in size. This uniformity of size and their autofluorescent nature suggest that these dots may be macrophages, engorged with phagocytized outer segments. The occasional yellow fleck appearance is explained by the lutein component of outer photoreceptor segments.[52]

 

 

OPTICAL COHERENCE TOMOGRAPHY IN CSC

OCT provides anatomical information in all types of CSC. A Spanish study compared conventional OCT findings with fluorescein angiographic patterns in 39 eyes with CSC.[53] The authors report that 36 eyes had an optically empty vaulted area under the neurosensory retina consistent with detachment that related to fluorescein-filled areas. Thirty-five eyes had highly characteristic small bulges protruding from the RPE, angiographically related to leaking spots. Three eyes showed an almost semicircular space under the RPE, with thinner overlying retina. Additionally, our group's study showed that conventional OCT is useful for detecting subclinical cystoid macular degeneration or foveal atrophy.[54] OCT, therefore, provides a noninvasive imaging test complementary to fluorescein angiography.

A study of 38 CSC eyes with OCT ophthalmoscope producing en face OCT scans (OCT C-scans) provides information beyond conventional OCT.[55] In this study, active CSC was associated with large neurosensory detachment (23/29), subretinal hyper-reflective deposits (20/29), and pigment epithelial detachment (15/29). Multiple small PEDs located both within and outside the neurosensory detachment were detected in one-third of the patients with either active or inactive CSC.

In a retrospective study of unilateral resolved CSC,[56] the involved eyes had a decrease in central foveal thickness which had a statistically significant correlation with visual acuity. The foveal thickness of the eye with resolved CSC was normalized by dividing its thickness by that of the uninvolved eye. Additional factors on OCT associated with poorer visual acuity were the inability to visualize the external limiting membrane or the boundary between photoreceptor bodies and outer segments.

 

 

DIFFERENTIAL DIAGNOSIS

Although the clinical and fluorescein angiographic features of CSC are often classic, several entities should be considered in the differential diagnosis: CNV, tumors, inflammatory disorders, vascular pathology and rhegmatogenous retinal detachment can sometimes have similar clinical characteristics to CSC. Careful biomicroscopy and fundus imaging, however, allows for the correct diagnosis.

The principal condition that needs to be differentiated from CSC is CNV, particularly occult CNV. The ocular findings of CNV share many similarities with those of CSC. Both groups of patients may have neurosensory detachments, PEDs, mottled depigmentation, hyperpigmentation, areas of RPE atrophy, and subretinal deposits of fibrin and lipid.[11] Patients with CNV, however, have thickening at the level of the RPE, notched PEDs and subretinal or subpigment epithelial blood. These findings are not seen in CSC. In addition, eyes with CNV generally have coexistent ocular findings related to the generation of new blood vessel growth. These factors include punched-out chorioretinal scars in ocular histoplasmosis syndrome, lacquer cracks, and areas of choroidal atrophy in pathological myopia, breaks in Bruch's membrane in cases of choroidal rupture, and drusen and pigmentary clumping in patients with age-related macular degeneration. The CNV secondary to proximal causes such as chorioretinal scars or choroidal ruptures generally has 'classic' findings on fluorescein angiography. These cases demonstrate a lacy vascular pattern of hyperfluorescence with increasing leakage and staining throughout a fluorescein angiographic evaluation. Occasionally a specific feeder vessel can be seen extending from the chorioretinal scar. The fluorescein angiographic findings of exudative age-related macular degeneration may be more difficult to differentiate from CSC because the majority of AMD leakage is occult CNV. ICG angiography of CSC demonstrates multifocal, and usually bilateral, choroidal vascular hyperpermeability that has specific temporal and topographical characteristics. The hyperpermeability in CSC is most evident in the mid-phases of the angiographic evaluation. The later phases of ICG angiography show dispersion of the dye with negative staining of the larger choroidal vessels. CNV, on the other hand, shows a unilateral, unifocal area of hyperfluorescence that usually shows progressively increasing contrast with the surrounding choroid in the later phases of the angiogram. ICG angiography may provide important information to help rule out the presence of occult CNV. Also, repeating the fluorescein angiogram 2-3 weeks later may be helpful as CNV may become more apparent with time.

Tumors and infiltrative conditions, such as leukemia, amelanotic melanoma, or metastatic disease, can also appear similar to CSC. Clinical examination, however, shows that these infiltrative lesions generally have a different color than the surrounding normal choroid, demonstrate thickening of the choroid by ultrasonography, and do not have serous PEDs. Inflammatory conditions with serous retinal detachments can also masquerade as CSC, but clinical diagnostic clues exist. For example, eyes affected with posterior scleritis or Harada's disease show signs of intraocular inflammation such as iritis or vitritis, have patches of yellowish discoloration in the posterior pole, demonstrate staining of the optic nerve head during fluorescein angiography, and have thickening of the choroid by ultrasonography. These findings are not seen in CSC. Extraocular symptoms, such as meningeal signs including headache, neck stiffness, and vomiting, are common in Harada's disease but not in CSC.

