Oman Journal of Ophthalmology

REVIEW ARTICLE
Year
: 2018  |  Volume : 11  |  Issue : 2  |  Page : 103--112

Central serous chorioretinopathy: Current update on pathophysiology and multimodal imaging


George Joseph Manayath, Ratnesh Ranjan, Vanee Sheth Shah, Smita S Karandikar, Veerappan R Saravanan, Venkatapathy Narendran 
 Department of Vitreo-Retina Services, Aravind Eye Hospital and Post-graduate Institute of Ophthalmology, Coimbatore, Tamilnadu, India

Correspondence Address:
Ratnesh Ranjan
Aravind Eye Hospital and Post-graduate Institute of Ophthalmology, Coimbatore - 641 014, Tamil Nadu
India

Abstract

Central serous chorioretinopathy (CSC), the fourth most common nonsurgical retinopathy, is characterized by serous retinal detachment most commonly involving the macular region. Although natural history of CSC shows a self-limiting course, patients are known to present with persistent, recurrent, or even bilateral CSC with distressing visual loss. Multimodal imaging techniques for CSC include optical coherence tomography (OCT) with enhanced depth imaging, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, and OCT angiography. Evolution of new imaging techniques in addition to conventional imaging modalities has revolutionized the understanding about the pathophysiology of CSC and hence the diagnosis and management. This review article elaborates on current understanding about pathophysiology and risk factors, as well as multimodal imaging-based features of CSC.



How to cite this article:
Manayath GJ, Ranjan R, Shah VS, Karandikar SS, Saravanan VR, Narendran V. Central serous chorioretinopathy: Current update on pathophysiology and multimodal imaging.Oman J Ophthalmol 2018;11:103-112


How to cite this URL:
Manayath GJ, Ranjan R, Shah VS, Karandikar SS, Saravanan VR, Narendran V. Central serous chorioretinopathy: Current update on pathophysiology and multimodal imaging. Oman J Ophthalmol [serial online] 2018 [cited 2020 Aug 4 ];11:103-112
Available from: http://www.ojoonline.org/text.asp?2018/11/2/103/233321


Full Text



 Introduction



Central serous chorioretinopathy (CSC), the fourth most common nonsurgical retinopathy,[1] is defined as serous retinal detachment with or without pigment epithelial detachment (PED) most commonly seen in the macular region. It was first described by Von Graffe in 1866.[2] Since then, the understanding of the disease has undergone a paradigm shift owing to the advances in the imaging modalities. Initially, it was described as “central retinitis,” and capillary vasospasm was thought to be responsible for the same. Maumenee suggested the primary pathology to be in retinal pigment epithelium (RPE) and choroid, as the leak on fundus fluorescein angiography (FFA) was at the level of RPE. The term “CSC” was coined by Gass. It is generally a self-limiting disease; however, sequelae such has RPE damage resulting in diffuse retinal pigment epitheliopathy (DRPE), and choroidal neovascular membrane (CNVM) formation can be seen. Lately, it is shown to be a part of the spectrum of pachychoroid disease which includes pachychoroid pigment epitheliopathy, CSC, pachychoroid neovasculopathy as well as polypoidal choroidal vasculopathy (PCV).

This review article aims to provide basic as well as updated information related to CSC. We reviewed the published data on epidemiology, pathophysiology, clinical features, and multimodal imaging of CSC. Literature review was conducted by searching Scopus, PubMed, and web of science to find relevant published data till March 2017, using the following combined search terms: “CSC,” “epidemiology,” “pathophysiology,” “clinical features,” “multimodal imaging,” “optical coherence tomography (OCT),” “FFA,” “indocyanine green angiography (ICGA),” “fundus autofluorescence (FAF),” and “OCT angiography (OCTA).”

