Unraveling the Puzzle of Central Serous Chorioretinopathy: Exploring Psychological Factors and Pathophysiological Mechanisms

Background

Central serous chorioretinopathy (CSCR) is a relatively common retinal disease characterized by the localized serous detachment of the neurosensory retina from the retinal pigment epithelium (RPE). Although precise data on its incidence are not available, CSCR is rated the fourth most common vision-threatening retinopathy after age-related macular degeneration, diabetic retinopathy, and branch retinal vein occlusion [1]. It usually occurs unilaterally in young and middle-aged adults, with a peak incidence between 40 and 45 years of age. However, evidence of bilateral involvement is present in approximately 40% of cases [2]. According to a population-based study conducted in Olmsted County, Minnesota, the annual incidence of CSCR is approximatively 6 times higher in men than in women [3]. The number of risk factors and conditions found to be associated with CSCR has significantly increased over time and includes racial and genetic predisposition, hypertension, Helicobacter pylori infection, gastro-esophageal reflux, peptic ulcer, antihistamines, antacids/anti-reflux agents, pregnancy, Type A behavior, psychological stress, and the use of psychopharmacologic medication or steroids [1,4]. It is believed that hyperpermeable choroidal vessels lead to increased tissue hydrostatic pressure, which results in RPE damage and subretinal fluid accumulation, although the exact mechanisms of development as well as the role of risk factors in the pathogenesis of CSCR remain unclear [5].

CSCR is classically divided, based on the clinical presentation and duration of symptoms, into acute and chronic forms. Acute CSCR is most common in young adults, who typically present with blurred vision, metamorphopsia, micropsia, color vision deficiency, relative central scotoma, and reduced contrast sensitivity [1]. Visual disturbances are a consequence of the presence and localization of the subretinal detachment (SRD), which is clinically detectable through fundus examination as a round or an oval detachment of the neurosensory retina in the macular area [5]. Fluorescein angiography (FA) findings include a single focal or multiple fluorescein leaks at the level of the damaged RPE and the subretinal accumulation of the dye in different forms described as ‘smokestack’ or ‘inkblot’ patterns [6]. Spectral-domain optical coherence tomography (SD-OCT) provides a better visualization of the morphological changes in the choroidal vessels and retinal layers, such as increased choroidal thickness, pigment epithelium detachment (PED), and the elongation of photoreceptor outer segments, as well as focal RPE micro-rips and areas of RPE hypertrophy [7]. The acute or ‘classic’ form of CSCR usually resolves spontaneously with the recovery of visual function to normal or almost normal levels [6].

The appearance of a new episode of acute CSCR after complete SRD resolution or a duration of SRD more than 4 months following the onset of symptoms may be labelled recurrent or persistent CSCR [7]. The recurrence of subretinal fluid accumulation can be expected in up to 50% of cases and can also be spontaneously resolved [8]. The persistence of fluid collection may be associated with widespread RPE decompensation and an unclear boundary relative to the chronic form [7]. The chronic form of CSCR involves advanced changes in the RPE, which lead to a significant and permanent loss of vision and decreased light sensitivity. In this form of CSCR the elevation of the sensory retina is less pronounced than in the acute type and may be accompanied by a thinning of the retina or complicated by choroidal neovascularization, cystoid macular degeneration, and RPE tears [6,9].

In most cases, CSCR is a self-limiting disease with the spontaneous resolution of subretinal fluid within 3–4 months. The usual approach for the classic form of CSCR consists of simple observation combined with the exclusion of risk factors, such as the discontinuation of corticosteroids and avoidance of stress [10]. In the case of persistent macular SRD with reduced visual acuity, several medical and laser treatments have been proposed, but there is still no criterion standard therapy [5,10–12]. Despite numerous studies and recent findings, the comprehension of the different factors and mechanisms involved in the development of CSCR is relatively insufficient. Accordingly, the aim of this review is to provide an overview of the psychological factors and the current understanding of their role in the pathogenesis of CSCR.

