List of Abbreviations
CSC — central serous chorioretinopathy
ICD-10 — International Classification of Diseases 10th Revision
NE — neuroepithelium
ICGA — indocyanine green fundus angiography
FLP — focal laser photocoagulation of the fundus
OCT — optical coherence tomography (optical examination of the retina or optic nerve head and nerve fiber layer using a computerized analyzer)
OCT-A ― optical coherence tomography angiography (optical examination of the retina, optic nerve head, and nerve fiber layer using a computerized analyzer in angiography mode)
SRF ― subretinal fluid
PDT ― photodynamic therapy
PED ― pigment epithelium detachment
RPE ― retinal pigment epithelium
RPED ― retinal pigment epithelium detachment
FA ― fluorescein angiography
CNV ― choroidal neovascularization
VEGF — vascular endothelial growth factor
GCS ― corticosteroids
** — vital and essential drugs
Terms and Definitions
Neurosensory retinal detachment (NRD) is an accumulation of fluid or other pathological substances between the retinal pigment epithelium (RPE) and the neurosensory retina (NR).
Retinal pigment epithelium detachment (RPED) is an accumulation of fluid or other pathological substances beneath the retinal pigment epithelium.
Optical coherence tomography (optical examination of the retina, optic nerve head, and nerve fiber layer using a computerized analyzer) (OCT) is a non-invasive, non-contact diagnostic method for in vivo visualization, qualitative and quantitative analysis of the morphological features of fundus structures, based on the principle of optical interferometry.
Optical coherence tomography angiography (optical examination of the retina, optic nerve head, and nerve fiber layer using a computerized analyzer in angiography mode) (OCT-A) is a non-invasive, non-contact diagnostic method for in vivo visualization, qualitative and quantitative analysis of microcirculation in fundus structures, taking into account layer segmentation.
Subretinal fluid is fluid located beneath the neurosensory retina.
Fluorescein angiography (FA, sodium fluorescein angiography**) is a diagnostic method used to detect vascular abnormalities of the fundus and to assess the condition of the outer and inner blood-retinal barriers by recording the passage of a dye (intravenously administered sodium fluorescein**) through the retinal vessels.
Indocyanine green angiography (ICGA) is a diagnostic method used to detect choroidal blood flow abnormalities using a water-soluble dye (intravenously administered indocyanine green).
Photodynamic therapy is a treatment method based on the use of light-sensitive substances (photosensitizers) and light of a specific wavelength to occlude pathological vessels and/or stimulate the RPE.
Focal laser photocoagulation of the fundus is the local application of dosed microburns using a laser beam to the retina in order to seal leakage points and coagulate choroidal neovascularization (CNV) in an extrafoveolar location.
Choroidal neovascularization is the presence of newly formed vessels resulting from pathological neoangiogenesis originating from the choriocapillaris network through defects in Bruch's membrane beneath the RPE (Type 1 CNV) and/or the neurosensory retina (Type 2 CNV).
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Central serous chorioretinopathy (CSCR) is a disease that develops due to choroidal dysfunction, typically manifests with a pachychoroid phenotype, and is characterized by serous detachments of the neurosensory retina and/or retinal pigment epithelium, as well as atrophic changes in them.
Pachychoroid phenotype (the prefix "pachy-" meaning thickening) is a condition characterized by the following structural changes in the choroidal angioarchitecture:
– diffuse or focal increase in choroidal thickness;
– dilation of choroidal vessels;
– thinning of the choriocapillaris and medium vessel layer (Sattler's layer) in the presence of dilated large choroidal vessels (Haller's layer), which may occur with normal or reduced total choroidal thickness.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Central serous chorioretinopathy is a disease of the posterior segment of the eye, first described by A. Von Graefe in 1866 and introduced into the ophthalmological literature under the name «central recurrent retinitis» [1].
The term «central serous chorioretinopathy», which remains in use today, was first proposed by J. Gass in 1966 [2].
The main characteristic of the disease is the presence of localized, delimited serous neuroretinal detachment (SRD), associated with impaired barrier and pump functions of the RPE, often combined with retinal pigment epithelium detachments appearing against the background of choroidal decompensation, which in turn undergoes structural alterations and increased thickness. For this reason, the disease has been included in the spectrum of so-called pachychoroid conditions [3–6].
The etiology is not definitively established. To date, the most common suspected cause of the disease is an increase in the level of steroid hormones in the human body, arising both endogenously and exogenously [7–16].
Risk factors for CSC development include:
– type A personality [17];
– emotional stress [18, 19];
– use of glucocorticoids (GCs) (oral, intranasal, epidural, intra-articular, periocular, topical) [10, 12, 20–24];
– use of sympathomimetics, adrenomimetics (oxymetazoline as a component of nasal sprays, pseudoephedrine as an active ingredient in combination drugs), methylenedioxymethamphetamine (amphetamine), and ephedra found in bodybuilding products [25];
– gastrointestinal tract diseases caused by H. pylori; gastroesophageal reflux [26–28];
– Cushing's syndrome [7, 29];
– pregnancy (predominantly the 3rd trimester with spontaneous regression after delivery) [30, 31];
– hormone-producing tumors [30, 31];
– hormone replacement therapy during menopause or after hysterectomy [32];
– hypertension [33].
