Abstract Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress. Introduction Central serous chorioretinopathy (CSCR or CSC) is a posterior segment disease characterized by localized and limited serous detachments of the neurosensory retina often associated with focal detachments of an altered retinal pigment epithelium. The term "central" refers to the form of the disease causing visual symptoms due to the presence of serous detachments in the macular area. But asymptomatic subjects may have presented one or multiple episodes of extra macular serous detachments, as often observed in the contralateral eye of an active CSCR patient or when systematically examining relatives of CSCR patients (Lehmann et al., 2015; Weenink et al., 2001) (Figs. 1 and 5D ). The prevalence of CSCR is therefore likely to have been underestimated. Introduction Whilst the acute CSCR form is clinically obvious especially in middle-aged men, the clinical diagnosis in older patients is more challenging, as chronic CSCR often resembles age-related macular degeneration (AMD) or can be complicated by choroidal neovascularization (CNV) (Fung et al., 2012; Inhoffen et al., 2012; Pang and Freund, 2015; Schatz et al., 1992) . CSCR diagnosis is also difficult when occurring secondarily to steroid treatments administered for other retinal diseases (Khairallah et al., 2012) . Recently, enhanced visualization of the choroid with spectral-domain optical coherence tomography (SD-OCT) has facilitated a more robust assessment of the role played by the choroid in CSCR, which in the past five years has resulted in more than 100 publications (Mrejen and Spaide, 2013) . Based on these observations, it was recently proposed that "pachychoroid pigment epitheliopathy" could be a subclinical phenotype potentially complicated by serous detachments and/or choroidal vasculopathy, including type 1 CNV and polypoidal vasculopathy (Pang and Freund, 2015; Warrow et al., 2013) . The segregation of the CSCR phenotypes becomes unclear. In particular, whether there is a continuum between acute simple CSCR associated or not with pachychoroid ( Fig. 2) , and the chronic variants of the disease (referred to as Diffuse Retinal Pigment Epitheliopathy, DRPE) is yet to be prospectively investigated. Sparse or unique acute episodes of CSCR have a favorable visual prognosis but DRPE is associated with progressive and bilateral vision impairment, and has been estimated as the fourth most frequent non-surgical retinopathy (Wang et al., 2008) . To date, the genetic, environmental, biological or clinical factors that favor one or the other form of this disease have not been established. Introduction The relation between CSCR and corticoids is probably one of the most intriguing aspects of the disease. Glucocorticoids efficiently reduce macular edema of many origins, even when associated with subretinal fluid (Noma et al., 2012; Ossewaarde-van Norel et al., 2011) , but glucocorticoids can aggravate subretinal fluid accumulation in CSCR patients. Even exposure to low-dose non-ocular corticosteroids has been associated with the occurrence of CSCR (Bouzas et al., 2002; Thinda et al., 2015) . But high-dose intraocular injection of glucocorticoids, routinely administered for the treatment of macular edema, has not been associated with increased incidence of CSCR. Such discrepancies reflect the still nonelucidated complexity of steroids regulation on ocular physiopathology. Introduction Since glucocorticoids aggravate rather than improve CSCR, inflammation was disregarded among potential disease mechanisms. This should be re-examined from the time when inflammation is recognized as a key player in the pathogenesis of AMD, in which unexpectedly glucocorticoid treatments did not show any major benefit (Geltzer et al., 2013) . Introduction Specific psychological and personality profiles have been associated with CSCR (Piskunowicz et al., 2014; Yannuzzi, 1986) but the exact link between anxiety-sensitive personalities and steroid biology has not been elucidated and the full ocular and systemic steroid hormonal profile of CSCR patients has been only partially explored (Zakir et al., 2009 ). More determinants should be now considered in light of recent discoveries linking stress, corticosteroids, epigenetic modifications and cardiovascular risk factors (Hunter, 2012; Reynolds, 2013) . Introduction All this considered, it is clear that complex links between CSCR and corticosteroids are yet to be described. In this context, we have investigated and identified the mineralocorticoid receptor as a . Near-infrared reflectance (B) shows a circular hyporeflectivity corresponding to the subretinal detachment, involving the fovea as confirmed by SD-OCT (C). The same imaging of his asymptomatic right eye (D, E and F, respectively) revealed an extrafoveal unnoticed subretinal detachment, associated to a leakage point (star) and an area of RPE defect, probably resulting from a previous episode. potential player in CSCR pathogenesis. This review will focus on recent findings that have furthered the epidemiology, the clinical understanding and the management of CSCR and will detail the possible role of the mineralocorticoid pathway in CSCR pathogenesis and treatment. General overview of CSCR Several comprehensive reviews dealing with CSCR diagnosis, pathophysiology and therapeutic interventions have been recently published Nicholson et al., 2013; Ross et al., 2011) . We will therefore focus on the more recent findings and debated issues regarding CSCR. General and essential evidence-based knowledge will be compiled in tables to facilitate a broad overview of the available literature. Epidemiology CSCR ranks among the most common vision-threatening retinopathies after AMD, diabetic retinopathy and branch retinal vein occlusion (Wang et al., 2008) . A higher prevalence among men was observed in several studies, with 72%e88% of cases occurring in male subjects (Spaide et al., 1996a; Tittl et al., 1999) . In a population-based study carried out in Olmsted County, Minnesota, the reported annual incidence was 9.9 per 100,000 individuals for men and 1.7 for women, indicating a 6-times higher incidence in men than in women (Kitzmann et al., 2008) . Epidemiology There is a variability in the reported age of affected patients, the more recent epidemiological data reporting a higher mean age than generally assumed, ranging between 39 and 51 years (Kitzmann et al., 2008; Tsai et al., 2013a) . CSCR can occur at later ages, particularly in women and patients affected by atypical chronic forms (Cohen et al., 1983; Kitzmann et al., 2008; Lafaut et al., 1998; Perkins et