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Abstract
Purpose To analyse static characteristics and dynamic functionality of retinal vessels in eyes with central serous chorioretinopathy (CSCR) by means of Dynamic Vessel Analyzer (DVA).
Methods Patients presenting with treatment-naïve CSCR and normal subjects (controls) matched for age and sex between May 2015 and November 2015 were enrolled in the study. Participants underwent a complete ophthalmological examination, including dynamic and static retinal vessels analysis by DVA.
Results A total of 28 eyes of 28 subjects (14 eyes for each group) were included in the analysis. Dynamic analysis during stimulation by flickering light showed mean venous dilation of 3.3%±2.0% in patients with CSCR and 5.5%±2.6% in controls (p=0.0258); mean arterial dilation did not differ between patients and controls (3.2%±2.5% and 4.2%±1.5%, p=0.2). No differences were reported at static retinal analysis between patients with CSCR and control subjects. Subfoveal choroidal thickness as evaluated by optical coherence tomography was 438.6±86.1 µm in CSCR eyes, significantly increased compared with control subjects (301.5±72.5 µm, p=0.0001).
Conclusions Dynamic analysis revealed a reduced retinal venous dilation in response to flicker light stimulation in CSCR eyes. The decreased retinal vein response to flicker light stimulation, possibly due to increased sympathetic tone and potentially leading to venous stasis, together with the increased choroidal thickness may help understand CSCR and give insights in its pathogenesis.
- Central serous chorioretinopathy
- dynamic vessel analyzer
- static vessel analysis, retinal vessel analysis
- optical coherence tomography
- choroidal thickness
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- Central serous chorioretinopathy
- dynamic vessel analyzer
- static vessel analysis, retinal vessel analysis
- optical coherence tomography
- choroidal thickness
Introduction
Central serous chorioretinopathy (CSCR) is characterised by localised serous retinal detachment of the macula, often associated with retinal pigment epithelium (RPE) detachment.1 CSCR is a fairly common disorder that predominantly affects young to middle-aged men.1 The typical clinical picture is of a male aged 20–50 years, presenting with an acute onset of severe unilateral central vision loss.2 This condition could be associated with metamorphopsia, micropsia, central scotoma or alteration in the perception of colours.2 Beyond male gender, several risk factors have been pointed out including stress-prone personality, increased sympathetic activity, systemic corticosteroid use, hypertension, hypercholesterolaemia, pregnancy and gastric colonisation by Helicobacter pylori.1 Hypercortisolism and mental stress are factors associated with the precipitation or aggravation of this relapsing and remitting disease.3
At fundus examination, a transparent blister at the posterior pole with a ring reflex marking the limits of the elevated area is often visible.4 Although optical coherence tomography (OCT) plays a major role, CSCR diagnosis is based on multimodal imaging. Fluorescein angiography (FA) is a useful diagnostic test since it reveals one or more leakage points from the RPE.5 Enhanced depth imaging (EDI) OCT typically reveals a significant increase in choroidal thickness (CT).1 Studies of indocyanine-green angiography (ICGA) have revealed choroidal hyperpermeability, localised choroidal filling delays and venous congestion.1 The association between the increased choroidal thickness and areas of choroidal hyperpermeability has been further demonstrated with swept-source OCT.6 These results support the mechanistic explanation of choroidal hyperperfusion or increased hydrostatic pressure leading to elevation of the RPE and subsequent development of the RPE microrips corresponding to leakage spots.1
Dynamic Vessel Analyzer (DVA, Imedos Systems, Jena, Germany) is a commercially available device that evaluates retinal vessels at baseline (static) and after flicker stimulation (dynamic) in a non-invasive fashion. DVA relies on the principle of neurovascular coupling, which postulated that retinal cells activity, and thus their metabolic demand, increases in response to flicker light; in order to satisfy retinal metabolic demands, vascular dilation is based on the principle that retinal cells activity, and thus their oxygen consumption, is increased in response to flicker light. To meet the retinal metabolic demands, reactive hyperaemia and vasodilatation occur and this phenomenon has been defined as neurovascular coupling.7 Following vasodilatation, transient vasoconstriction can be observed in arterial vessels, reaching a minimum diameter approximately 10–40 s after flicker extinction.8
Retinal vascular response to flicker light is a complex phenomenon regulated by several biochemical factors including nitric oxide, arachidonic acid metabolites, potassium, lactate, adenosine and endothelin-1.7 DVA has been applied to inquire endothelial dysfunction and impaired dynamic retinal vessel functionality has been demonstrated in several cardiovascular risk factors (eg, tobacco, hypertension, diabetes) and changes in vessel diameters have been linked to coronary heart disease, stroke and stroke mortality.8 It is noteworthy that CSCR has been linked to coronary heart disease, stroke and stroke mortality.9 10
The purpose of this study was to analyse the static characteristics and dynamic functionality of retinal vessels in eyes with CSCR by means of DVA. Such analysis allows to investigate non-invasively retinal vessels diameters (static) along with the effects of sympathetic tone on retinal vessels dynamic, and the potential correlations of these parameters with the disease status.