It has been shown that CSC is an independent risk factor for ischemic stroke [34], organic, psychogenic, and erectile dysfunction [35]. These findings indicate that the choroidal vasculopathy described in CSC may not be isolated, but rather part of a systemic vascular dysfunction.
Patients with CSC exhibit sympathetic hyperactivation and parasympathetic suppression, which affects blood pressure and heart rate parameters [36]. Autonomic imbalance may be responsible for the modulation of choroidal blood flow.
L. Yannuzzi (1987) established that CSC predominates in emotionally labile patients with a so-called type A behavior pattern. This behavioral type, more commonly observed in men, is characterized by displays of energy, impatience, ambition, competitiveness, and even aggressiveness. The leading cause of CSC development in these patients is considered to be psychological stress and hyperactivation of the sympathetic nervous system, leading to elevated levels of circulating catecholamines and cortisol in the body [17]. A potential link between the narcissistic personality type, characterized by the excessive gratification of personal needs, and the development of CSC has also been suggested [37].
Several cases of familial CSC have been reported in the literature [38, 39].
According to M. Lehmann et al. (2015), half of the relatives of patients with CSC were diagnosed with a choroidal thickness greater than 395 µm, suggesting that pachychoroid may be a genetically determined condition with a dominant inheritance pattern [3]. The CFH gene, which encodes complement factor H, has been identified as a potential susceptibility gene for CSC. The complement protein binds to adrenomedullin, causing vasodilation, including of the choroidal vessels [40]. C. Schubert et al. (2014), in a cohort of 400 CSC cases, found a significant association with 4 common single nucleotide polymorphisms in genes encoding cadherin-5 (a vascular endothelial cell adhesion molecule whose action is suppressed by GCs) in male patients. It is possible that genetically determined alterations in cadherin-5, combined with corticosteroid therapy, may explain the high proportion of CSC cases among male patients [41].
The pathophysiological mechanisms in the development of central serous chorioretinopathy (CSC) are closely related to the patients' hormonal status, altered state of the choroid, and RPE [42]. In the development of CSC, corticosteroids contribute to the impairment of vascular regulation mechanisms by suppressing vasodilation and enhancing vasoconstriction, which leads to spasm and ischemia of choriocapillaris, predominantly due to increased platelet aggregation [43]. These changes result in sectoral hypoperfusion combined with increased intraluminal perfusion pressure, which manifests as local or diffuse choroidal thickening, thinning of the choriocapillaris layer according to OCT data, choriocapillaris hyperpermeability, and dilation of large choroidal vessels according to ICGA data. Due to the action of several factors, including elevated pressure in choroidal vessels, local RPE disturbances, and the effect of GCS, the polarity of RPE cells is disrupted, leading to impairment of their pumping and barrier functions, creating conditions for fluid movement towards the subretinal space and contributing to the formation of SRD [42, 44]. Conversely, local RPE disturbances formed in CSC promote fluid movement towards the choroid [45]. The delayed recovery of RPE defects is associated with the pronounced anti-inflammatory properties of GCS, while structural impairment of Bruch's membrane is linked to the inhibition of its collagen synthesis [42-44].
A. Daruich et al. (2015) hypothesized that glucocorticosteroids can potentially regulate ion and water channels in the eye through the activation of mineralocorticoid receptors, leading to paradoxical effects of GCS in CSC [46]. In addition to the kidneys, other organs, tissues, and cells express mineralocorticoid receptors and are recognized as non-classical mineralocorticoid-responsive targets: the heart, blood vessels, brain, adipose tissue, skin, and macrophages [47, 48].
Consequently, the balance of glucocorticoid and mineralocorticoid receptors is crucial for water and electrolyte regulation. In most tissues under physiological conditions, GCS occupy mineralocorticoid receptors, and their excessive activation is pathogenic [49].
Mineralocorticoid receptors and 11-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) are expressed in the neurosensory retina, retinal pigment epithelium, and choroid in rats, monkeys, and humans, placing the retina in the category of non-classical mineralocorticoid-sensitive tissues [50, 51].
Mineralocorticoid receptors have two natural ligands: aldosterone and cortisol, which bind to them with equal affinity. The blood cortisol level is much higher than that of aldosterone. In tissues where 11-HSD2 is expressed, mineralocorticoid receptors are protected from GCS through the action of 11-HSD2, which metabolizes cortisol to cortisone, which has a much lower affinity for the receptors. In most non-epithelial receptor targets, 11-HSD2 is not expressed, and thus GCS occupy the mineralocorticoid receptors [52, 53].
It is hypothesized that excessive or inappropriate activation of mineralocorticoid receptors due to predispositions may cause a higher risk of hypertension, coronary events, psychological vulnerability to stress, and CSC in susceptible individuals, especially upon stimulation of mineralocorticoid receptors by GCS. This hypothesis formed the basis for using aldosterone antagonists, such as eplerenone and spironolactone**, in the treatment of chronic forms of CSC.
The mechanism of subretinal material appearance in chronic CSC, first described by J. Gass back in 1967, is not fully understood. For a long time, it was believed to consist of fibrin and lipids. Later, several studies noted that hyperreflective deposits and subretinal material enhance autofluorescence during examination [54-56].