al., 2002; Quillen et al., 1996) . Noteworthy, CSCR has been rarely reported in children . Epidemiology Variations of CSCR incidence among various ethnic groups remain controversial. A suspected higher frequency among Asians, Caucasians and Hispanics as compared to African Americans (Chan et al., 2010; Yannuzzi, 1987) was not confirmed in all studies (Desai et al., 2003) . A more severe form of CSCR with lower visual acuity seems to affect the African American subjects. In the Asian population, CSCR is frequent and severe, with bilateral and multifocal forms being reported more frequently than in other ethnic groups (How and Koh, 2006) . In a Taiwanese population-based study, the mean annual incidence of non-steroid induced CSCR was 21/ 100,000 (twice the incidence reported in Olmsted County, Minnesota) with a male/female ratio of 1.74. The incidence was highest in the 35e39 year-old age group, followed by the 40e44 year-old Fig. 3 . Multimodal imaging of active chronic CSCR in the right eye of a 45-year old man. FAF showed hypo-autofluorescent gravitational tracks (A). FA revealed a corresponding increased transmission of fluorescence related to the extended RPE alterations, and an active leakage site (arrow) corresponding to the RPE elevation on EDI-OCT (H, star). ICG showed dilated choroidal vessels and hyperpermeability (D, E), and late hyperfluorescence of the leakage site (F). EDI-OCT (H) visualized a RPE elevation and a hyper-reflective flow within the subretinal fluid. Beneath the RPE elevation, the choroidal vessels were more dilated, with hyper-reflective walls, and the choriocapillaris was thinner than in adjacent areas (star). FAF: fundus autofluorescence; FA: fluorescein angiography; ICG: indocyanine green angiography; IR: infrared reflectance; EDI-OCT: enhance-depth imaging optical coherence tomography. Epidemiology group. Males had a higher mean annual incidence than females, but this difference was significant only in the younger age groups, suggesting that women present CSCR at older ages (Tsai et al., 2013a) . Finally, in the Asian population, large pigment epithelial detachments and highly elevated serous retinal detachments are more frequently observed, which might be misdiagnosed as Harada disease and aggravated by high-dose systemic corticosteroids (Kunavisarut et al., 2009 ). Risk factors Genetic predisposition Several sporadic cases of familial CSCR have been reported in the literature (Amalric et al., 1971; Haik et al., 1968; Lin et al., 2000; Oosterhuis, 1996; Park et al., 1998; Wyman, 1963) . Stronger evidence for a genetic contribution to the pathogenesis of CSCR comes from the observation that in 14 out of 27 families of CSCR patients (52%), at least one relative presented multiple areas of RPE atrophy or fundus lesions suggestive of chronic CSCR (Weenink et al., 2001) . To date, no clear transmission pattern and no specific genotype have been associated to CSCR. In a recent analysis of five families, 50% of the eyes from relatives of CSCR patients had a choroid thicker than 395 mm, suggesting that pachychoroid could be an inherited condition with a possible dominant transmission pattern (Lehmann et al., 2015) . Genetic predisposition If confirmed, this hypothesis would suggest that a genetic background may predispose to CSCR and that thick choroids could be one of its phenotypic indicators. Genetic predisposition Genetic studies based on single nucleotide polymorphisms have been performed on different cohorts of CSCR subjects. Complement factor H (CFH) was chosen as a candidate susceptibility gene for CSCR because the protein binds to adrenomedullin, a peptide that belongs to the calcitonin family and elicits a vasodilator action on the choroid. An association was found in 5 common polymorphisms of the CFH gene in a group of 140 Asian CSCR cases (compared to 934 population-based and 335 hospital-based controls), suggesting in this population a potential involvement of CFH in CSCR pathogenesis (Miki et al., 2013) . In a larger cohort of 292 chronic CSCR patients (compared to 1147 AMD cases and 1311 healthy individuals), single nucleotide polymorphisms at 19 loci previously associated with AMD have been investigated. An association of chronic CSCR with genetic variants in ARMS2 and CFH was demonstrated, suggesting a genetic and pathogenic overlap between chronic CSCR and AMD (De Jong et al., 2014) . However, in this study, alleles in ARMS2 and CFH that confer risks for AMD were protective for CSCR and alleles in CFH that were protective for AMD were associated to CSCR. Genetic predisposition Interestingly, we have analyzed the subretinal fluid obtained 3 ). FAF exhibited two circular patchy areas of increased autofluorescence related to previous CSCR episodes (A). FA revealed two areas of mild residual RPE window defect (B, C). ICG showed two areas of persistent hyperpermeability (D, E) during early and midphase, with centrifugal expansion and central hypofluorescence at late phase. EDI-OCT confirmed the absence of active episode (H). It also showed a pachychoroid with dilated choroidal vessels, and a mild photoreceptor outer segments atrophy (between arrows and dotted lines). This atrophy corresponded partially to the hyperautofluorescence (A), possibly via a window defect in photopigment density. FAF: fundus autofluorescence; FA: fluorescein angiography; ICG: indocyanine green angiography; IR: infrared reflectance; EDI-OCT: enhance-depth imaging optical coherence tomography. Genetic predisposition from a patient with chronic CSCR and found higher levels of CFH and lower levels of all other complement fractions compared to the subretinal fluid of control patients with rhegmatogenous retinal detachments (unpublished personal data). This observation is in agreement with the previous genetic findings. Finally, in a cohort of 400 CSCR cases (compared to 1400 matched controls), a significant association was found with 4 common cadherin 5 single-nucleotide polymorphisms in CSCR male patients. Since cadherin 5 contributes to intercellular adhesions in the vascular endothelium, and is down-regulated by corticosteroids, genetic variations in cadherin 5, combined with triggering events such as corticosteroid treatment, could explain a proportion of CSCR occurrences among male patients (Schubert et al., 2014) . Cardiovascular diseases and hypertension Patients with hypertension have a higher risk of developing CSCR (Odds Ratio (OR): 2.25e2.3) (Eom et al., 2012; Tittl et al., 1999) . As compared to control patients, males with CSCR have a significantly higher rate of coronary heart disease (Hazard Ratio (HR): 1.72), indicating that CSCR