Methods
Study participants
Patients with CSCR presenting at the Medical Retina and Imaging Unit of the Department of Ophthalmology of the University Vita-Salute San Raffaele Hospital in Milan (Italy), between May 2015 and November 2016 were enrolled in the study. The criteria for inclusion were: (1) age >18 years, (2) diagnosis of treatment-naïve active CSCR, (3) presence of subretinal fluid involving the fovea on structural OCT, (4) angiographic evidence of active leakage. The exclusion criteria were: (1) presence of any other retinal disorder potentially confounding the clinical assessment (eg, age-related macular disease, diabetic retinopathy, retinal vein occlusion, retinal artery occlusion), (2) any previous treatment for CSCR (eg, photodynamic therapy, antivascular endothelial growth factor intravitreal injection), (3) any ocular surgery in the study eye in the past 6 months, (4) presence of significant media opacities (eg, cataract or corneal opacity), 5) uncontrolled systemic hypertension or other systemic diseases. If both eyes satisfied inclusion criteria, one eye was randomly included in the study.
During the study period, age-matched and sex-matched healthy control subjects were also recruited. Included subjects were older than 18 years with systemic blood pressure within normal limits; the exclusion criteria were any eye pathology, any self-reported history of systemic disease and smoking. One eye was randomly chosen from control group.
All patients and control subjects signed a written consent for observational study, approved by the ethics committee of San Raffaele Hospital. The study was conducted in agreement with the Declaration of Helsinki for research involving human subjects.
Study protocol
Patients with CSCR and controls underwent a complete ophthalmic evaluation, including assessment of distance best-corrected visual acuity (BCVA) using Snellen charts, Goldmann applanation tonometry, slit lamp biomicroscopy and dilated fundus examination, structural OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany) and DVA. Patients with CSCR underwent also FA and ICGA (Spectralis). All measurements were performed at the same range of time (between 15:00 and 17:00 hours) to avoid diurnal alterations.
High-resolution EDI OCT assessment
A 9 mm high-resolution horizontal EDI OCT line scan through the fovea was performed. The line scan was saved for analysis after 100 frames were averaged, using the automatic averaging and eye tracking features of the proprietary device. Subfoveal CT was obtained on the structural EDI OCT (horizontal line) by a single operator (LB) who manually measured the distance between the hyporeflective line corresponding to the sclerochoroidal interface and the outer portion of the hyper-reflective band corresponding to the RPE.
Dynamic vessel analysis
Protocol of DVA acquisition have been extensively described.11 12 In order to perform this analysis, an adequate pupil dilation using topical tropicamide was obtained and examinations were conducted in a dark room. Abstention from alcohol and caffeine-containing products was requested from participants in the 12 hours period prior to the study. Patient was asked to stay focused on the tip of a fixation bar, while the fundus was examined under green light with an average luminance of 130 cd/m2 (ILT1700 Research Radiometer, International Light Technologies, USA). Using a green light illumination (530–600 nm), the DVA creates a great contrast between retinal blood vessels and the adjacent tissue.8 A charge-coupled device camera detects this reflected light and uses it to quantify the width of the vessels. The DVA includes a software to track the eye movements, so once obtained a focus image of the fundus, a fixation target was located in a single zone (eg, a vessel branch) over the entire 30° visual field.
The complete examination had a duration of 350 s, which included three cycles of flicker/non-flicker light. Selected vessel diameters were first recorded for 50 s, then a flicker stimulation was applied for 20 s (to allow vessels dilation) followed by a non-flicker period for 80 s; the sequence was repeated three times. Vessel diameters were calculated and expressed in measurement units; vessel dilation was measured by calculating the percentage increase in vessel diameter relative to baseline after 20 s of flicker stimulation, and averaging the three measurement cycles.