Long-term observations of patients with CSC confirmed a correlation between areas of hyperautofluorescence and the persistence of subretinal material and deposits. Given that lipids and fibrin do not enhance autofluorescence, I. Maruko et al. (2011) suggested that macrophages migrating into the subretinal space may phagocytose and metabolize photoreceptor outer segments. Consequently, these complexes of phagocytes and photoreceptor outer segments may be the main hyperautofluorescent substrate of subretinal material, and its presence may indicate damage to photoreceptors and RPE cells [57].
1.3 Epidemiology of the Disease or Condition
CSC is among the most common vision-threatening retinopathies after AMD, diabetic retinopathy, and retinal branch vein occlusions [42]. A higher prevalence of CSC is detected among working-age men (72–88% of cases), with the mean age ranging from 39 to 51 years [24, 58]. At an older age, the disease is more common in women [58] and has a chronic course, as well as in patients of both sexes with atypical clinical variants [24, 32, 59, 60].
The higher incidence of the disease among Asians, Caucasians, and Hispanics compared to African Americans [17] was not confirmed in all studies [61]. Presumably, more severe forms of CSC with pronounced visual acuity loss develop more frequently in African American patients. In the Asian population, CSC is a severe disease, with bilateral and multifactorial forms recorded more often than in other ethnic groups [62].
Patients with asymptomatic CSC may present with SRD outside the macula in the fellow eye, which can be an incidental finding during examination [3, 63].
Therefore, it can be assumed that the prevalence of CSC is likely underestimated. Bilateral involvement is more characteristic of the chronic course, occurring in 40% of cases according to literature data [42].
1.4 Features of Coding the Disease or Condition
H35.7 Separation of retinal layers (central serous chorioretinopathy).
1.5 Classification of the disease or condition
Classification of CSC
1. Acute CSC.
Characterized by newly diagnosed or newly emerged (after complete resolution of the previous episode) one or more serous detachments of the neurosensory retina and/or RPE and minor atrophic changes thereof. FAZ reveals one or more leakage points. Subretinal fluid (SRF) usually resolves spontaneously within 3–4 months.
2. Chronic CSC.
Characterized by a prolonged course of the disease episode (more than 4 months), SRD, more pronounced atrophic changes of the RPE and neurosensory retina with the possible formation of cystic spaces in the neurosensory retina, which can be an indirect sign of CNV.
3. Atypical CSC (bullous, with accumulation of subretinal proteinaceous substrate, diffuse retinal pigment epitheliopathy).
– Bullous CSC: multiple high detachments of the neurosensory retina, which occur in acute and chronic forms.
– SRD with subretinal proteinaceous substrate: manifests as an accumulation of a large amount of fibrin, usually combined with RPE detachment. Often leads to subretinal fibrosis accompanied by a pronounced decrease in visual functions. Occurs in acute and chronic forms.
– Diffuse retinal pigment epitheliopathy: extensive atrophic damage to the RPE associated with prolonged SRF leakage, its spread due to gravity into the lower parts of the fundus, and manifesting as the "comet tail" phenomenon on FAW and "gravitational tracks" on autofluorescence imaging. It is a variant of the chronic course of the disease.
Complications and outcomes of CSC:
– choroidal neovascularization;
– retinal pigment epithelial tear;
– subretinal fibrosis;
– atrophy of the outer retinal layers;
– retinal pigment epithelium atrophy.
1.6 Clinical presentation of the disease or condition
Complaints are non-pathognomonic, usually have an acute onset characterized by the appearance of metamorphopsia, micropsia, dyschromatopsia; in some cases, relative or absolute scotomas can be diagnosed in the central visual field. Visual acuity in acute CSC may be mildly reduced. In recurrent, chronic, atypical forms and complications, a significant decrease in visual functions may be recorded.
Ophthalmoscopically, the acute form visualizes one or more SRDs, sometimes combined with RPE detachment. Spontaneous regression of neurosensory retinal detachment in acute CSC develops within 3–4 months, usually without complications [64]. New episodes occur in 15–50% of cases [46]. The chronic form develops after 4 months of neurosensory retinal detachment persistence and is characterized by extensive zones of atrophic RPE damage, well visualized by fundus biomicroscopy and fundus autofluorescence imaging. The transparency of subretinal fluid in CSC can be reduced due to a large amount of fibrin deposited in the form of a ring ("donut") with a lumen in one of the protein accumulation zones.
Retinal pigment epithelium detachment (RPED) is the separation of the RPE basement membrane from the inner collagenous layer of Bruch's membrane. It is detected both ophthalmoscopically and using OCT.
Avascular serous PED is characterized by the absence of newly formed vessels, hard exudates, and hemorrhages, the presence of a hyporeflective zone beneath the PED, and distinct margins.
CSC is most frequently complicated by type 1 CNV located beneath the RPE and characterized by an irregular and/or flat PED with hyperreflective content. With the introduction of OCT angiography (OCT-A), a higher detection rate of CNV was recorded—58%, compared to 2% detected ophthalmoscopically. Secondary type 2 CNV may develop in patients after focal laser photocoagulation of fluid leakage points located close to the foveal avascular zone (no more than 1 disc diameter).
2. Diagnostics, medical indications and contraindications for diagnostic methods
The diagnosis of CSC should aim to identify changes in the retina, retinal pigment epithelium, and choroid.
Table 1. Main diagnostic criteria for establishing the diagnosis of CSC.