may be a potential risk factor for the development of coronary heart disease in men . CSCR was also shown to be an independent risk factor for ischemic stroke (HR: 1.56; 95% confidence interval (CI), 1.11e2.18) (Tsai et al., 2012) , and for organic and psychogenic erectile dysfunction (HR: 2.14; 95% CI, 1.34e3.44 and 3.83; 95% CI, 1.47e10.01, respectively) (Tsai et al., 2013b) . Consequently, the choroidal vasculopathy described in CSCR may not be isolated but rather part of a more diffuse vascular dysfunction that is yet to be better characterized. Sympathetic-parasympathetic activity and reactivity Compared to healthy subjects, CSCR patients present a significant sympathetic-parasympathetic imbalance. There is sympathetic over-activation and a decreased parasympathetic activity, as assessed by measures of blood pressure and heart rate variability (Tewari et al., 2006) . This may be related to the modulation of the choroidal blood flow by the autonomic nervous system, and appears consistent with the damages induced in vitro by epinephrine on RPE cells, ultimately leading to apoptosis (Sibayan et al., 2000) . Corticosteroids CSCR patients are more likely to have been previously exposed to oral corticosteroid medications, and patients under corticosteroid therapy are at higher risk for developing CSCR (CarvalhoRecchia et al., 2002; Haimovici et al., 2004; Karadimas and Bouzas, 2004; Kitzmann et al., 2008; Tittl et al., 1999; Tsai et al., 2014; Wakakura et al., 1997) . When considering the route of administration, most series have clearly reported that systemic intake (oral or intravenous) is an independent risk factor for CSCR (Haimovici et al., 2004; Tittl et al., 1999; Tsai et al., 2014; Wakakura et al., 1997) . CSCR has also been described after local administration of corticosteroids via the following routes: inhaled and intranasal (Haimovici et al., 1997; Kleinberger et al., 2011) , epidural (Iida et al., 2001; Kao, 1998; Pizzimenti and Daniel, 2005) , intra-articular (Hurvitz et al., 2009; Kassam et al., 2011; Mondal et al., 2005) , topical dermal (Ezra et al., 2011; Fernandez et al., 2004; Karadimas and Bouzas, 2004; Romero et al., 2005) and periocular (Baumal et al., 2004) . Whether intraocular steroids induce CSCR remains to be demonstrated. The aggravation of a pre-existing CSCR and the induction of a CSCR after vitrectomy and triamcinilone injection have been described in two case reports (Imasawa et al., 2005; Kocabora et al., 2008) . A systematic literature search of corticosteroid-induced CSCR reports is summarized in Table 1 , indicating the incriminated drugs, routes of intake and doses. Corticosteroids Systemic corticosteroids have been associated with occurrences, prolongation, exacerbation and recurrences of CSCR (Khairallah et al., 2012) . Steroid-induced CSCR has less male predilection than idiopathic CSCR, and has frequently a bilateral and atypical presentation (Bouzas et al., 2002; Khairallah et al., 2012) . It was suggested that steroid-induced CSCR may be related to an idiosyncratic response in selected vulnerable individuals rather than to a dose-dependent effect, since very low doses can induce CSCR episodes (Han et al., 2014) . During corticosteroid treatment for posterior uveitis, the discrimination between steroid-induced serous retinal detachments and uveitis-related manifestations can be challenging (Khairallah et al., 2012) . Some studies have suggested that concomitant use of steroid and catecholamines may have additive effects in animal models of serous retinal detachment (Falkenstein et al., 2000; Jampol et al., 2002; Walker et al., 1996; Yoshioka et al., 1982) . Organ transplant procedures require treatments with high doses of glucocorticoids and vasopressive catecholamines and stimulate the endogenous production of stress hormones increasing the risk of CSCR. Indeed, there are numerous reports of CSCR following organ transplantation, the more frequently involved interventions being: kidney, bone marrow and heart transplantations (Chaine et al., 2001; Cheng et al., 2002; Chung et al., 2007; Farzan et al., 2014; Fawzi et al., 2006; Fawzi and Cunningham, 2001; Friberg and Eller, 1990; Kamoun et al., 2005; Karashima et al., 2002; Kian-Ersi et al., 2008; Moon and Mieler, 2003; Oliaei et al., 2007; Polak et al., 1995; Sabet-Peyman et al., 2012; Singh et al., 2003) . Finally, allergy has been suggested to favor CSCR, yet various allergic manifestations are managed with local or systemic corticosteroids and the distinction between the contribution of allergy or its treatment remains to be determined (Edalati et al., 2009 ). Endocrine changes The risk of CSCR is higher in case of prior or current pregnancy (adjusted OR: 7.1; 95% CI, 1.0e50.7) (Haimovici et al., 2004) , particularly during the third semester. It can resolve spontaneously after delivery (Chumbley and Frank, 1974; Errera et al., 2013; Schultz et al., 2014) , linking cortisol levels and/or pregnancyassociated hormonal variations to CSCR (Cousins et al., 1983; Errera et al., 2013; Schultz et al., 2014) . CSCR develops in up to 5% of patients with endogenous Cushing syndrome (Bouzas et al., 1993; Carvalho-Recchia et al., 2002) . The relationship between endogenous steroids and CSCR was evaluated in several comparative studies: the 8-am and 11-pm serum cortisol levels (Garg et al., 1997; Zakir et al., 2009 ) and total 24-h urine cortisol level (Garg et al., 1997; Kapetanios et al., 1998) were increased in acute CSCR patients as compared to normal subjects. In an observational series of 24 acute CSCR cases (Haimovici et al., 2003) , 50% of patients had elevated 24-h urine cortisol and tetrahydroaldosterone levels, whereas serum aldosterone levels were low in 29% of patients, indicating that mineralocorticoid regulation could also intervene in the pathogenesis of CSCR. Twenty-nine percent of patients exhibited elevated single morning plasma catecholamine level, but normal 24-h urine metanephrines, the byproducts of catecholamine breakdown. Serum testosterone levels were not raised in a cohort of CSCR patients compared to controls (Zakir et al., 2009 ). Psychopathology In 1986, Yannuzzi observed an association between CSCR and "type-A" personality pattern, characterized by a competitive drive, a sense of urgency, an aggressive nature and a hostile temperament (Yannuzzi, 1986) . Subsequently, anti-psychotropic medication use and psychological stress were described as independent risk factors for CSCR (OR: 2.6; 95% CI, 1.30e5.19) (Tittl et al., 1999) and psychiatric illness (depression) was associated with an increased risk of recurrence (HR: 3.50; 95% CI, 1.33e9.23) (Fok