Psychological Factors

From the first mention of CSCR in 1866, when von Graefe named and described it as ‘relapsing central luetic retinitis’, the disease was considered to have an infectious etiology [13]. Horniker proposed the term ‘central angiospastic retinitis’ for this condition and suggested that psychic disturbances and a ‘vasoneurotic’ type of patient could be contributing or precipitating factors in the development of CSCR [14]. Later, other authors, based on their own experience, favored angiospastic theory as the etiological basis for the occurrence of CSCR. Gifford and Marquardt supported the concept of circulation instability, considering that changes in the macula are the result of the spastic contractions of small retinal arterioles and capillaries [15].

Zeligs analyzed the acute anxiety states induced by the military situation and proposed that anxiety has a significant influence in producing this form of retinopathy. He also believed that the spasm of retinal arterioles represents a focal manifestation of the generalized peripheral vasospastic state [16]. Bennett suggested that some kind of psychotherapy may be relevant, given that the incidence of stress-producing life situations and stress-related diseases is higher in CSCR patients [17]. Over time, numerous investigations have analyzed the association between psychological factors and CSCR (Table 1). A meta-analysis of 17 studies confirmed that a Type A personality, psychological stress, and the use of psychopharmacological medications can be significant risk factors for the occurrence of CSCR [4].

Personality Traits

Yannuzzi observed the relationship between CSCR and the Type A personality pattern, which is characterized by a competitive drive, a sense of urgency, an aggressive nature, and a hostile temperament. He analyzed 110 CSCR patients and compared them with an equal number of patients in 2 control groups, the first with other chorioretinal diseases and the second with non-chorioretinal conditions. The Jenkins Activity Survey (JAS) questionnaire used in this study demonstrated a high level of agreement with the structured interview and indicated 3 separate sub-scores corresponding to 3 distinct dimensions of the behavioral pattern. A Type A behavior pattern was significantly more frequent in patients with CSCR in comparison to the control groups and was equally distributed between the control groups. The JAS questionnaire revealed that patients with CSCR have Type A behavior 60% of the time and the ratio of Type A/Type B is 3.4. Further comparative analysis of the JAS subscales indicated that Factor S, which relates to a person’s style of behavior, may be an important risk factor for CSCR in people with a Type A behavior pattern. A slightly less significant risk factor was Factor H, which reflects personal traits and values, while Factor J, which measures a patient’s employment setting, had no significant influence [13].

The suspicion that CSCR is a psychosomatic disease arose from the measurement of affliction associated with stressful events in the patients’ lives. The results revealed a significant tendency to somatization in these patients. However, it was not possible to assemble a typical personality profile, despite the description of some notable personality features [18]. Spahn et al tested the personality profile of CSCR patients using the Sixteen Personality Factor Questionnaire (16 PF) and reported that they tend to be more emotionally unstable, insecure, flexible, and spontaneous [19]. The evaluation of temperament profiles showed higher risk avoidance, as well as restraint, low extravagance, and fewer exploratory behaviors in patients with CSCR. They were also less tolerant of frustration, more insecure, anxious, and quick-tempered, disorganized, and easily frustrated, with a tendency to avoid negative and potentially harmful stimuli [20,21]. Emotional dissociation, hostility, competitiveness, reward dependence, and a lower level of cooperativeness support the existence of specific aspects of Type A behavior in CSCR patients. Loss of control and a low level of perceived social support could explain the contribution of the previously described personality dimension to disease-related work stress [22]. A prospective study conducted in a Greek population suggested that Type A personality and stress are independently associated with CSCR [23]. Contrary to these findings, it has been demonstrated that Type A behavioral characteristics are not more prevalent in patients with chronic CSCR, which can be explained by a more successful use of certain coping strategies to improve self-management [24].