Diagnostic option | Criteria for establishing the diagnosis |
|---|---|
Anamnesis and complaints | Often associated with stress or overexertion, particularly in patients with type A personality, against the background of autoimmune diseases requiring systemic GCS treatment, or in an otherwise healthy individual, rarely associated with pregnancy. Symptoms Acute course: decreased visual acuity, appearance of a translucent "spot", "fog", micropsia, macropsia, metamorphopsia, dyschromatopsia. Chronic course: the same as in the acute course with symptom duration of 4 months or more, with episodes of improvement and worsening of visual functions. Upon the development of CNV: increased metamorphopsia, decreased visual acuity, opaque "spot". |
Criteria | In the acute course, in the macular zone or the affected area—round or oval SRF (one or several) and/or PED, minor atrophic RPE changes, often a "thick" choroid; FAW reveals active leakage points ("inkblot", "smokestack"); ICGA reveals dilation and hyperpermeability of choroidal vessels. In the chronic course—most commonly bilateral diffuse atrophic RPE changes, potentially with the presence of SRF and PED, small subretinal deposits, fibrinous subretinal deposits, "gravitational tracks", and cystic spaces in the neurosensory retina. In the complicated course—in addition to the aforementioned signs, features of CNV are detected. |
2.1 Complaints and Anamnesis
It is recommended to collect medical history in all patients to identify facts that may influence management tactics [65, 66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: it is necessary to thoroughly question patients about previous episodes of vision loss (in both the affected and fellow eye), the time of onset of the first visual disturbances, their connection with stress, overexertion, and past illnesses. Special attention should be paid to the presence of pregnancy, autoimmune diseases, and GCS intake.
It is recommended to collect complaints in all patients to determine the presence of functional visual disturbances and identify symptoms that may influence management tactics [65, 66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: there may be an absence of complaints for a long time despite the recurrent course of the disease. The detection of fundus changes associated with prior CSC is often an incidental finding (especially in the fellow eye). Patients may complain of decreased visual acuity, the appearance of a translucent "spot", "fog", micropsia, macropsia, metamorphopsia, and altered color perception. When CSC is complicated by choroidal neovascularization, characteristic complaints include marked decrease in visual acuity, metamorphopsia, reading difficulties, and the appearance of an opaque "spot".
2.2 Physical Examination
It is not recommended to perform a physical examination for the purpose of diagnosing and treating CSC [66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to refer patients with autoimmune diseases taking glucocorticoids to relevant specialists for consultation with the aim of potentially discontinuing this therapy, as well as patients with concomitant diseases and risk factors for systemic complications prior to intravitreal administration of an anti-angiogenic drug, in order to identify potential contraindications to this type of treatment or minimize the risk of complications [66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the choice of specialist profile is determined depending on the presence of concomitant systemic disease and risk factors for systemic complications in the patient.
2.3 Laboratory Diagnostics
Diagnostic criteria for CSC based on clinical laboratory test data do not exist.
It is recommended to perform a complete blood count (CBC), general biochemical blood test (investigation of total protein level in blood, blood glucose level, blood urea level, blood creatinine level, total bilirubin level, conjugated bilirubin level, aspartate aminotransferase activity, alanine aminotransferase activity, alkaline phosphatase activity, blood cholesterol level, low-density lipoprotein cholesterol level, triglycerides level, glycated hemoglobin (HbA1C) level), coagulogram (exploratory hemostasis screening), urinalysis, determination of antibodies to Treponema pallidum by enzyme-linked immunosorbent assay (ELISA) in blood, determination of hepatitis B virus (Hepatitis B virus) surface antigen (HbsAg) in blood, determination of antibodies to hepatitis C virus (Hepatitis С virus) in blood, molecular biological blood test for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1), determination of IgM and IgG antibodies (IgM, IgG) to human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1) in blood, determination of IgM and IgG antibodies (IgM, IgG) to human immunodeficiency virus HIV-2 (Human immunodeficiency virus HIV 2) in blood, qualitative PCR detection of human immunodeficiency virus DNA in patients with CSC complicated by macular neovascularization, when preparing for hospitalization for intravitreal anti-VEGF therapy, or for other purposes at a frequency in accordance with current federal, regional, and local regulatory documents to assess general status, identify concomitant diseases and potential contraindications to these types of treatment, and minimize the risk of complications [65-69].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the examination is carried out on the basis of voluntary consent (sanitary and epidemiological rules SP 3.1.5.2826-10 "Prevention of HIV infection"). The choice of laboratory test is determined based on the presence of concomitant systemic disease and risk factors for systemic complications in the patient.
2.4 Instrumental Diagnostics
It is recommended to perform visometry in all patients with CSC upon disease diagnosis, follow-up, and treatment monitoring to determine the severity of visual impairment [65, 66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform refractometry or determine refraction using a trial lens set in all patients upon disease diagnosis, follow-up, and treatment monitoring to determine the best corrected visual acuity for an accurate assessment of visual impairment severity [66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform tonometry (including under topical anesthesia using a local anesthetic solution) in all patients upon disease diagnosis, follow-up, and treatment monitoring to detect intraocular pressure abnormalities [65].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform ocular biomicroscopy in all patients upon disease diagnosis, follow-up, and treatment monitoring to assess the state of the ocular media and structures [65].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform fundus biomicroscopy or ophthalmoscopy under conditions of drug-induced mydriasis (using anticholinergics and sympathomimetics, excluding antiglaucoma drugs, including fixed combinations) upon disease diagnosis, follow-up, and treatment monitoring to identify fundus changes, assess their severity, monitor them, and select optimal management tactics [65].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: fundus biomicroscopy with aspheric lenses using a slit lamp (or ophthalmoscopy) is the primary method for diagnosing fundus changes during an ophthalmological examination under any type (primary health care, specialized care) and setting (inpatient, outpatient) of medical care. It is important to remember that anterior chamber depth must be assessed prior to pharmacological pupil dilation.