et al., 2011) . In a questionnaire-based study of 31 CSCR cases compared to 31 matched controls, no excess of critical life events (regarding social, professional, health and financial categories) was observed among CSCR patients, but higher levels of emotional distress, somatization, depression and hostility were observed (Conrad et al., 2007) . More recently, the possible association between narcissistic personality (characterized by an extreme gratification of self) and CSCR was suggested (Carlesimo et al., 2014) . Indeed, a systematic analysis of 57 CSCR patients and 57 age-and gender-matched controls was performed using psychometric questionnaires, which evaluate the emotional distress and psychopathology (i.e., somatization, obsessive-compulsive disorder, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism) and the personality (based on the Temperament and Character Inventory). Compared to healthy controls, CSCR patients presented with significant higher emotional distress index in all psychopathological categories and lower cooperativeness and reward dependence. Such individuals are hostile, critical, unhelpful, and opportunistic, have low consideration of other people's rights or feelings with a tendency to manipulate others for their own gain. This trait is in line with type-A personality that is associated with opportunistic competitiveness, aggression, hostility and low threshold of frustration tolerance. CSCR patients are particularly at risk of the development of stress-induced vision threat in their working environment and may have low therapeutic compliance (Conrad et al., 2014) . Gastroesophageal disorders Gastroesophageal reflux and CSCR share stress and adaptive response to stress as risk factors. In a retrospective caseecontrol study, CSCR patients had a higher risk of gastroesophageal reflux (OR: 6.05; 95% CI, 2.14e17.11) and of anti-acid or anti-reflux medication use (OR: 15.00; 95% CI, 1.91e117.58) (Mansuetta et al., 2004) . Interestingly, a recent population-based retrospective study investigating the risk factors of CSCR in Taiwan identified peptic ulcer (adjusted OR: 1.39; 95% CI, 1.14e1.70) and higher monthly income (adjusted OR: 1.30; 95% CI, 1.08e1.57) as independent risk factors . Among CSCR patients, the risk of peptic ulcer was higher after the diagnosis of CSCR. Several studies also reported a high prevalence of Helicobacter pylori infection in CSCR patients (Ahnoux-Zabsonre et al., 2004; Cotticelli et al., 2006; Giusti, 2001; Mateo-Montoya and MaugetFaÿse, 2014; Mauget-Faÿsse et al., 2002; Roshani et al., 2014) . H. pylori-dependent immune mechanism and molecular mimicry between pathogenic antigens and host proteins (Giusti, 2004 ) has been hypothesized but additional studies are needed to confirm the relationship between CSCR and H. pylori, and the benefit of H. pylori treatment on the course of CSCR, as suggested by some studies (Casella et al., 2012; Dang et al., 2013; Rahbani-Nobar et al., 2011) . Drug-induced CSCR (other than steroids) CSCR episodes have been associated to the use of sympathomimetic drugs, which can be related to the altered reactivity profile of CSCR patients to sympathetic stimuli (see 2.2.3). In two separate case series, CSCR has been linked to the following adrenergic receptor antagonists: pseudoephedrine and oxymetazoline (contained in nasal sprays prescribed for upper airways congestion), MMDA (an illicit amphetamine) and ephedra (contained in bodybuilding dietary products) (Michael et al., 2003; Pierce and Lane, 2009) . CSCR has also been described after the use of phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) , but there is conflicting evidence regarding CSCR resolution after treatment discontinuation (Aliferis et al., 2012; Fraunfelder and Fraunfelder, 2008) . Drug-induced CSCR (other than steroids) Up to 65% of patients receiving oral MEK-inhibitors (binimetinib) for metastatic cancer, develop transient bilateral serous retinal detachments and moderately blurred vision (McCannel et al., 2014; Urner-Bloch et al., 2014) . Clinical manifestations occurred within days after initiation of MEK-inhibitor therapy and, with a dosedependent effect on central retinal thickness on OCT imaging. In all reports, symptoms and subretinal fluid spontaneously resolved without treatment interruption. In part of these cases, an associated anterior uveitis suggests the hypothesis of an inflammationinduced serous detachment. Interestingly, no abnormalities were found on fluorescein or indocyanine green (ICG) angiography. Sleep disturbances The role of sleep disturbances and particularly obstructive sleep apnea in CSCR is controversial. Obstructive sleep apnea has been reported in 22% of CSCR patients, which is markedly elevated compared to 2e4% reported in the general population (Eom et al., 2012; Kloos et al., 2008) . But the retrospective questionnairebased analysis of 48 CSCR patients and 48 age-, gender-and body mass index-matched control subjects revealed a similar rate of obstructive sleep apnea in CSCR (46%) and controls (44%) (Brodie et al., 2015) . This discrepancy can be explained by neutralization of the body mass index co-factor, an established risk of obstructive sleep apnea. Clinical presentation: forms and definitions The term "CSCR" covers two distinct entities, classically defined as the acute and chronic forms of the disease. This distinction is somewhat ambiguous because it relies on a temporal criteria (the duration of the serous retinal detachment), and on the presence of extended RPE changes. In the acute form ( Figs. 1 and 2 ), patients report symptoms related to the localization of the subretinal detachment (SRD) in the macular area: blurred vision, relative central scotoma, metamorphopsia, moderate dyschromatopsia, hypermetropization, micropsia and reduced contrast sensitivity, which have been already extensively investigated (Wang et al., 2008) . The acute form is characterized by the presence of SRD, clinically detectable on fundus examination and on OCT, with limited focal or multifocal RPE alterations that may be limited to small pigment epithelial detachments (PEDs), and leakage through the RPE on fluorescein angiography (FA). The SRD usually resolves within 3e4 months, leaving in most cases no long-term symptoms, except color discrimination defects in some patients (Baran et al., 2005) . Possible permanent functional changes were described on ERGs. The term "classic" CSCR has been also used to describe these patients with a circumscribed area of subretinal fluid associated with one or a few leaks seen on FA. Clinical presentation: forms and definitions No consensus