However, a prospective cross-sectional study conducted in the United States, Brazil, Egypt, and Lebanon has confirmed that a Type A personality, obsessive-compulsive disorder, and aggressive behavior, as well as the use of psychopharmacological drugs and a history of panic attacks, in addition to continuous stressful conditions, are highly associated with CSCR. Multivariate analysis revealed a strong association between CSCR and a Type A personality, obsessive-compulsive behavior and continuous stress [25].

Psychological Stress

It has been reported that very upsetting psychological events precede vision loss in 91% of CSCR patients. The acute disturbances begin on average 7 days before the first visual symptoms. In cases of CSCR recurrence, the psychological disturbances are often less severe and appear minutes or hours before visual symptoms [26]. Other studies have confirmed that a propensity to stress may predispose patients to acute CSCR [19,27]. Moreover, higher levels of psychological stress could lead to the more severe forms of acute CSCR with incomplete vision recovery [28]. The possible association between the development of CSCR and stressful events such as divorce, bankruptcy, close relatives’ illness, political/military crisis, economic crisis, and the COVID-19 pandemic has also been described [1,29–31].

Pusic Sesar et al noted that patients with CSCR had a lower level of emotional intelligence and higher perceived stress in comparison to healthy subjects. Decreased levels of emotional intelligence need to be considered primarily in the context of a higher reactivity to stressful events [32]. Another study has shown that patients with CSCR are more stressed due to the use of unsuitable coping strategies [33]. By using the Global Severity Index, Conrad et al confirmed that CSCR patients had significantly higher emotional distress. Cooperativeness and a subjective assessment of the CSCR severity have been established as significant predictors for disease-related work stress [22]. Additionally, shift work and recent psychological stress have been found to be independently associated with the onset of CSCR [34]. A later investigation confirmed that shift work is a significant and independent risk factor for recurrence of the disease [35].

Furthermore, stress scores were increased in CSCR patients and highly correlated with serum cortisol levels [36]. Some authors have identified more psychological problems and a poorer quality of life in CSCR patients, suggesting that psychosocial support and interventions could be beneficial [37]. It has been comprehensively demonstrated that CSCR patients reported more critical life events and unfavorable stress-coping strategies and expressed psychosomatic problems. Except for these features, elevated tension, strain, emotional instability, and achievement orientation were more pronounced in patients with acute rather than chronic CSCR [38].

Psychiatric Disorders

An early report showed significantly higher scores for hypochondria and hysteria in patients with angiographically-proven CSCR [39]. In comparison to healthy subjects, patients with CSCR have a higher level of anxiety, with no significant difference regarding sex or the number of attacks. Some authors have suggested that there is no psychological adjustment in the sense of reduced anxiety among patients with recurrent CSCR [40]. It has been demonstrated that patients with a history of psychiatric conditions such as anxiety and depression have an increased risk for CSCR recurrence and vice versa, meaning that patients with CSCR are at a significantly higher risk of developing depression [7,41].

Kim et al analyzed the correlation between the psychosocial factors associated with CSCR, according to its phases and subtypes, and the extent of choroidal hyperpermeability. Active CSCR patients reported having more stressful events and were more depressive than matched controls, while inactive CSCR patients were similar to matched controls when considering all psychosocial factors. Among the active CSCR patients, acute subjects were more depressive and the size of the hyperpermeable choroidal lesion was correlated with the severity of depression. Chronic patients experienced more stressful events and lesion size was linked with anxiety scores [42]. Studies conducted among the Asian population revealed that patients with CSCR have a high tendency to develop mixed anxiety disorders, depression, schizophrenia, and hysteria [43–45].

Tittl et al identified the use of psychopharmacologic medications as a risk factor associated with CSCR and concluded that stress and adaptations to stress play a role in this disorder. In this case, the usage of psychopharmacologic medications refers to the application of any anxiolytic or antidepressant drug on a regular basis [46]. A population-based investigation conducted in Taiwan analyzed 786 newly diagnosed patients with CSCR and only the utilization of anxiolytic drugs was found to be independently associated with idiopathic CSCR among males [47]. The largest case-control study carried out in Turkey evaluated demographic characteristics, morphological features and risk factors in patients with CSCR. It showed that antidepressant and anxiolytic drugs was a significant risk factor for the development of CSCR [48].