It is recommended to perform fundus biomicrophotography using a fundus camera (if technically available) in patients under conditions of drug-induced mydriasis (using anticholinergics and sympathomimetics, excluding antiglaucoma drugs, including fixed combinations) during disease diagnosis, follow-up, and treatment monitoring for the purpose of screening, monitoring, and evaluating treatment efficacy [70].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: the necessity and frequency of fundus photography using a fundus camera are determined by the ophthalmologist depending on the specific course of the disease.
It is recommended to perform fundus autofluorescence imaging in patients with suspected RPE involvement during disease diagnosis, follow-up, and treatment monitoring for the purpose of detecting and monitoring RPE changes [55, 71].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: the necessity and frequency of fundus autofluorescence imaging are determined by the ophthalmologist depending on the specific course of the disease. Fundus autofluorescence imaging must be performed under pharmacological mydriasis, as this significantly increases the diagnostic value of the method.
It is recommended to perform optical examination of the retina using a computer analyzer (optical coherence tomography – OCT) under conditions of drug-induced mydriasis (using anticholinergics and sympathomimetics, excluding antiglaucoma drugs, including fixed combinations) in all patients with central serous chorioretinopathy (CSCR) or suspected CSCR during disease diagnosis, follow-up, and treatment monitoring for the purpose of its quantitative and qualitative assessment, as well as monitoring treatment efficacy [19, 72].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: a qualitative and quantitative analysis of retinal tomograms should be performed with a detailed assessment of the presence, localization, and nature of fluid, the presence of subretinal deposits, involvement of the outer retinal layers, involvement of the retinal pigment epithelium, choroidal thickness, as well as an evaluation of the configuration of the obtained scans when examining the macular region. Differential diagnosis with diseases accompanied by choroidal neovascularization must be carried out. Optical examination of the retina using a computer analyzer must be performed under pharmacological mydriasis, as this significantly improves the quality of the examination.
It is recommended to perform optical examination of the retina using a computer analyzer in angiography mode (optical coherence tomography angiography – OCT-A) under conditions of drug-induced mydriasis (using anticholinergics and sympathomimetics, excluding antiglaucoma drugs, including fixed combinations) in all patients with CSCR suspected of having choroidal neovascularization during disease diagnosis, follow-up, and treatment monitoring [73].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: a qualitative and quantitative analysis of angiograms should be performed to detect pathological neovascular networks and perform differential diagnosis of other causes of their occurrence. The necessity and frequency of OCT-A are determined by the ophthalmologist depending on the specific course of the disease. Optical examination of the retina using a computer analyzer in angiography mode must be performed under pharmacological mydriasis, as this significantly improves the quality of the examination.
It is recommended to perform fluorescein angiography (FA) under conditions of drug-induced mydriasis (using anticholinergics and sympathomimetics (excluding antiglaucoma drugs), including fixed combinations) during disease diagnosis, follow-up, and treatment monitoring in patients with CSCR in diagnostically complex cases, with a chronic or complicated course, for the purpose of differential diagnosis, detection of leakage points and/or choroidal neovascularization, with subsequent determination of treatment tactics [74].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the necessity and frequency of FA are determined by the ophthalmologist depending on the specific course of the disease. Fluorescein angiography is recommended to be performed under pharmacological mydriasis, as this significantly improves the quality of the examination.
It is recommended to perform indocyanine green angiography (ICGA) of the fundus under conditions of drug-induced mydriasis (using anticholinergics and sympathomimetics, excluding antiglaucoma drugs, including fixed combinations) during disease diagnosis, follow-up, and treatment monitoring in patients with CSCR in diagnostically complex cases, with a chronic or complicated course, for the purpose of differential diagnosis, and when polypoidal choroidal vasculopathy is suspected, for subsequent determination of treatment tactics [74, 75].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: the necessity and frequency of ICGA are determined by the ophthalmologist depending on the specific course of the disease. Indocyanine green angiography of the fundus must be performed under pharmacological mydriasis, as this significantly improves the quality of the examination.
It is recommended to perform perimetry in patients with CSCR and suspected optic nerve involvement when in-depth analysis of functional impairments is necessary during differential diagnosis, follow-up, and treatment monitoring to assess retinal and visual pathway function [65].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to record multifocal electroretinography in patients with unexplained visual function decline to assess retinal and visual pathway function [19].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: The decision to prescribe other additional diagnostic methods is made by the physician based on the results of the baseline examination.
2.5 Other Procedures
It is recommended to perform chest fluorography (or digital chest fluorography) in all patients with a complicated course of CSCR when preparing for hospitalization for intravitreal administration of anti-angiogenic agents or for other purposes, at a frequency in accordance with current federal, regional, and local regulatory documents, to assess general status, identify comorbid conditions and potential contraindications to these types of treatment, and minimize the risk of complications [66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the list of examinations is determined by the relevant specialist in the presence of comorbid pathology.