 Epidemiology



CSC is classically described in a middle-aged man, however, can be seen from 20 to 64 years.[3],[4] The mean age in various studies is noted to be from 39 to 51 years.[4],[5] Spaide et al. noted poorer visual acuity, DRPE changes, and secondary CNVM more in the elderly than young.[5] Kitzmann et al. showed the annual incidence of CSC to be 9.9 per 100,000 men and 1.7/100,000 women in a population-based study in Minnesota.[3] CSC is more common in males, the male: female ratio being from 2.6:1 to 6:1 in various studies.[3],[5] Elias et al. noted male sex to be associated with higher incidence of recurrence as well.[6] CSC has been noted to be bilateral in 14% to 40%.[7],[8] The incidence of multifocal CSC and bilateral CSC is higher in Asians compared to Caucasians and African Americans.[9]

 Risk Factors and Pathophysiology



A recent meta-analysis by Liu et al., which included 9839 patients from 17 studies, found the risk factors showing significant association with the occurrence of CSC to be hypertension (odds ratio [OR] =1.7; 95% confidence interval [CI]: 1.28–2.25), Helicobacter pylori infection (OR = 3.12; 95% CI: 1.81–5.40), steroid usage (OR = 4.29; 95% CI: 2.01–9.15), sleeping disturbance (OR = 1.90; 95% CI: 1.28–1.83), autoimmune disease (OR = 3.44; 95% CI: 1.90–6.26), psychopharmacologic medication use (OR = 2.69; 95% CI: 1.63–4.45), and Type A behavior (OR = 2.53; 95% CI: 1.08–5.96).[10]

The alteration in choroidal circulation is probably the main mechanism leading to the development of CSC. Tewari et al. suggested that autonomic dysfunction (increased sympathetic and decreased parasympathetic activities) may lead to the inability of choroidal vessels to maintain homeostasis and lead to choroidal hyperperfusion ultimately resulting in subretinal fluid (SRF) accumulation.[11] Increased levels of epinephrine and norepinephrine were noted in cases with active CSC.[12] The association between type A personality and CSC is known since 1987.[13] Type A personality, characterized by a competitive drive, sense of urgency, hostile temperament, and aggressive nature, leads to the activation of the neuroendocrine system with the release of catecholamines and corticosteroids, thus altering the choroidal permeability.[13] There are reports linking obstructive sleep apnea with CSC,[14],[15] while other studies contradict this association.[16]

A very consistent association has been noted between CSC and exogenous corticosteroid use, most commonly with systemic administration either intravenous or oral. However, steroids used through other modes such as intranasal in nasal spray, topical dermal in skin creams, intra-articular, epidural, or periocular modes of corticosteroids may be associated with CSC.[17] There are no reports till now where intraocular corticosteroid use is associated with CSC. Even increased level of endogenous steroids such as in Cushing syndrome or during pregnancy is also shown to be associated with CSC.[17] The corticosteroids may have an effect on vascular autoregulation, systemic hypertension, prothrombotic effect, or inhibit collagen synthesis in Bruch's membrane. It may also alter the epithelial water and ion transport, thus affecting function of RPE.[2]

Association between H. pylori infection, as well as acid peptic disease and CSC, has been noted in several reports.[18],[19] The acid peptic disease is also associated with increased stress or sleep disturbance. However, apart from this, the mechanism proposed for this association is immune-mediated damage to choroidal endothelial cells through molecular mimicry.[18]

Drugs other than corticosteroids which have been associated with CSC are sympathomimetic agents such as pseudoephedrine and oxymetazoline, 3,4-methylenedioxymethamphetamine, and ephedra.[20],[21] This can be related to the altered response of the sympathetic and the parasympathetic systems. There are anecdotal case reports where phosphodiesterase-5 inhibitors are associated with CSC.[22]

The familial predisposition of CSC has been noted in the literature.[23] Although the exact gene is not yet identified, single nucleotide polymorphisms in Complement factor H and Cathedrin 4 have been shown to be associated.[17] The CSC-associated pachychoroid morphology such as thick choroid with dilated outer choroidal vessels (pachyvessels) may also be inherited and has been found in up to 50% of relatives.[24]

With all the information about the predisposing factors as well as the dysfunction of autonomic system and the choroidal blood flow, the pathophysiology of CSC is still unclear. Initially, it was thought to be a vasospastic disease till FFA revealed the leak to be at the level of RPE. The role of the choroid in the pathogenesis has been increasingly emphasized by the newer imaging modalities. The choroid is shown to be thicker and hyperpermeable in cases of CSC. Manayath et al. proposed myopia to be a protective factor for CSC owing to the thinning and atrophy of RPE as well as choroid.[25] The choroidal hyperpermeability might be secondary to inflammation, ischemia, or stasis of the choroidal circulation.[2] Choroidal lobular ischemia, venous congestion, and choroidal hyperpermeability have also been noted on ICGA.[26],[27] Hence, the interplay between the RPE dysfunction, choroidal hyperpermeability, and increased hydrostatic pressure in the choroid may result in PED or accumulation of SRF when there is a breakdown of the RPE barrier to result in CSC. Microrips have also been demonstrated at the site of CSC leak.[2]