Pathophysiological Mechanisms

The diversity of risk factors has resulted in various CSCR pathogenesis theories that suggest infections, toxins, immune, neuronal, circulatory, and hormonal regulatory factors as triggers responsible for pathological changes in the macular area [49]. Although the initial factor is unknown and the pathogenesis of the disease is still unclear, it is generally accepted that CSCR is a consequence of the choroidal hyperpermeability and RPE damage, which can also be induced by various psychological factors. Thus, all relevant pathophysiological mechanisms related to CSCR, which were discussed in this review, are summarized in Table 1.

Choroidal and RPE Dysfunction

Considering the role of the RPE barrier, various theories have proposed that focal damage to the RPE is a primary cause of subretinal fluid accumulation. However, Negi and Marmor denied that dysfunctional RPE cells promote reverse fluid movement into the subretinal space with consequent SRD. They made small non-rhegmatogenous retinal blebs in rabbits mechanically or by laser photocoagulation and showed that focal RPE defects favor fluid outflow from the subretinal space [50]. Alternatively, Gemenetzi et al suggested a combined choroid and RPE dysfunction theory, in which persistent choriocapillaris abnormality leads to the prolonged stress of the RPE cells, reducing their ability to pump fluid in a retinochoroidal direction [49].

Yannuzzi suggested that stasis, ischemia, inflammation, or their combination may lead to an abnormal permeability of the inner choroid [51]. Indocyanine green (ICG) videoangiography revealed choroidal vascular hyperpermeability with and without associated active pigment epithelial leaks [52,53], while areas of choroidal ischemia and the leakage of ICG dye from the choriocapillaris have also been noted [54]. Prünte and Flamer documented that delayed arterial filling followed by choroidal hypoperfusion was frequently associated with dilated capillaries and draining venules in the area of the damaged RPE. The authors suggested that capillary or venous congestion after ischemia could be the reason for choroidal hyperpermeability [55]. Laser Doppler flowmetry has shown a significant decrease in choroidal blood flow in eyes with CSCR in comparison to unaffected contralateral eyes [56]. Imamura et al used enhanced depth imaging OCT and found a significant thickening of the choroid in patients with CSCR, concluding that it may be caused by elevated choroidal hydrostatic pressure [57].

Furthermore, a meta-analysis of 12 studies demonstrated that subfoveal choroidal thickness in eyes with CSCR is significantly increased in comparison to control eyes [58]. Utilizing laser interferometry, Tittl et al identified increased foveal pulsatile choroidal blood flow and an aberrant distribution of the fundus pulsation amplitude in the area near to the leak [59]. It is generally accepted that hyperpermeable choroidal vessels are responsible for increased tissue hydrostatic pressure, which breaks the barrier function of the RPE and leads to subretinal fluid accumulation [5].

The Role of Stress

Although there is still no consensus, it seems reasonable to suspect that stress could be a major factor that promotes biological processes, which could be responsible for the development of CSCR. Severe or continuous stress is considered to increase the risk for psychopathologies such as anxiety, depression, and schizophrenia, as well as the impact on the biological reactivity to stressful events in susceptible individuals with certain personality traits [60,61]. Through its hormonal, neural, and inflammatory mediators, stress can change physical and mental characteristics and lead to development of acute and chronic diseases in individuals with a genetic and constitutional predisposition [62]. The physiological stress response can manifest as a very quick and a delayed response. The first phase is the ‘alarm reaction’, which involves the rapid activation of the sympathetic nervous system causing the release of epinephrine and norepinephrine from the adrenal medulla. In the delayed phase, the hypothalamic-pituitary-adrenal axis is activated with an increased production of glucocorticoids [60].