It is recommended to record an electrocardiogram (with decoding, description, and interpretation of electrographic data) in all patients with a complicated course of CSCR when preparing for hospitalization for intravitreal administration of anti-angiogenic agents or for other purposes, at a frequency in accordance with current federal, regional, and local regulatory documents, to assess general status, identify comorbid conditions and potential contraindications to these types of treatment, and minimize the risk of complications [66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the list of examinations is determined by the relevant specialist in the presence of comorbid pathology.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Conservative Treatment
It is not recommended to provide special treatment to patients with CSCR for the purpose of subretinal fluid resorption and resolution of neuroepithelial detachment [76-79].
GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)
Comments: meta-analyses and systematic reviews of data conducted to date have not revealed convincing high-quality evidence that any of the therapeutic strategies has significant advantages over placebo or observation in patients with CSCR. The approaches listed below have only low-quality evidence and are largely inconclusive (data from small retrospective studies in CSCR should be interpreted with caution as the disease is prone to spontaneous resolution) [76-79].
3.2 Laser Treatment
It is recommended to perform focal laser photocoagulation of the fundus (in the presence of local retinal edema) under local anesthesia (using a local anesthetic solution) under conditions of drug-induced mydriasis (using anticholinergics and sympathomimetics, excluding antiglaucoma drugs, including fixed combinations) in patients with CSCR in cases of extrafoveolar location of the leakage point for the purpose of sealing it [18-19, 76-79].
GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)
Comments: Focal laser photocoagulation (FLPC) of the retina can be used in both acute and chronic forms of the disease in the presence of extrafoveolar leakage points. In most cases of acute central serous chorioretinopathy (CSCR), serous retinal detachments resolve spontaneously within four months, and observation without treatment is usually recommended. In the acute form, if the patient does not wish to wait for spontaneous resolution and if the disease interferes with their work capacity, FLPC of the retina may be performed at any time. In cases of persistent serous retinal detachment or recurrence, FLPC of extrafoveolar leakage points can shorten the duration of such episodes. In the chronic form, FLPC should be performed as soon as possible, given the risk of further damage to the RPE and neurosensory retina. Prior to FLPC, precise determination of the size and localization of the leakage point is necessary based on a comprehensive examination including FA, OCT, and potentially OCT-A. It should also be considered that FLPC increases the risk of choroidal neovascularization (CNV) development.
Focal laser photocoagulation of the retina using subthreshold micropulse diode laser treatment with various wavelengths is performed for acute CSCR at any time after detection, and for chronic CSCR when other treatment methods are not feasible [18, 19, 76-79].
3.3 Surgical Treatment
It is recommended to perform intravitreal administration (in an operating room, under local anesthesia using topical anesthetic eye drops, after disinfecting the eyelids, periocular area, and ocular surface with antiseptics and disinfectants including iodine preparations, and using antiseptic, antimicrobial, and anti-inflammatory eye drops before and after the procedure, including fixed combinations) of an angiogenesis inhibitor, ranibizumab**, in patients with CSCR complicated by CNV, with injection frequency according to the prescribing information of the drug used, in order to suppress CNV activity, stabilize or improve best-corrected visual acuity [74, 76-79, 80].
GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)
Comments: the effect of this treatment method described in the literature is most likely associated with the presence of occult or background CNV in patients, which can be detected using OCT-A or multimodal imaging techniques; the efficacy of this treatment in the absence of CNV has not been proven.
Ranibizumab** is a fragment of a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A). It selectively binds to VEGF-A (VEGF110, VEGF121, VEGF165), preventing its interaction with receptors on the surface of endothelial cells, which leads to the suppression of neovascularization and endothelial cell proliferation [80].
3.4 Pain Management
Anesthesia methods are not used, as CSCR is not accompanied by pain syndrome.
3.5 Diet therapy
There is no special diet for CSCR.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Special methods of medical rehabilitation and health-resort treatment are not used.
5. Prevention and Dispensary Observation
It is recommended to eliminate risk factors for patients with acute and chronic CSCR in order to accelerate fluid resorption, improve visual function, and reduce the risk of recurrence: first of all, discontinue, if possible, all forms of GCS (including topical and inhaled formulations) [21, 74].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: patients with symptoms of Cushing's syndrome/disease, including moon facies and truncal obesity (van Haalen et al., 2018b), should be referred to an endocrinologist, as CSCR may be a manifestation of this condition (van Dijk et al., 2016). Pregnant women with a history of CSCR episodes should be informed about the possibility of disease recurrence during pregnancy. There is literature data indicating that reducing emotional stress, normalizing sleep, and treating sleep apnea can positively affect the course of the disease [74, 76-79].
Dispensary observation (follow-up) is not performed for patients with CSCR.
6. Organization of Medical Care
Primary specialized health care is provided by an ophthalmologist in the outpatient department of a medical organization.
Treatment (focal laser photocoagulation of the retina, intravitreal administration of an angiogenesis inhibitor) is performed by an ophthalmologist in an outpatient setting, a day care setting, or an inpatient setting.