Anatomical changes can also complicate the picture. For example, patients with optic nerve pits may have a serous detachment of the macula that may appear similar to CSC. Fortunately, the optic nerve pathology is generally readily visible. Also, the macular elevation due to optic nerve pits differs from CSC because it is generally a bilayer detachment caused by retinoschisis in the macula. There are no leaks from the level of the RPE during fluorescein angiography in patients with optic nerve pits. Another anatomical abnormality that can mimic CSC is rhegmatogenous retinal detachments. They may cause elevation of the macula like CSC, but differ in that they have an associated retinal hole or tear and do not have leaks visible during fluorescein angiography.

Vascular disorders are also in the differential diagnosis. Malignant hypertension can produce a serous retinal detachment. The presence of systemic hypertension, Elschnig's spots, shifting fluid, and choroidal or retinal vasculature changes, or both, can distinguish it from CSC. Serous retinal detachment can occur in toxemia of pregnancy. The systemic findings of hypertension, proteinuria, and edema will separate this condition from CSC seen in pregnant women. Disseminated intravascular coagulopathy should also be considered in the differential diagnosis of serous retinal detachment and can be distinguished by its systemic findings.

 

 

PATHOPHYSIOLOGY

Multiple theories of pathophysiology exist and continue to evolve as we understand the disease better. Fluorescein angiography contributed to the current pathogenesis concept. With the advent of this retinal imaging test, ophthalmologists had a more precise method of diagnosing and evaluating CSC. Fluorescein angiography demonstrates one or more sites of leakage in cases of active CSC. With cessation of these leaks, the detachment regresses. This suggested, at least to some observers, that the leak seen during fluorescein angiography represented fluid coming from the choroid into the subretinal space through a precisely located defect in the RPE. The fluorescein, contained in the choroidal fluid, was brought into the subretinal space with the bulk fluid flow going from the choroid toward the retina.

The balance of the tissue oncotic and hydrostatic pressures ordinarily causes fluid flow from the retina towards the choroid. In experimental models, injury or destruction of the RPE was seen to speed up the resorption of subretinal fluid.[57] These findings suggested that an isolated defect in the RPE could not account for the findings seen in CSC, but rather that more diffuse RPE abnormalities would be required to overcome the RPE pumping function. To clarify the pathophysiology of CSC, several newer theories were postulated based in part on findings from animal models. One theory stated that what appeared to be leaks at the level of the RPE were in fact not necessarily active leaks, but were areas where dye diffused into the subretinal space.[58] The neurosensory detachment was thought to be secondary to widespread areas of RPE dysfunction. This theory, however, did not clearly elucidate why the areas of RPE dysfunction occurred or why CSC spontaneously improves, as it frequently does. This theory also did not explain why patients with CSC frequently develop PEDs, or why laser treatment to a 'leak' causes a rapid resolution of the neurosensory detachment. Another theory suggested that a focus of RPE cells, losing their normal polarity, pumps fluid from a choroid to retina direction, causing a neurosensory detachment.[59] Yet this theory could neither explain the presence of PEDs and subretinal fibrin nor how a few RPE cells pumping in the wrong direction could overcome the pumping ability of broad areas of surrounding RPE cells.

Integration of the clinical findings of CSC with the ICG angiographic abnormalities of the choroidal circulation in patients with CSC led to new theoretical considerations. During ICG angiography, the choroidal circulation appears to have multifocal areas of hyperpermeability.[40,42,60-63] These areas of hyperpermeability may arise from venous congestion. Excessive tissue hydrostatic pressure within the choroid from the vascular hyperpermeability may lead to PEDs, disruption of the retinal pigment epithelial barrier, and abnormal egress of fluid under the retina. In past studies, leaks demonstrable at the level of the RPE invariably are contiguous with areas of choroidal vascular hyperpermeability.[40,42,60-63] On the other hand, most areas of hyperpermeability are not associated with actual leaks. These areas of hyperpermeability without leaks may affect the size, shape, and chronicity of any overlying neurosensory detachment by inducing changes in the ability of the overlying RPE to pump.

Theoretical considerations about why the choriocapillaris would develop increased permeability have been described elsewhere. Increased circulating epinephrine and norepinephine levels have been found in patients with CSC. Administration of sympathomimetic compounds has been associated with CSC in humans. A CSC-like condition exists in monkeys given both sympathomimetic agents and corticosteroids. It is possible to postulate that sympathomimetic compounds or corticosteroids, either endogenous or exogenous, alter the permeability of the choriocapillaris directly, or through secondary means such as affecting choroidal vasculature autoregulation. Although the rate of developing CSC with corticosteroid use is not known, CSC is a relatively common disease. Clearly, systemic administration of cortiosteroids can lead to CSC, but local administration does not appear to do so with anywhere near the same frequency. Although there has been one isolated case report of CSC following intravitreal triamcinolone acetonide for diabetic macular edema,[28] the author has given hundreds of intravitreal steroid injections to patients and has not seen one case of CSC. Perhaps systemic administration causes particular physiologic alterations not as readily induced by local application.