 Clinical Features



The features of CSC can be mainly divided into acute and chronic stage, although the distinction is not quite clear. The time duration for chronic CSC is described from 4 to 6 months. The presenting symptoms include central scotoma, metamorphopsia, micropsia, or blurred vision. The refraction may show a hypermetropic shift. In the acute stage, classically, a serous macular detachment is seen [Figure 1]a. Occasionally, yellowish subretinal material which is due to fibrin may also be seen [Figure 1]c. Subretinal precipitate-like deposits are seen in cases with a longer duration of symptoms.[28] RPE defects may be seen clinically. The acute episode of CSC generally resolves within 3–4 months. If fluid persists beyond this period, it is called as “nonresolving or persistent CSC.”{Figure 1}

The chronic stage, also described as DRPE, shows RPE degeneration along with shallow SRF and cystoid or schitic retinal edema [Figure 2]. RPE degenerative changes may be seen all over macula affecting the vision. The RPE tracks, mostly in a teardrop configuration due to the gravitational tracking of the fluid, may also be seen [Figure 2]. In cases, where after a documented resolution of fluid and betterment of symptoms, if the SRF reappears, it is called as “recurrent CSC.” There can be recurrences from the same or a different point of the leak as well.{Figure 2}

Atypically, CSC may be associated with inferior exudative retinal detachment with shifting of fluid. Such cases may be associated with multifocal PED at the posterior pole and multifocal leaks on FFA.[29] Large RPE tears may also be seen. This is generally seen where the patient is undergoing systemic corticosteroid therapy for conditions such as an organ transplant or autoimmune disease. Discontinuation of steroids showed resolution in 87.5% cases.[30]

Although CSC is generally self-limiting, chronic cases with RPE degeneration may progress to foveal atrophy or CNVM (2%–9% cases) causing vision loss. Furthermore, cases of PCV are shown to be associated with CSC.[31]

 Multimodal Imaging



Multimodal imaging techniques have revolutionized the understanding about the pathophysiology of CSC, the diagnosis as well as management of this condition.

 Optical Coherence Tomography



Currently, spectral domain OCT (SD-OCT) is the first-line imaging modality used for the diagnosis of CSC and is an objective way to follow the changes. Recently, emergence of OCT with deep imaging techniques such as enhanced depth imaging (EDI), en face swept source-OCT (SS-OCT) have allowedin vivo documentation of RPE-Bruch membrane complex, and choroidal vasculature at variable depths. These newer imaging techniques help in improved morphological analysis and hence better elucidation of the pathophysiology and management of CSC as well as detection of occult CNVM in such cases.

Choroid

CSC is currently considered as an entity of the pachychoroid spectrum of disorders. A number of EDI-OCT-based studies have shown increased choroidal thickness in eyes with CSC as well as in the fellow eyes, compared to normal healthy subjects [32],[33],[34],[35] [Figure 3]. In addition, studies have shown thicker choroid in the involved eye compared to that in uninvolved fellow eye.[2],[36] Although increased choroidal thickness is a common association with CSC, it is not a mandatory criterion for making a diagnosis of CSC.{Figure 3}

En face SS-OCT shows the detailed pattern of choroidal vasculature in CSC eyes. Usually, the inner choroidal layer shows thinning in the involved area either due to primary atrophy of choriocapillaris or due to compression by dilated outer choroidal vessels.[32] Outer choroidal vessel dilatation is seen in eyes with CSC as well as other entities of pachychoroid spectrum.[33] Vascular dilatation could be focal or diffuse with differential involvement of various choroidal vascular layers and differs in acute and chronic cases.[34] A recent retrospective study of en face OCT imaging of 25 eyes with CSC and 13 contralateral eyes showed abnormal hyperreflective areas at level of Bruch's membrane and choriocapillaris complex, which correlated to abnormal hypofluorescent areas detected on ICGA in the late phase.[35]