exists over the duration threshold that differentiates acute and chronic CSCR, arbitrarily set between 4 and 6 months in most published reports. This limit is critical for therapeutic studies since it determines the appropriate timing for intervention, when self-resolution is no longer to be expected. Authors have referred to acute CSCR with persistent SRD after this initial period as "chronic" CSCR. However, we suggest that the terms "non-resolving" or "persistent" CSCR are more appropriate to describe these cases with long-lasting SRD, preventing confusion with the chronic form characterized by a diffuse pigment epitheliopathy. Clinical presentation: forms and definitions This chronic form (Figs. 3 and 4), which had been initially termed "diffuse retinal epitheliopathy" and was described as a variant of CSCR (Yannuzzi et al., 1992 ) is characterized by widespread tracks of RPE atrophy characterized by their decreased fundus autofluorescence (FAF) (Imamura et al., 2011; Teke et al., 2014) . Symptoms are permanent with moderate to severe visual acuity loss and decreased light sensitivity depending on the degree of photoreceptors outer segments damage (Ooto et al., 2010b; Piccolino et al., 2005) . In addition to chronic SRD, OCT shows multifocal RPE atrophy in areas corresponding to the hypoautofluorescent tracks, and irregular RPE detachments. Intraretinal cystoid cavities can also be observed (Iida et al., 2003; Piccolino et al., 2008a) and are associated with disease duration longer than 5 years (Piccolino et al., 2008b) . Aggressive forms of chronic CSCR characterized by bullous SRD and massive exudation with subretinal fibrin deposits have been referred to as "multifocal posterior pigment epitheliopathy" (Uyama et al., 1999) , a term rarely employed in the recent literature. As detailed in 2.1.3, bullous serous detachments seem more frequent in the Asian population, and are exacerbated by systemic corticosteroid treatment, as it occurs when CSCR is misdiagnosed for an inflammatory chorioretinal disorder. Clinical presentation: forms and definitions A consensual definition of the various clinical subtypes of CSCR and their exact limits is critical in the prospect of clinical trial design. We suggest the following definitions and indicate the main issues raised for each entity: Clinical presentation: forms and definitions Acute CSCR: self-resolving SRD within 4 months from the onset of symptoms. Should we consider it differently if pachychoroid and/or epitheliopathy are present in the contralateral eye? Or if signs of previous episodes are present in the diseased eye? Non-resolving CSCR (or "persistent" CSCR): acute CSCR with duration of SRD longer than 4 months after onset of symptoms, often associated with elongated photoreceptor outer segments on SD-OCT. Should we consider the existence of a new leaky point on FA as an exclusion criteria, classifying thus the patient as recurrent CSCR? Recurrent CSCR: episode of acute CSCR following a previous episode with complete SRD resolution. Should recurrent CSCR be regarded differently if they originate from the same or from new leaky point on FA? Chronic CSCR (formerly "diffuse retinal epitheliopathy"): chronic chorioretinopathy with widespread RPE decompensation with or without SRD, associated or not with active leakage sites. Should we include in this definition the recently introduced "pachychoroid pigment epitheliopathy" (Warrow et al., 2013) , or should it be considered as a separate entity? Inactive CSCR: patients with history of acute CSCR but without SRD at the time of evaluation An important point of terminology is the distinction between non-resolving and chronic CSCR. Whether uncomplicated acute CSCR can evolve into chronic CSCR with diffuse RPE disease, or whether they are two different entities, is still debated. Evidence of this connection relies on illustrative case reports and case series (Bujarborua, 2001; Katsimpris et al., 2007) . In one report, 8 of 50 patients demonstrate three years after initial evaluation a more extended surface of RPE defects on FA (Castro-Correia et al., 1992) . Noticeably, most reports include cases from ethnic groups in which CSCR often follows a more aggressive course (African, Indian and Portuguese patients), as discussed in 2.1.3. Clinical presentation: forms and definitions Although disease manifestations are usually reported by patients in one eye due to the presence of a macular SRD, CSCR presents often as a bilateral condition. Bilateral involvement has been reported in up to 40% of cases (G€ ackle et al., 1998) . In an analysis of 74 cases, 4% presented bilateral CSCR at the time of diagnosis, 8% of unilateral cases had either a history of CSCR or FA findings indicative of CSCR in the contralateral eye, and 9% of patients initially diagnosed with unilateral disease developed CSCR in the other eye during follow-up (Kitzmann et al., 2008) . In a retrospective case series of 229 patients, 32% of asymptomatic fellow eyes presented fluorescein angiographic features indicating healed or subclinical CSCR, including SRD, PEDs, depigmented or atrophic RPE patches, drusen-like deposits, or pigment clumps (Bujarborua et al., 2005) . Multimodal imaging of CSCR The diagnosis and follow-up of CSCR relies mostly on multimodal imaging. While SD-OCT is the primary modality, FAF is useful to non-invasively identify RPE alterations from previous episodes, and FA indicates the origin of jodi07@example.net. Recurrent, nonresolving and chronic cases should benefit from comprehensive multimodal imaging with SD-OCT, FAF, FA and ICG angiography in order to guide treatment, follow extension and detect neovascular or polypoidal components. Spectral-domain optical coherence tomography SD-OCT is the primary imaging modality for the diagnosis and follow-up of CSCR. State-of-the-art SD-OCT devices provide quick, non-invasive and reproducible high-definition images of the retinal layers and pathological modifications occurring in the macular area, facilitated by eye-tracking and landmark alignment algorithms which correlate serial images. Recently, enhanced-depth imaging and swept-source technologies have allowed full-depth visualization of the choroid, improving the morphological analysis of choroidal vessels and choroidal thickness measurements. Beyond subretinal fluid and PEDs associated or not to RPE leakage sites, other changes observed with SD-OCT imaging have given insight into the pathogenesis of CSCR. A review of the retinal and choroidal alterations identified by SD-OCT in CSCR patients is summarized in Table 2 . Spectral-domain optical coherence tomography 83.161.120.155. Choroid. Compared