 

 

HISTOPATHOLOGY OF CSC

There exists only limited histopathologic information on CSC. Neurosensory detachment with subretinal and subpigment epithelial deposition of fibrin has been reported. A model of exudative detachment has been produced in monkeys with repeated injection of corticosteroids and epinephrine.[64-67] In their monkey model of CSC, Yoshioka and Katsume[31] described a focal area of degenerated RPE with adjacent damaged choriocapillaris endothelial cells. These endothelial abnormalities were sealed by platelet-fibrin clots. Some dispute the validity of Yoshioka's animal model and suggest the monkeys likely had accelerated hypertension rather than just simple CSC.

OCT, thanks to its high resolution, can effectively provide optical biopsies. Although OCT has been commonly used to determine the presence of subretinal fluid, it can provide even more useful information. Retinal atrophy has been seen in some patients. In addition, the ability to visualize finer anatomic details such as the external limiting membrane was much less in patients with lower levels of visual acuity, suggesting that anatomic alterations occur that are associated with decreased acuity.[56] Patients with a history of chronic detachment and poor visual acuity after reattachment may have cystoid spaces within the retina, a condition that has been termed cystoid macular degeneration.[54]

 

 

NATURAL COURSE

Most patients with CSC spontaneously resolve and experience an almost complete restoration of vision. In the series of Klein and colleagues,[68] resolution was noted in all 34 eyes studied prospectively without any treatment. The average resolution time in this study was 3 months. All patients had visual acuity of 20/40 or better, and 94% of the eyes had visual acuity of 20/30 or better at follow-up examination (average 23 months). However, even if patients do recover Snellen visual acuity, many still complain of decreased color vision, relative scotomas, micropsia, metamorphopsia, decreased contrast sensitivity, and nyctalopia in the affected eye. Some may even notice a slight distortion in their central vision. Although these patients have resolution of their neurosensory detachment, they regain only part of their central vision because they have suffered photoreceptor damage, atrophy, irregular RPE pigmentation, or subretinal fibrosis.

Recurrence of CSC is a problem, affecting 40-50% of patients.[10,68] Some of these patients will go on to have recurrent focal leaks while others will inexorably progress to the more visually threatening DRPE. Recurrences can occur many years later. The recurrent leakage point is within 1 mm of the initial leakage point in 80% of patients.[9,l0] Secondary CNV may occur, particularly in patients over 50 years of age.[11]

 

 

TREATMENT

Each treatment technique for CSC has been based to a certain extent on proposed mechanisms of pathophysiology at the time. The resultant treatment approaches for CSC have been varied and have usually been examined as part of uncontrolled studies. No medical therapy has been shown to be effective for patients with CSC. Tranquilizers, sedatives, and barbiturates have been advocated to decrease the psychogenic component of this disorder, but their efficacy has not been demonstrated. Because of the suggestion that CSC may be related to abnormal levels of circulating epinephrine, the use of ?-blockers has been suggested as a treatment. A small study suggested a possible benefit,[69] but the findings have not been confirmed with either a larger study or a randomized trial. Epinephrine stimulates ? and ?receptors; blocking only ? receptors would allow unopposed ? stimulation. This might produce unwanted vascular constriction. If a patient is on corticosteroids, the medical treatment includes withdrawal of the drug. Ketoconazole has been shown to reduce endogenous corticosteroid levels and is a theoretical treatment, but no study regarding this treatment is published at this time. Currently, no randomized controlled study has shown any drug to be useful in the treatment of CSC.

 

 

PHOTOCOAGULATION THERAPY

Laser photocoagulation is the most commonly studied modality in the treatment of CSC. The principal goal of this treatment is to reduce the leakage through the RPE and cause resolution of the subretinal fluid with improvement in visual acuity. Laser photocoagulation to the site of leakage seen during fluorescein angiography shortens the duration of macular detachment in patients with typical CSC, but does not appear to affect the final visual acuity.[70-75] Similarly for DRPE, thermal grid laser to an area with small leaks appeared to cause a decrease in the amount of subretinal fluid present,[76] but did not cause a long-term change in the visual acuity. The effect of laser treatment on the rate of recurrence is inconclusive as it reduced the rate of recurrence in some studies,[74,75] but not in others.[70,71,73] For the severe bullous variant, laser photocoagulation did not confer any significant advantage in terms of temporal resolution of serous retinal detachment or final visual acuity outcome.[77] Potential dire side effects of photocoagulation include CNV, scotoma, and RPE scar expansion.