Additional choroidal findings noted in active chronic CSC include hyperreflective dots (HRDs) in inner choroid and hyperreflectivity of wall of dilated vessels, which suggests ongoing qualitative changes in choroid [37] [Figure 2]c. However, prognostic significance of these structural changes remains to be evaluated. En face OCT also helps in the identification of CNV, without the use of angiography, in cases of chronic CSC.[38]

Retinal pigment epithelium

Although OCT does not show any pathology specific to RPE layer in acute CSC, PED is a common association of CSC, noted in >50% eyes.[32],[39] CSC-associated PED, usually a serous detachment, could be located both within and outside the SRF, and co-localizes with area of choroidal vascular abnormality noted as dilatation on EDI-OCT and hyperpermeability on ICGA.[32],[40] An absence of a signal at the RPE level, seen on en face OCT, corresponds to RPE detachment or RPE loss.[38] A double layer sign defined as undulated RPE layer with hyporeflective content over the intact underlying Bruch's membrane has been described in chronic CSC [Figure 4]a. However, the prevalence of RPE microrip, resulting from sustained elevated hydrostatic pressure, does not differ between the acute and chronic CSC.[32] SD-OCT images can also show RPE layer irregularity in chronic CSC suggesting the RPE atrophy due to prolonged detachment [Figure 2]c.{Figure 4}

Subretinal space

SRF is one of the characteristic features of CSC. In acute CSC, SRF is serous and appears as hyporeflective area between neurosensory retina (NSR) and RPE [Figure 1]b. Sequential OCT imaging helps to assess the response of treatment by comparing the SRF level. As the disease duration increases, HRDs appear in SRF and increase in number with duration, indicative of chronicity of SRF. The origin of these HRD is not clear, but they could be photoreceptor outer segments shedding, activated microglia and macrophages, or concentrated fibrin or lipid compounds.[2],[17]

Atypical CSC or pregnancy-induced CSC may present with a clump or band-like fibrin deposits in subretinal space [2] [Figure 1]d. Sometimes, a bridging tissue extending from outer retinal layers to RPE is also seen [Figure 4]b, which may account for atypical leakage pattern on FFA.[41]

Neurosensory retina

In acute CSC, the morphology of NSR remains intact with no intraretinal fluid despite the presence of SRF. As SRF persists for longer period, the photoreceptor outer segment elongation, a change secondary to the lack of direct apposition and phagocytosis by the RPE in the detached retina, is noted frequently on SD-OCT [42] [Figure 5]c. An active flow through the RPE break can cause a focal erosion of PR outer segments, seen on SD-OCT, just above the leaking point.[17] Intraretinal HRD may be noted sometimes in acute CSC, and these dots may migrate from inner to the outer retinal layers with CSC evolution and slowly resolve with resolution of SRF.[43]{Figure 5}

In chronic CSC, intraretinal cysts or schitic spaces are often observed on OCT imaging after several years of disease duration, suggesting fluid passage through compromised RPE function [44] [Figure 2]c. Intraretinal HRD is more frequently seen in chronic or recurrent cases of CSC.[45] Persistent elongation of photoreceptor outer segments in chronic cases may result in either permanent subretinal deposits after SRF absorption or complete disappearance of outer segments resulting in poor visual prognosis [Figure 5]e.[42],[44],[45]

 Fundus Autofluorescence



FAF, a noninvasive imaging modality which has gained popularity during the last decade, is being used to assess RPE function at various stages of CSC. There are two types of FAF imaging techniques, namely, short-wave FAF (SW-FAF) and near-infrared FAF (NIR-FAF). SW-FAF originates from the lipofuscin pigment of the RPE and hence provides information about RPE health. NIR-FAF images the autofluorescence originating from melanin pigment of the choroid and RPE.[46] Although NIR-FAF is being used less commonly, studies have shown that NIR-FAF could be more sensitive than SW-FAF at detecting outer retinal changes in CSC.[46],[47]

In acute CSC, SW-FAF shows an area of hypoautofluorescence precisely corresponding to the leakage point noted on FA in more than three-fourth patients.[48],[49] The areas of subretinal detachment show corresponding hypoautofluorescence due to masking of autofluorescence originating from RPE by SRF and early elongation of photoreceptor outer segment in early stage of acute CSC.[50] NIR-FAF shows, similar to SW-FAF, focal hypoautofluorescence at the leakage site and reduced autofluorescence corresponding to the SRF in acute CSCR [51] [Figure 5]a and [Figure 5]b. NIR-FAF also shows granular hyperautofluorescence during follow-up, which, unlike SW-FAF, change to hypoautofluorescence or disappear completely over a period.[51],[52] These studies have speculated that the melanin contents of RPE could be affected earlier than the lipofuscin in resolved CSC and hence contribute to the characteristic changes of NIR-FAF.