to healthy subjects, increased choroidal thickness has been reported in both affected Jirarattanasopa et al., 2012b; Kuroda et al., 2013; Yang et al., 2013a ) and fellow eyes of CSCR patients (Goktas, 2014; Maruko et al., 2011c; Yang et al., 2013b) (Fig. 5 ). In addition, affected eyes of unilateral cases were shown to have a greater choroidal thickness than fellow eyes (Goktas, 2014; Maruko et al., 2011c; Oh et al., 2014; Yang et al., 2013b) . The threshold limit of "normal" choroidal thickness remains to be determined taking into account correction for axial length, age and circadian rhythm. Spectral-domain optical coherence tomography Considering cohort studies measurements, 395 mm could be used as a sensitive value to diagnose "thick choroid" or "pachychoroid" (Lehmann et al., 2015) . Table 3 summarizes the reported choroidal thickness measurements in CSCR from the recent literature. Spectral-domain optical coherence tomography Choroidal thickening can result from focal or diffuse dilatation of large choroidal vessels (Fig. 5AeF) . These dilated vessels are commonly localized within areas of increased choroidal vascular permeability on ICG angiography (Jirarattanasopa et al., 2012b; Kuroda et al., 2013; Maruko et al., 2011c; Razavi et al., 2014; Yang et al., 2013a) . Above these dilated choroidal vessels, the inner choroidal layer, which includes medium and small vessels, is thinner than in adjacent areas (Yang et al., 2013a) (Fig. 5A ). This could result from primary atrophy of the choriocapillaris or compression by the enlarged vessels from the outer choroid. Interestingly, RPE elevations are usually observed at the site of dilated vessels, possibly indicating a mechanical stress on the RPE caused by an underlying compression (Fig. 5B) . In some patients, particularly in the contralateral eyes of active CSCR, an extremely thickened choroid is observed, inside which all vascular layers are equally visible without specific vessel enlargements (Fig. 5D) . In chronic cases, large vessel walls harbor a granular hyper-reflectivity suggesting possible changes in vascular wall structure (Fig. 5F ). Spectral-domain optical coherence tomography Hyperflective dots on SD-OCT have been described in the neuroretina and subretinal space of CSCR eyes (see 83.161.120.155). They can also be observed in the choroid, mostly in the inner choroid Whether the choroid is thicker in chronic than in acute CSCR is unclear, according to the available literature (Hamzah et al., 2014; Jirarattanasopa et al., 2012b) . The discrepancy between reports is due in part to the inconsistency of the definition of chronic CSCR, as discussed in 2.3.1. A decrease in choroidal thickness has been reported following CSCR resolution, or after physical or medical treatments (Table 4) . However, a decrease in large dilated vessels diameter may not be associated with a reduction in choroidal thickness ( Fig. 6A and C) , masking treatment effect and questioning the optimal endpoints for clinical trials. Spectral-domain optical coherence tomography Whilst increased choroidal thickness is associated with CSCR, it is not mandatory for its diagnosis as typical cases may not present with increased thickness (Fig. 2B) (Jirarattanasopa et al., 2012b; Kuroda et al., 2013) . Furthermore, there is limitation to the comparability of choroidal thickness measurements. Firstly there is a reduction in choroidal thickness with age, axial length, and myopic refractive error, and the choroid is also thinner in females than in males Ikuno et al., 2010; Li et al., 2011; Margolis and Spaide, 2009 ). Secondly, despite recent advances in automated delineation methods, the repeatability of measurements remains questionable. In all available devices the segmentation of the choroidal boundaries is manual and subject to large intra-observer variability (Mrejen and Spaide, 2013) , especially in CSCR where increased choroidal thickness further reduces the reflectivity change at the interface between the outer choroid and the sclera . In CSCR, the reported intra-observer and inter-observer differences in choroidal thickness measurements were 32e38 mm and 46e57 mm, compared to 19e25 mm and 26e35 mm in normal eyes, respectively . These limitations should be considered when reporting variations of choroidal thickness after therapeutic intervention. Spectral-domain optical coherence tomography 83.161.120.155. RPE. PED is encountered in 53%e100% of CSCR-affected eyes (Ahlers et al., 2009; Mitarai et al., 2006; Van Velthoven et al., 2005; Yang et al., 2013a) (Fig. 6) . PED is more frequently reported in chronic CSCR, and is observed inside or outside the subretinal fluid area (Van Velthoven et al., 2005) . In addition, PEDs may co-localize with areas of dilated, large choroidal vessels and thickened choroid on SD-OCT, and with vascular hyperpermeability on ICG angiography (Hirami et al., 2007; Yang et al., 2013a) , suggesting that PED may result from choroidal flow deregulation. In active CSCR cases, combination of SD-OCT with FA identified an elevation of the RPE or a PED at the leakage sites (Fig. 6G ) in most (Fujimoto et al., 2008; Mitarai et al., 2006) or all cases (Shinojima et al., 2010 ) from reported series. Multiple mechanisms of focal RPE barrier breakdown are likely involved in CSCR progression: mechanical stress resulting from increased intra-choroidal pressure or dilated choroidal vessels, reduced RPE adhesion, alteration of hydro-ionic RPE regulation, and RPE atrophy secondary to choriocapillaris hypoperfusion. Spectral-domain optical coherence tomography Different types of PED have been described. Whether they result from different mechanisms has not been characterized. Domeshaped PEDs have a sharply demarcated and protruding appearance, and lack signs of RPE hyperplasia (Fig. 6AeD) ; en face OCT has been used to assess their morphology and revealed a homogenous hyporeflective circular area with an hyper-reflective border (Ahlers et al., 2009; Van Velthoven et al., 2005) . Voluminous dome-shaped PEDs can develop (Fig. 6C) , and exceptionally rupture through the neurosensory retina into the vitreous cavity, as observed in an Asian patient (Fig. 6J ). This suggests a sustained elevation of the hydrostatic pressure occurring underneath the detached RPE. Irregular or wavy flat PEDs (Fig. 6FeH) have also been described. Irregular PEDs with hyper-reflective content overlying an intact thin hyper-reflective layer (attributed to the Bruch membrane), creating a "double layer sign" are more frequently observed in chronic CSCR (Shin and Lee, 2012; Yang et al., 2013a) (Fig. 6H) . Irregular PEDs could result from a loss