Static vessel analysis
Protocol of acquisition have been previously described.11 12 Using the FF450 retinal camera (Zeiss AG, Jena, Germany), contained into the DVA, a 50° fundus photograph was acquired. Images were analysed with VISUALIS and VesselMap Software (Imedos Systems). Using an optic disc-centred image, the papilla is marked and the software creates an area of one-half to one disc diameter from its centre to measure all vessels in which arteries and veins are manually marked. Central retinal artery equivalent (CRAE), which refers to the diameter of the central retinal artery; the central retinal vein equivalent (CRVE), which refers to the diameter of central retinal vein and the arteriovenous ratio (AVR), which represents the central retinal artery equivalent/central retinal vein equivalent ratio were calculated for each examination.
Statistical analyses
Variables included in the analysis were: age, sex, race, eye (right/left), BCVA converted to logarithm of the minimum angle of resolution (logMAR), subfoveal CT, CRAE, CRVE, ARV, arterial and venous dilations. All variables were tested for normal distributions using the Kolmogorov-Smirnov test. All numerical data were reported as mean±SD. Differences between study eyes and controls eyes were analysed by means of unpaired t-test, Wilcoxon signed rank test and Mann-Whitney U test. All tests were two-sided and a p≤0.05 was considered to be statistically significant. Calculations were performed with SPSS statistics software V.22.0 (SPSS, IBM, Chicago, Illinois, USA).
Results
Fourteen eyes of 14 patients (10 men, 4 women; age 53±10 years) affected by active CSCR, as evaluated by structural OCT and FA, and 14 eyes of 14 age- matched and sex-matched control subjects (9 men, 5 women; age 53±8 years) were enrolled in this study.
Mean BCVA was significant worse in eyes with active CSCR compared with controls (0.20±0.28 vs 0.00±0.00 logMAR, p<0.0001). Eyes with active CSCR had a thicker choroid compared with controls (438.6±86.1 vs 301.5±72.5 µm, p=0.0001) (figure 1A).
Statistical comparison among eyes with active central serous chorioretinopathy (CSCR) and controls with regards to (A) subfoveal choroidal thickness (SFCT), (B) venous and (C) arterial dilation in response to flicker light at dynamic analysis, (D) central retinal vein equivalent (CRVE), (E) central retinal artery equivalent (CRAE) and (F) arteriovenous ratio (AVR) at static analysis. ***p<0.001; *p<0.05; NS, not significant.
With regard to dynamic analysis (figure 2), eyes with active CSCR disclosed reduced venous dilation compared with control eyes (3.3%±2.0% vs 5.5%±2.6%, p=0.0258) (figure 1B). No significant difference (p=0.2) was appreciated among the two groups for arterial dilation (figure 1C). With regard to static retinal analysis (figure 3), no significant difference was disclosed for CRVE (p=0.6) (figure 1D), CRAE (p=0.9) (figure 1E) or AVR (p=0.6) (figure 1F).
Dynamic vessel analysis of patient #5 with central serous chorioretinopathy (CSCR) and of healthy control subject #3. At baseline in patients with CSCR (first row, left panel) arterial and venous segments are chosen and marked with a probe (red for the artery and blue for the vein) to evaluate the arterial (first row, right panel) and venous (second row, right panel) flicker response. The same procedure is repeated in healthy control subjects (second row, left panel)—arterial and venous segments are chosen and marked with a probe (red for the artery and blue for the vein) to evaluate the arterial (third row, right panel) and venous (fourth row, right panel) flicker response.
Static analysis performed with Dynamic Vessel Analyzer in patient #5 with central serous chorioretinopathy (CSCR) and in healthy control subject #3. In patients with CSCR, arterial and venous vessels are selected manually to calculate the central retinal artery equivalent, central retinal vein equivalent and arteriovenous ratio (left panel). The same procedure is repeated in healthy control subjects (right panel).
Discussion
In the present study, we compared the retinal vascular features of 14 eyes of 14 consecutive patients with active CSCR, with those of 14 eyes of 14 matched control subjects. Eyes with active CSCR exhibited a reduced retinal venous dilation in response to flicker light stimulation when compared with control eyes. In addition, the results of this study revealed an increased CT in patients with CSCR compared with controls.