Indication for planned hospitalization in a medical organization:
– the need for intravitreal administration of an angiogenesis inhibitor and/or laser treatment when outpatient treatment is not feasible.
Indication for emergency hospitalization in a medical organization:
– endophthalmitis as a complication of intravitreal administration of an angiogenesis inhibitor.
Indication for patient discharge from a medical organization:
1) completion of treatment or one of the stages of specialized medical care in an inpatient or day care setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;
2) refusal of specialized medical care in an inpatient or day care setting by the patient or their legal representative;
3) the need to transfer the patient to another medical organization.
7. Additional Information
The patient must be informed about their disease, risk factors, and relapse prevention methods. The patient should be warned that consultations with other specialists may be necessary to eliminate risk factors for the onset and recurrence of CSCR. It is also necessary to encourage the patient to strictly comply with all recommendations of the ophthalmologist.
It is important to emphasize to the patient the need to immediately consult an ophthalmologist if new visual symptoms appear, especially those indicating the potential development of choroidal neovascularization (the appearance of metamorphopsia). Patients must be informed that the effectiveness of treatment for complicated forms of CSCR directly depends on the timeliness of its initiation.
It is necessary to emphasize to the patient the need to test the visual function of each eye separately.
The patient must be taught simple methods of self-monitoring of visual disturbances. The best way to self-monitor for detecting even minor changes is to use a simple test—the so-called Amsler grid. This method is highly informative, has good sensitivity, and allows for the detection of various changes in the macular area.
The patient can be advised to use a regular sheet of graph paper from a school notebook as an Amsler grid. A 10 x 10 cm square should be drawn and a dot placed in its center. The test should then be performed in the following order:
– put on reading glasses;
– cover one eye;
– look constantly only at the central dot;
– without looking away from the central dot, assess whether all lines are straight and even, and whether all squares are equal in size;
– pay attention to whether there are any areas where the pattern is distorted, blurred, or discolored;
– perform the test in the exact same manner for the other eye.
If any changes are detected during this test, a doctor must be consulted immediately.
In cases of irreversible blindness or low vision, the patient must be fully informed about the opportunities for vocational, social, and psychological rehabilitation.
When intravitreal drug administration is used, the following points must be discussed with the patient:
– the prospects of treatment using intravitreal drug administration in patients with CSCR complicated by CNV depend on the timely initiation of treatment and compliance with the optimal injection regimen in accordance with the drug prescribing information and clinical guidelines based on regular monitoring data;
– it is important to warn patients receiving intravitreal injections of the need to immediately report symptoms that may suggest intraocular inflammation (endophthalmitis): eye pain or increased discomfort in the eye, increased eye redness, blurred or decreased vision, increased photosensitivity, an increase in floaters in the visual field, and to immediately seek medical help at the facility where the intravitreal injection was performed or another specialized medical organization.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance evaluation |
|---|---|---|
1. | Visometry was performed | Yes/No |
2. | Ocular biomicroscopy performed | Yes/No |
3. | Fundus biomicroscopy and/or ophthalmoscopy under mydriasis performed | Yes/No |
4. | Optical coherence tomography performed or recommended | Yes/no |
5. | Watchful waiting strategy prescribed for acute CSCR. Focal laser photocoagulation of the retina and/or intravitreal administration of an angiogenesis inhibitor performed (or recommended) in the presence of indications and absence of contraindications for acute and chronic CSCR. | Yes/no |
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Appendix A1. Working Group Composition
Fursova Anghella Zhanovna, Group Leader, D.Sc. (Med.), Head of the Department of Ophthalmology, Novosibirsk State Medical University; Head of the Ophthalmological Department, Novosibirsk State Regional Clinical Hospital; member of the Association of Ophthalmologists;
Budzinskaya M.V., D.Sc. (Med.), Professor of the Department of Ophthalmology, Krasnov Research Institute of Eye Diseases;
Shadrichev F.E., Ph.D. (Med.), Head of the Ophthalmological Department, Saint Petersburg Territorial Diabetological Center (Clinical Diagnostic Center No. 1); Assistant Professor, Department of Ophthalmology with the Astakhov Clinic, First Pavlov Saint Petersburg State Medical University; member of the Association of Ophthalmologists;
Nechiporenko P.A., Ph.D. (Med.), Assistant Professor, Department of Ophthalmology with the Professor Astakhov Clinic, First Pavlov Saint Petersburg State Medical University; member of the Association of Ophthalmologists;
Izmaylov A.S., D.Sc. (Med.), Head of Department, Saint Petersburg Branch of the National Medical Research Center "S.N. Fedorov National Eye Microsurgery Complex" of the Ministry of Health of the Russian Federation; Associate Professor, Department of Ophthalmology, North-Western State Medical University named after I.I. Mechnikov of the Ministry of Health of the Russian Federation;
Gatsu M.V., D.Sc. (Med.), Associate Professor, Deputy Director for Organizational and Clinical Work, Saint Petersburg Branch of the National Medical Research Center "S.N. Fedorov National Eye Microsurgery Complex" of the Ministry of Health of the Russian Federation; Associate Professor, Department of Ophthalmology, North-Western State Medical University named after I.I. Mechnikov of the Ministry of Health of the Russian Federation; member of the Ophthalmological Society of Russia;
Grigorieva N.N., Ph.D. (Med.), Assistant Professor, Department of Otorhinolaryngology and Ophthalmology, Faculty of Medicine, Saint Petersburg State University of the Ministry of Health of the Russian Federation; member of the Association of Ophthalmologists;
Shklyarov E.B., Ph.D. (Med.), Ophthalmologist at the Ophthalmological Department, Saint Petersburg Territorial Diabetological Center (Clinical Diagnostic Center No. 1); Assistant Professor, Department of Family Medicine, North-Western State Medical University named after I.I. Mechnikov of the Ministry of Health of the Russian Federation; member of the Association of Ophthalmologists.