of elasticity of the adjacent RPE basement membrane, due to chronically elevated RPE. We also have observed shallow PEDs in chronic CSCR cases, as shown in Fig. 6E , suggesting that adhesion of the RPE might be altered in such cases. The exact site of cleavage has not been ascertained by any histologic analysis of a CSCR eye but it seems that the RPE and its own basal membrane (the most inner layer of Bruch membrane) detach from the other layers of Bruch membrane, which remain attached to the choriocapillaris basal membrane. Abnormal ion and water transport through the RPE could contribute to the formation of a fluid pocket on the basolateral side of the RPE, favoring its subsequent detachment. The mechanisms of RPE reattachment are not well understood, and PED can fluctuate independently from the subretinal fluid. With time, the content of a PED could change and the residual protein content could contribute to the formation of a thicker RPE band as observed on SD-OCTs of long-standing cases. Spectral-domain optical coherence tomography As mentioned, the formation of PEDs seems to be tightly associated with choroidopathy since PEDs co-localize frequently with areas of choroidal vascular anomalies on SD-OCT and ICG. Recently, a study evaluating 15 eyes by swept-source en face OCT found RPE changes overlying areas of choroidal vascular dilatation in all eyes, further supporting the correlation between epitheliopathy and choroidopathy. Interestingly, these dilatations were mostly focal within the choriocapillaris, equally focal and diffuse at the level of Sattler's layer and mostly diffuse at the level of Haller's layer (Ferrara et al., 2014) . Spectral-domain optical coherence tomography Whether epitheliopathy and choroidopathy both result from a common pathogenic factor or whether the abnormal choroid induces secondary epitheliopathy that in turn permits fluid passage into the subretinal space remains uncertain. In advanced CSCR cases (also termed "diffuse retinal pigment epitheliopathy"), large areas of RPE alterations and detached RPE may not be systematically associated with subretinal fluid (Fig. 6F) . In a series of 38 eyes, one third of patients with either active or inactive CSCR had multiple small PEDs located both within and outside the area of serous retinal detachment, suggesting a more diffuse RPE dysfunction (Van Velthoven et al., 2005) . The difference between "simple" acute CSCR and chronic cases relies mainly on the extension of RPE involvement. Besides PEDs, focal RPE rips, areas of RPE atrophy and RPE hypertrophy have been described, and may belong to a wider spectrum of localized and diffuse epitheliopathy involved in the different stages of CSCR (Lim and Wong, 2008; Piccolino et al., 2008a; Yalcinbayir et al., 2014; Yang et al., 2013a) (Fig. 6I) . With time, the chronic course of the disease associated with aging leads to widespread RPE atrophy and irregular PEDs. Exclusion of a neovascular component can be challenging at this advanced stages. Interestingly, drusen are typically not observed in CSCR eyes, suggesting that epitheliopathy in CSCR and AMD originates from different mechanisms, even if late complications may be similar. Spectral-domain optical coherence tomography 83.161.120.155. Neurosensory retina. One of the characteristics of acute CSCR is that despite subretinal fluid, the morphology of retinal layers remains unchanged, except for the elongation of photoreceptor outer segments. No reduction or fluid accumulation is observed in neuronal layers. However after several years of disease duration, intraretinal cysts can form (Fig. 6I ). They may disappear or fluctuate, suggesting fluid passage through a compromised RPE contribute to their formation. Interestingly, in the interpapilomacular region, intraretinal cysts are often observed earlier in the disease evolution, over areas of RPE atrophy (Iida et al., 2003; Piccolino et al., 2008a Piccolino et al., , 2008b . Hyper-reflective dots frequently accumulate in the subretinal space below the detached neurosensory retina (Kon et al., 2008; Maruko et al., 2011a; Spaide and Klancnik, 2005) and within several retinal layers (Ahlers et al., 2009; Kon et al., 2008; Yalcinbayir et al., 2014) . These dots, identified on SD-OCT, co-localize with hyper-autofluorescent area on FAF (Iacono et al., 2015; Maruko et al., 2011a; Spaide and Klancnik, 2005) . As disease persists over time, the number of dots located in the subretinal space tends to increase (Wang et al., 2005) and correlates with worse final visual acuity (Landa et al., 2013, p. 201; Yalcinbayir et al., 2014) . The origin and nature of these dots may be multiple depending on their size and location. In the subretinal space, macrophages and microglia are likely to be activated by the photoreceptor outer segments shedding (Maruko et al., 2011a) . Concentration of protein-like compounds, fibrin or lipids could also be identified as dots (Kon et al., 2008) . During acute CSCR evolution, the intraretinal hyper-reflective dots progress from the inner to the outer retinal layers and slowly resolve upon resolution of SRD (Plateroti et al., 2014) . Chronic and recurrent forms of CSCR are more frequently associated with intraretinal hyper-reflective dots (Ojima et al., 2007) . Elongation of photoreceptor outer segments in the area of a macular SRD is a frequent SD-OCT finding in CSCR (Matsumoto et al., 2008) . They are more frequent when white-yellowish precipitates are observed on fundus examination, corresponding to patchy increased autofluorescence (Fig. 7) (Matsumoto et al., 2011) . Just above the leaking point, an erosion of photoreceptor outer segments may be visible on SD-OCT, suggesting a mechanical abrasion resulting from an active flow through the RPE break ( Fig. 2A) . Persistent thick outer segments may progress to permanent subretinal deposits with subsequent poor visual prognosis after subretinal fluid absorption. Complete disappearance of outer segments as observed in very long-standing SRD correlates with poor visual outcome. Disruption of the ellipsoid zone (formerly known as the junction between the inner and outer segments of photoreceptors), of the external limiting membrane and thinning of the outer nuclear layer are also negative visual prognosis factors Matsumoto et al., 2009 Matsumoto et al., , 2008 Ojima et al., 2007; Piccolino et al., 2005; Yalcinbayir et al., 2014) . These findings are consistent with recent observations on adaptive optics scanning laser ophthalmoscopy (see 2.4.5). Fundus autofluorescence Short-wavelength FAF mostly originates from the RPE lipofuscin (Delori et al., 1995) . Images obtained by