In chronic CSC, similar to acute CSC, most of the eyes show hypoautofluorescence at the point of leakage noted on FFA; however, occasionally, a hyperautofluorescence can be seen at the previous leakage point due to RPE hyperplasia.[49] Area of persistent SRF in chronic CSC can show hypo or hyperautofluorescence depending on the duration [48] [Figure 5]f. Despite the presence of SRF, with increasing duration, the increase in autofluorescence is noted due to persistent photoreceptor outer segment elongation, which gradually accumulates autofluorescent fluorophores as by-products.[50],[53] This hyperautofluorescence may persist even after the resolution of SRF, corresponding to outer retinal atrophy with loss of photoreceptor cells, but intact RPE on SD-OCT, and hence could be result of unmasking of normal background autofluorescence from RPE.[27] Punctate or granular hyperautofluorescence usually corresponds to the ophthalmoscopic precipitates and may be concentrated fluorophores released from elongated photoreceptor outer segments [50],[54] [Figure 5]c and [Figure 5]d.

Eyes with CSC sequelae show mixed FAF patterns with variable intensities over area of RPE atrophy and gravity-driven descending tracts of RPE atrophy.[54] These tracts are typically hyperautofluorescent when the SRF is present in early stage, but later become increasingly hypoautofluorescent as RPE cells are damaged in the pathway of the fluid.[2] Granular hyperautofluorescence can also be observed in resolved CSC.[2],[49] Studies have shown a good correlation of FAF pattern with retinal sensitivity quantified by microperimetry and visual acuity, and hence it can also be used to estimate the functional impairment in eyes with CSC.[36],[55]

Thus, FAF findings in eyes with CSC differ according to the course of the disease, reflecting the RPE and outer retinal changes as well as functional damage. It can also be used as a noninvasive alternative to FFA to localize the leakage point, whenever later is contraindicated. Combining the two methods of autofluorescence imaging, SW-FAF and NIR-FAF, can better predict recent or resolved CSC episodes.

 Fundus Fluorescein Angiography



FFA is the oldest and classic imaging technique for CSC evaluation, which is often used to establish the diagnosis and to rule out other differential conditions. It helps to determine the type of leakage pattern and to localize the leakage point.[56]

In acute CSC, FFA typically shows a single leakage point or less commonly multifocal point leaks, which could be localized within or adjacent to the area of SRF [Figure 6]. Most commonly point leak is seen within the macula.[57] The point leakage seen as point hyperfluorescence in early phase of FFA evolves into two types of classical pattern in mid and late phase described as “ink-blot” and “smoke-stack” pattern [Figure 6] and [Figure 7]c,[Figure 7]d,[Figure 7]e. The ink-blot appearance is the more common (ranging from 53% to 93%) leakage pattern,[56],[57],[58] while the smoke-stack pattern is usually seen in the early phase of the acute CSC.[57],[58] In chronic CSC, FFA usually shows multifocal leakage or diffuse oozing of dye due to diffuse RPE defect resulting in patches of granular or mottled hyperfluorescence in mid and late phase [58],[59] [Figure 2]b and [Figure 6]d,[Figure 6]e,[Figure 6]f While in eyes with resolved CSC sequelae, FFA shows early hyperfluorescent areas due to window defect through localized RPE atrophy [8] [Figure 6]d. Other rarer and atypical angiographic leakage patterns described as “leaking scar,” or “blowout leak” have also been reported in CSC [41] [Figure 7].{Figure 6}{Figure 7}

In eyes with SRF with active leakage, evenly distribution and pooling of dye in SRF results in diffuse circular hyperfluorescence in mid and late phases. Serous PED, a common finding in CSC, shows early hyperfluorescence with progressive increase in the intensity due to pooling of dye, but size of hyperfluorescence remains unchanged [Figure 7].