There is no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience of these clinical guidelines:
Ophthalmologists;
General Practice (Family Medicine) physicians.
Methods used for evidence collection/selection: search in electronic databases; analysis of current scientific developments on AMD in Russia and abroad; synthesis of practical experience of Russian and foreign specialists. Description of methods used for evidence collection/selection: the evidence base for the recommendations includes publications from the Cochrane Library, EMBASE, and MEDLINE databases, as well as monographs and articles in leading specialized peer-reviewed domestic medical journals on the subject. Methods used for assessing the quality and strength of evidence: expert consensus, significance assessment according to the rating scale.
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic review of randomized clinical trials using meta-analysis |
2 | Individual studies with reference standard control or individual randomized clinical trials and systematic reviews of studies of any design, except for randomized clinical trials, using meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Level of Evidence (LoE) grading scale for methods of prevention, treatment, and rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)
LoE | Definition |
|---|---|
1 | Systematic review of randomized controlled trials with meta-analysis |
2 | Individual randomized clinical trials and systematic reviews of studies of any design, except for randomized clinical trials using meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Grade of Recommendation (GoR) scale for methods of prevention, diagnosis, treatment, and rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
C | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
1. Current instructions for medicinal products mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru
Table 4. Dosage, route of administration, and treatment regimens of medicinal products
Drug | Dose | Route of administration | Regimen |
|---|---|---|---|
Ranibizumab** | 0.5 mg (0.05 ml) | Intravitreal administration | Three or more consecutive monthly intravitreal injections until maximum stable visual acuity is achieved and/or until signs and symptoms of disease activity disappear. Subsequently, the injection schedule is determined by the attending physician depending on the clinical presentation. An interval of at least 4 weeks should be maintained between injections into the same eye. |
2. International Classification of Diseases, Injuries and Causes of Death, 10th Revision (ICD-10). World Health Organization.
3. Nomenclature of medical services. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 "On approval of the nomenclature of medical services".
4. Federal Law No. 323-FZ dated November 21, 2011 "On the fundamentals of protecting the health of citizens in the Russian Federation".
5. Procedure for providing medical care to adult patients with diseases of the eye, its adnexa, and orbit. Order of the Ministry of Health of the Russian Federation No. 902n dated November 12, 2012 "On approval of the Procedure for providing medical care to adult patients with diseases of the eye, its adnexa, and orbit".
6. List of vital and essential drugs for medical use for 2020. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 "On approval of the list of vital and essential drugs for medical use for 2020, the list of drugs for medical use, the list of drugs intended for the provision of persons with hemophilia, cystic fibrosis, pituitary dwarfism, Gaucher disease, malignant neoplasms of lymphoid, hematopoietic and related tissues, multiple sclerosis, hemolytic-uremic syndrome, systemic onset juvenile arthritis, mucopolysaccharidosis types I, II, and VI, persons after organ and/or tissue transplantation, as well as the minimum assortment of drugs required for the provision of medical care".
7. SanPiN 2.1.3.2630-10 "Sanitary and epidemiological requirements for organizations engaged in medical activities".
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
The patient must be informed about their disease, risk factors, and relapse prevention methods. The patient must be warned that eliminating risk factors for the onset and recurrence of central serous chorioretinopathy (CSCR) may require consultations with other specialists.
In the case of CSCR, the required frequency of follow-up examinations by an ophthalmologist must be observed, depending on the severity of changes determined by the physician. If new visual symptoms occur, especially those indicating the potential development of choroidal neovascularization (metamorphopsia), an ophthalmologist must be consulted immediately. The patient must understand that the efficacy of treatment for complicated forms of CSCR directly depends on how timely it is initiated.
The patient should be instructed on the necessity of testing the visual functions of each eye separately. As a self-monitoring method for disease progression, patients with CSCR are advised to perform the Amsler grid test, which involves identifying scotomas and distortion of straight lines of the drawn grid while fixing gaze on the central point.
The clinical presentation of CSCR, the course and prognosis of the disease, and the applied diagnostic and treatment methods vary depending on the stage and form of the disease, and the presence of risk factors for its progression. The chronic course of the disease necessitates regular examinations by an ophthalmologist and, in the event of choroidal neovascularization, intravitreal administration of medicinal products (anti-VEGF agents). Intravitreal drug injections require regular ophthalmological evaluations and, as a rule, repeated injections, the frequency of which is determined by the physician. The risk of complications from intravitreal drug administration is minimal, but present; therefore, if symptoms potentially indicating inflammation (eye pain or increased discomfort in the eye, increased eye redness, increased blurred vision or further reduction in visual acuity, increased light sensitivity, increased number of floaters in the visual field) appear within a few days after the injection, they must be reported to the physician immediately.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
No.