confocal FAF provide information reflecting RPE health and allow a non-invasive detection of a spectrum of changes at different phases and forms of CSCR. Focal areas of hypo-autofluorescence at the level of the leakage points are indeed observed in 70e100% of eyes with acute CSCR (Fig. 2D) , which supports the hypothesis of a focal RPE defect or detachment of RPE cells at this site (Ayata et al., 2009; Eandi et al., 2005; Iacono et al., 2015; . In recurrent CSCR, the leakage point is usually different from previous episodes but locates in the vicinity of the first one, reflecting a barrier weakness persisting in this area. Fundus autofluorescence In acute CSCR cases, a diminished FAF is initially seen in an area corresponding to the SRD. It may either return to normal, as observed in a majority of cases after SRD resolution (Iacono et al., 2015) , or be progressively replaced by an increased FAF, as observed in episodes persisting more than 4 months (Framme et al., 2005) . While the masking produced by the SRD and the elongated photoreceptor outer segments could explain the initial decrease in FAF (Fig. 7) , the accumulation of non-shed fluorophores in these Fig. 7 . Progressive elongation of photoreceptor outer segments in acute central serous chorioretinopathy. Acute CSCR in a 61 year-old female patient. SD-OCT at baseline, 1, 2 and 4 months (B, D, F, H, respectively) shows progressive elongation of photoreceptor outer segments over the course of CSCR resolution. Fundus autofluorescence initially showed a decreased autofluorescence (dots) due to the RPE masking by these elongated outer segments (A), which progressively faded due to the accumulation of autofluorescent byproducts in these segments (C, E), and finally left a granular hyper-autofluorescence after episode resolution (G, arrow) . This hyper-autofluorescence may originate from outer segments disruption (H, within dotted lines) creating a window defect. elongated outer segments may account for the subsequent increased patchy FAF in the SRD area of non-resolving cases (Matsumoto et al., 2011) . In addition, a residual granular increased FAF may remain visible after resolution and correlates with intraretinal hyper-reflective dots on SD-OCT (Iacono et al., 2015) . It has been recently proposed that this residual granular hyperautofluorescence after CSCR resolution could originate from a loss of photoreceptor outer segments. Indeed, these outer segments are densely filled by photopigments (opsins in cones and rhodopsin in rods), which absorb the blue light and block partially the RPE autofluorescence in healthy conditions (Figs. 4A, H and 7G, H) . Finally, in two separate case series involving Fig. 8 . Indocyanine green angiography anomalies in two cases of acute CSCR. In a fifty-year old man with acute CSCR, focal hypofluorescence during early phase (A) indicated delayed choriocapillaris filling (star) and enlarged choroidal veins were visible (arrows). Multifocal hyperfluorescence areas with blurred contours indicating choroidal vascular hyperpermeability (white arrows) appeared during mid phase (B) and faded at late phase (C). A hyperfluorescent punctate spot (yellow arrow) during mid-and late phase corresponded to the leakage point on fluorescein angiography (not shown). In a thirty-two year-old male with acute CSCR, there was multifocal hyperpermeability (arrows) visible during mid phase indocyanine green angiography (D), with a progressive circular extension (E) and fading during the late phase (F). Again, two punctate spots (yellow arrow) with persisting focal hyperfluorescence corresponded to leakage points on the fluorescein angiogram (not shown). CSCR patients geographic or granular decrease in foveal FAF correlated with poor visual acuity (Imamura et al., 2011; Spaide and Klancnik, 2005) , confirming that FAF provides valuable morphological and functional information regarding RPE health. Fundus autofluorescence In fellow eyes of unilateral cases, previous unnoticed extramacular episodes or focal RPE alterations may produce variable FAF changes, mostly depending on the age of the lesions, with increased autofluorescence for fresh lesions and decreased autofluorescence for older lesions, frequently associated with punctate hyperautofluorescent spots. Fundus autofluorescence In the chronic forms of CSCR, FAF appearance is pathognomonic with multiple oblong descending tracks of decreased FAF, often originating from the optic disc and the macula, that have been referred to as "gravitational tracks" due to their inferior and vertical topography. They are surrounded by a thin contour of increased FAF (Figs. 3 and 6I) . The exact significance of these lesions is not elucidated, although it has been suggested that they may result from chronic movements of residual subretinal fluid (Agarwal, 2012; Framme et al., 2005; Spaide and Klancnik, 2005; von Rückmann et al., 2002) . Fundus autofluorescence Near-infrared autofluorescence is another non-invasive imaging modality based on the autofluorescence emanating mostly from choroidal and RPE melanin (Keilhauer and Delori, 2006) . Although not routinely employed in the evaluation of patients with CSCR, near-infrared FAF is an interesting imaging modality showing in acute cases an initial autofluorescence decrease. Subsequently it evolves into complete resolution , or exhibits a granular pattern indicating long-term changes in RPE melanin distribution following a CSCR episode (Ayata et al., 2009; Sekiryu et al., 2010) . Fluorescein angiography In acute CSCR, FA usually identifies one or several leakage points Although not mandatory for the diagnosis of CSCR, FA is helpful to confirm the diagnosis and serves as a guide for possible laser treatment of eccentric leaks (Yannuzzi et al., 2000) . Acute cases usually present with a single leakage site, rarely two or more (Burumcek et al., 1997) . In occurrences where more than one site of leakage is observed, a single site is usually responsible for the ongoing episode and can be identified by FA. In acute CSCR, leakage sites present most frequently as pinpoints of increasing fluorescence along the sequence. They can also follow two classical patterns: the "ink-blot" pattern, with a progressive expansion of a circular hyperfluorescence arising from a central pinpoint, or the "smokestack" pattern, in which the hyperfluorescence ascends with a slight lateral diffusion producing a mushroom-like image above the leaking point. In a study of 479 acute, recurrent and chronic cases, a smokestack leak was observed in 14% of subjects, and was predominantly associated
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