When is it appropriate to laser photocoagulate CSC? Because of the unfavorable risk-benefit ratio, laser photocoagulation generally is reserved for patients with the following criteria: symptoms greater than 4 months, leakage sites located greater than 375 ?m from fixation, a history of CSC in the fellow eye with an unfavorable outcome, and the need or desire for treatment. If the leak is located well away from the central macula, then there is less reason to hesitate about laser photocoagulation. A detailed biomicroscopic examination and fluorescein angiogram is essential to monitor for CNV. If laser is initiated, it is imperative that the patient understands that treatment only shortens the duration of the disease and does not affect the final visual acuity or recurrence rate.

 

 

METHODS OF PHOTOCOAGULATION

Laser photocoagulation should be performed to the leakage site with low-intensity energy. The laser is set for a spot size of 100-200 ?m, power of 100-150 mW, with application time of 0.1-0.2 s. With a recent angiogram as guidance, the more peripheral leaks are treated first. The amount of laser uptake is affected by several variables. These include the amount of subretinal fluid present, the degree of pigmentation of the RPE, which is variably pigmented in areas of chronic subretinal fluid, the degree of RPE detachment, and the wavelength of laser used. The leakage point is treated as well as a small surrounding region of normal RPE. Great care should be taken to obtain only a dull gray coagulation to avoid the possibility of secondary CNV.

The patient should be monitored carefully to assess for recurrence or laser-induced complications. The subretinal fluid generally takes a few weeks to resorb. The visual symptoms start to abate with diminution of the subretinal fluid, but the time it takes for the patient to regain final visual acuity seems proportional to the amount of time the retina was detached. The initial follow-up examinations are to evaluate the patient for CNV.

If hemorrhage, increased turbidity of the subretinal fluid, or thickening at the level of the RPE in or adjacent to the area of laser treatment is noted, secondary CNV should be suspected. The patient should have a repeat fluorescein angiogram at that point to help in establishing the diagnosis. Secondary CNV generally causes a nodular or crescent-shaped area of hyperfluorescence under or adjacent to the area of previous laser photocoagulation. If the original site of treatment was sufficiently extrafoveal, it is possible to discover and treat secondary CNV, in many cases, before the neovascularization extends under the fovea. The CNV may be treated with either thermal laser, if sufficient room exists, or with photodynamic therapy (PDT).

 

 

PHOTODYNAMIC THERAPY

PDT is a newer treatment modality for CSC. While the therapeutic mechanism of PDT is known for the CNV in age-related macular degeneration, it is not known for CSC. Studies have shown that PDT may be useful for treatment of DRPE, and even acute classical CSC in certain circumstances.

DRPE is a challenge to treat because of the wide distribution of multiple indistinct leaks. Several groups have investigated the use of PDT with verteporfin for more chronic forms of CSC.[78-80] Generally PDT causes the subretinal fluid to decrease or resolve completely. Recurrences of subretinal fluid do occur, but they are responsive to retreatment with PDT. Pigmentary changes persist, however, so earlier treatment is desired.

Our group conducted a study of ICG angiography-guided PDT of 20 chronic CSC eyes in which we found an inverse correlation between baseline visual acuity at the time of treatment initiation and improvement of visual acuity afterwards.[79] The location of laser light application, in our study, was based on regions of choroidal vascular hyperpermeability seen during ICG angiography that were responsible for the fluid leakage into the macula. In typical clinical practice, conventional fluorescein angiography may be used in lieu of ICG as it provides sufficient useful information. Safety precautions include avoidance of directly treating the central fovea to help reduce the possibility of inducing foveal atrophy with the PDT. Although we used the usual dose of verteporfin, it may be possible to reduce the dosage, possibly resulting in decreased costs.

On occasion PDT has been used for typical acute leaks. Because of the high cost of PDT, its use has typically been limited in classic CSC to those patients with focal leaks near the center of the fovea where laser photocoagulation may induce excessive harm. Our group conducted a small case series of focal RPE leaks treated with PDT.[81] No areas of hyperpermeability distant from the RPE leak were included in the treatment. All nine eyes showed resolution of both fluorescein leakage and anatomic macular fluid. Visual acuity improved in seven eyes and remained the same in two eyes. There were no adverse events. Interestingly, many of the study cases treated did not have ICG. The leak plus 1 mm was treated in these patients and the clinical results showed resolution of the leakage and fluid. Therefore, it probably is not necessary to treat the hyperpermeable area as delineated by ICG for acute leaks. Although our case series suggests that PDT with verteporfin can lead to resolution of focal RPE leaks in CSC, the study is limited by its small size, retrospective nature, and lack of a control group to help ascertain if the resolution was due to the PDT or the natural disease course.

 

 

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