 Indocyanine Green Angiography



ICGA has currently become a gold standard imaging tool for cases of chronic CSC to image the choroidal vasculature and to differentiate CSC from CNVM or PCV in such eyes.[26] In 1990s, a number of ICGA-based studies revealed abnormalities of choroidal vasculature in eyes with CSC which provided insights into the pathogenesis of the disease and that it originates from the choroid.[60],[61]

Main findings noted on ICGA in active CSC include choroidal filling delay in early phase, large choroidal venous dilatation, and focal choroidal hyperfluorescence attributed to choroidal vascular hyperpermeability surrounding the leakage point in mid-phase.[62],[63],[64] The midphase hyperfluorescent areas evolve into either persistent hyperfluorescence, wash-out, or centrifugal displacement of hyperfluorescence in the late phase.[62] In most eyes, ICGA shows transient hyperpermeability of choroidal vessels, visible as a multifocal hyperfluorescence, increasing in midphase, and fading in the late phase [65] [Figure 8]. Similar ICGA findings indicating choroidal changes have been observed in more than half of asymptomatic contralateral eyes.[62]{Figure 8}

Area of RPE atrophy shows hyperfluorescence in the early phase of ICGA due to window defect and hypofluorescence in the late phase. Choroidal changes associated with PED result in foci of early hyperfluorescence, and in the late phase of ICGA as hypofluorescence surrounded by a ring of hyperfluorescence at the margin of detachment.[65]

ICGA is an important diagnostic tool for the detection of CNVM in chronic CSC.[66] In a recent study, ultra-wide-field ICGA revealed dilated choroidal vessels and choroidal hyperpermeability in association with one or more congested vortex vein ampullas in >80% eyes with CSC, which suggests that outflow congestion may be a contributing factor to the pathogenesis.[27] Recently, Hirahara et al. have described a new method to quantify the choroidal vessel density by binarizing ultra-wide-field ICGA images and found that density was altered in eyes with CSC compared to that in normal control eyes.[67] This ICGA imaging-based new method of choroidal vessel density measurement may provide new insights into the management of CSC.

 Optical Coherence Tomography Angiography



OCTA is a new promising, noninvasive, depth-resolved imaging technique, which is based on the concept of detection of changes in blood flow in the vessels, in a static eye, without need for dye injection. OCTA images may be studied by isolated segmentation in different vascular layers, thus allowing detailed analysis of vascular structures at various depths with no darkening due to staining or leakage.[68]

OCTA shows image pattern of high signal intensity in all eyes with CSC and dilated choriocapillaris in most eyes with CSC.[69] Although it does not show any alteration in NSR directly associated with the leakage point in acute CSC,[70] abnormal choroidal flow patterns suggestive of focal choroidal ischemia with surrounding hyperperfusion have been noted on OCTA corresponding to the ICGA findings, in both acute as well as chronic CSC.[70],[71]

Costanzo et al. described three specific findings at the choriocapillaris by OCTA imaging as dark areas, dark spots, and abnormal choroidal vessels. The dark areas are described as diffuse or focal, foggy, ill-defined, low-detectable flow areas, while dark spots are described as black, single or multiple, well-delineated areas with no detectable flow at the choriocapillaris level. The dark areas usually correspond to SRF and dark spots to PED. Abnormal choroidal vessels are described as distinct, well-delineated, high-flow, tangled pattern areas in the choriocapillaris as well as an abnormal dilation of choroidal vessels.[68] However, these abnormal choroidal vessels observed in CSC eyes should be interpreted with caution, as in many cases this could be distinct from CNVM.[68]

In addition, OCTA allows noninvasive detection of CNVM in chronic CSC, even when other imaging techniques do not show evidence of any CNVM. These CNVMs are seen as abnormal choroidal vessel pattern usually corresponding to the small undulating PED seen on OCT B-scan.[72]

 Conclusion



Advancement of multimodal imaging techniques has revolutionized our current understanding about pathophysiology of CSC as well as diagnostic accuracy in cases of chronic CSC. Consequently, current approach toward the management of CSC is also advancing and refining significantly, and now resulting in better final outcome of the disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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