Autonomic Nervous System Dysfunction

Activity of the autonomic nervous system modulates choroidal blood flow. Indeed, significantly increased sympathetic and decreased parasympathetic activity, which may cause choroid vasospasm, ischemia, and hyperpermeability, has been identified in patients with CSCR [63]. Sun et al reported that plasma concentrations of epinephrine and norepinephrine were significantly increased and were highly associated with macular edema in active CSCR patients [64]. Repeated injections of epinephrine and corticosteroids in monkey eyes created disciform serous retinal detachment, and fluorescein angiography demonstrated multiple dye leakage spots at the level of RPE [65]. Additionally, epinephrine has also been shown to induce apoptosis of the RPE cells in vitro [12,66]. The use of sympathomimetic agents, such as pseudoephedrine, oxymetazoline, and ephedra, can be a predisposing factor for the development of CSCR. Nevertheless, the resolution of CSCR is correlated with cessation of medications with sympathomimetic activity [67].

Corticosteroids and Inflammation

It has been noted that the oral, intravenous, intranasal, and intraarticular administration of corticosteroid preparations, as well as increased levels of endogenous glucocorticoids, are significant risk factors for the development of CSCR [68–70]. Moreover, increased levels of endogenous cortisol have been found in the urine and blood of patients with CSCR [71,72]. Some authors proposed that corticosteroids could damage the outer blood-retinal barrier and increase the permeability of the RPE and choriocapillaris, leading to subretinal fluid accumulation [22,46]. Animal studies have suggested that corticosteroids interact with endothelial mineralocorticoid receptors to upregulate calcium-activated potassium channels (KCa2.3), causing smooth muscle relaxation, which results in increased choroidal permeability [73,74]. Corticosteroids can damage the RPE barrier by interrupting ion transport, upregulating adrenergic receptors, and inducing a hypercoagulable state of choroid circulation [75–77]. Cortisol has been proven to increase vessel permeability by decreasing the expression of cadherin 5, a major cell adhesion protein, on choroidal vessels [78].

On the other hand, there are assumptions that CSCR could be a systemic low-grade inflammatory disease, but there is insufficient evidence on this so far [73]. Karska-Basta et al reported that increased levels of pro-inflammatory cytokines in aqueous humor, such as interleukin (IL)-5, IL-6, IL-8, IL-12, and monocyte chemoattractant protein-1, was significantly correlated with increased choroidal thickness, vascular hyperpermeability, damage to the RPE, and angiogenesis in patients with CSCR [79]. In addition, the pro-inflammatory milieu may result in generation of reactive oxygen species, causing oxidative damage to RPE and choroid endothelial cells. The relationship between systemic inflammation and corticosteroids, which are opposing mechanisms, needs further evaluation in the context of CSCR development [73]. According to the findings reported in the literature, the interaction between disrupted choroidal hemodynamics, inflammation, and high levels of stress hormones plays an important role in the complex mosaic of CSCR pathogenesis.

Future Directions

Over time, various studies have described the impact of different psychological risk factors, such as a Type A personality, stress, anxiety, and depression, on the development of CSCR [4,40,42]. In addition, numerous investigations revealed that infections, toxins, autonomic dysfunction, use of glucocorticoids or other medications, paracrine mediators, inflammation, and oxidative stress can disrupt choroidal hemodynamics and the RPE barrier, resulting in subretinal fluid accumulation in the macula [49,73]. The complete mosaic of CSCR is still unknown, since psychological risk factors and pathophysiological mechanisms, as well as their complex interrelationships, have not been fully elucidated. Accordingly, further original research involving a larger number of subjects, more comprehensive systematic review articles, and meta-analyses should be conducted to better understand the complexity of CSCR.

Conclusions

Various psychological risk factors may contribute to the development of CSCR and although there is still no consensus, a high level of perceived stress is considered to be the most important. Increased levels of stress hormones, such as epinephrine, norepinephrine, and cortisol, can cause pathological changes and dysfunction in the choroid and RPE, leading to subretinal fluid accumulation in the macular area. Therefore, CSCR is most likely a multifactorial disease with disturbed interrelationships among biological and psychological factors.