In 1967, Gass was the first to propose that pathogenesis of CSCR relies on the choroid.13 Nowadays, it is widely accepted that the choroid plays a major role in CSCR and its features have been extensively investigated under different imaging modalities. ICGA can identify choroidal hyperpermeability, defined as broad areas of hyper-cyanescence in the late frames, and this is a hallmark of the disease.14 As further confirmed by our study, increased CT (and dilated choroidal vessels)15 at OCT are key features. Using a quantitative approach, Kuroda et al16 demonstrated that increased choroidal thickness is due to increased vascular area over the stroma and this could reflect a choroidal circulatory disturbance. Choroidal blood flow in patients with CSCR has been investigated with different devices and it seems to be significantly impaired.17 Notably, choroidal blood flow velocity decreases concurrently with regression of CSCR, suggesting a validity of choroidal blood flow elevation in the pathogenesis of acute CSCR.18 The increased sympathetic activity could only partially explain this choroidal vascular dysregulation. The activation of sympathetic system together with the inhibition of parasympathetic system could impact the choroidal circulation by increasing the vascular permeability or interfering with cytokines for autoregulation of blood vessels and the function of blood-retina barrier of RPE.4
Saito et al19 found a vasoconstriction of choroidal arterioles, possibly due to sympathetic alpha-adrenoceptor activation. This mechanism leads to altered perfusion into the choriocapillaris and finally to passive overflow into the surrounding large choroidal veins via alternative pathways such as adjacent branches of circulatory units of lobules.19 Chung et al20 found that Haller's layer and total choroidal thicknesses were greater in eyes affected by CSCR than in both fellow, unaffected eyes and normal control eyes, whereas there were no significant differences in the choriocapillaris/Sattler's layer. The altered thickness of Haller's layer in eyes affected by CSCR could be explained by non-vascular smooth muscle cells (NVSMC). These cells, which are abundant in the choroid, are affected by both parasympathetic and sympathetic innervation21 and could play a role in the development of choroidal thickness, based on a complex network within the choroidal stroma.22 As sympathetic activity is increased, NVSMC may stretch out, leading to vascular enlargement or interstitial oedema through stretching the vascular walls and making space for the accumulation of fluid in stroma. Alternatively, overactivation of mineralocorticoid receptor may hyperpolarise choroidal endothelial cells causing choroidal thickening, as mineralocorticoid receptor signalling has been suggested to upregulate Ca2+-activated K+ channels in choroidal endothelial cells, leading to choroidal vascular dilatation.23 On the other hand, no significant differences in the choriocapillaris/Sattler's layer were registered, probably due to the lower number of NVSMC in these layers than in Haller 's layer.21
Under conditions of sympathetic vasoconstriction, capillary hydrostatic pressure could be reduced by the increased precapillary to postcapillary resistance, enhancing fluid absorption into the capillaries rather than its transudation into the interstitial space. Under these conditions, thickening of the choriocapillaris/Sattler's layer may be prevented since thickening of Haller 's layer is regarded in part as due to interstitial oedema.20
While several studies analysed the alterations of choroidal blood flow in patients with CSCR, the role of retinal vasculature involvement has not been elucidated yet. For this reason, we decided to study retinal vessel function in addition to choroid in order to inquiry for retinal vasculature involvement and, moreover, to gather insights on choroidal dysfunction by translation of retinal findings. Our results revealed a reduction in retinal vein response to flicker light stimulation in eyes with active CSCR compared with controls. No difference in arterial dilation was found between the two groups. One possible explanation for these findings could be the increased sympathetic tone in eyes with active CSCR. It has been previously observed that patients with CSCR have impaired autonomic system with hyperactivation of sympathetic over parasympathetic system.24 The reduction in retinal vessels motility, in particular at the vein side, could lead to venous stasis in eyes with CSCR.
The retinal vessels stasis together with the delayed choroidal vessels filling could lead to capillary and venous congestion, which is a characteristic frequently observed in eyes with CSCR and may correspond to the increased choroidal thickness. It is also possible that subretinal fluid could impair vessel motility, as described for other causes of retinal fluid accumulation.11 25
The present study has several limitations mainly due to the small number of included eyes.
To conclude, using DVA in patients with CSCR we found a reduced venous dilation on dynamic analysis. The impaired retinal vascular function, namely decreased retinal vein response to flicker light stimulation, possibly due to increased sympathetic tone and potentially leading to venous stasis, together with the increased choroidal thickness may help understand CSCR and give insights in its pathogenesis. Further studies evaluating larger sample sizes are needed to confirm these results.
References
Footnotes
Contributors GQ and FB conceived of the study. LT, LB, AC, LQ and IZ collected data. AR provided statistical analysis.
Competing interests None declared.
Ethics approval Ethics Committee of San Raffaele Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
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