Introduction
Central serous chorioretinopathy (CSCR) is a disease characterized by localized neurosensory detachment with or without focal pigment epithelial detachments and altered retinal pigment epithelium (RPE). It most commonly affects the submacular region, young- to middle-aged men. Many etiological hypotheses have been postulated, but the true cause and mechanism of development of the disease are yet to be discovered. It is usually self-limited.
Various studies have hypothesized that CSCR is related to choroidal vascular pathology and increased choroidal thickness (CT).[1] Studies have shown that the CT is increased in patients with CSCR as compared to the normal populations.[2,3] However, this is not seen in every patient with CSCR and is considered to be present in patients who develop serous macular detachment as part of the pachychoroid group of diseases. Therefore, it cannot entirely account for or explain the pathogenesis of CSCR. Some cases of CSCR do not resolve and develop extensive exudative retinal detachments and resemble uveal effusion syndrome (UES) in some ways. UES is characterized by a thick sclera and one study has mentioned the role of partial sclerectomy in resolving the subretinal fluid in a case of recalcitrant CSCR.[4] That article, and discussions with fellow retinal surgeons led us to the intriguing hypothesis: "Patients developing CSCR might have a thicker sclera compared to normal population and CSCR might be a milder form of UES. Thick sclera may disturb choroidal venous as well as trans-scleral outflow.[5] This may be correlated to increased CT. Our study was designed to test this hypothesis.
This study would have ideally aimed to evaluate the choroidal and scleral thickness at the posterior pole in patients with CSCR, and in controls and compare both to see the relation. Due to the unavailability of suitable technology like three-dimensional micro-magnetic resonance imaging, for the measurement of scleral thickness at the posterior pole, we chose to measure the anterior scleral thickness (AST) since it is easily accessible for measurement. AST is a surrogate measure of overall scleral thickness in this study. Therefore, the AST was assessed in patients with CSCR versus age- and sex-matched controls. We excluded controls with refractive error more than three diopters to avoid confounding caused by: scleral thinning in axially elongated eyes, eyes with short axial length and thick sclera, and thinning of anterior sclera with accommodation in myopes.[6,7,8] Since there is little literature on the measurement of AST,[9,10,11]we also took the opportunity to assess the agreement of AST measured by anterior segment optical coherence tomography (ASOCT) and ultrasound biomicroscopy (UBM) as well as the relation of AST and CT in patients of CSCR.
Methods
This case–control study was approved by the institutional ethics committee and followed the tenets of the Declaration of Helsinki. Informed consent was obtained from all the subjects.
The study was carried out at a large tertiary care hospital. The study period was from October 2018 to January 2020. The study population included 50 patients with CSCR as cases and 50 individuals with refractive error (myopia/hypermetropia) of less than three diopters as controls. The cases were identified by clinical evaluation, followed by ancillary investigations such as optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA).
The complete study population was divided into four groups based on age to ensure age matching of controls. Controls were matched in a ratio of 1:1 with cases in each age group. In this manner, we included five (10%) controls <30 year, 26 (52%) controls between 30 and 40 years, 13 (26%) controls between 41 and 50 years and, six (12%) controls above 50 year. Gender matching was done by selecting four females and the rest of the males in control to match with that of cases. We did the CT and scleral thickness measurements in 56 cases and 63 controls. Later, six cases and 13 controls were excluded since there was ambiguity in the identification of scleral spur and inadequate image clarity. We excluded individuals less than 18 years of age, individuals with refractive error of more than three diopter, individuals with a previous history of ocular surgery, trauma or pathology, and ocular medication, and individuals suffering from connective tissue-related disorders were also excluded due to their known effect on collagen composition and hence scleral biomechanics, those cases or controls where scleral spur could not be identified on ASOCT or UBM.
AST was measured in cases, by ASOCT (Cirrus HD-OCT 5000, Carl Zeiss Meditec Inc., Dublin, CA) and UBM (Appasamy Associates, Chennai, India), at two points which were located 1 mm and 2 mm temporal to the temporal scleral spur. The mean AST was calculated separately for data obtained from ASOCT and UBM. Similarly in the controls, AST was measured only by ASOCT, and the mean AST was calculated [Figure 1]. Controls did not undergo UBM due to ethical issues of subjecting controls to a contact-based test.
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Figure 1: Original image: Measurement of AST: ASOCT (Top)-White arrows from top to bottom showing structures as labelled. UBM (Bottom)-Orange arrow indicating scleral spur. Blue (ASOCT) and Orange (UBM) lines indicating distance from scleral spur and thickness of sclera. AST: Anterior scleral thickness, UBM: Ultrasound biomicroscopy, ASOCT: Anterior segment optical coherence tomography
In all participants, posterior CT was measured subfoveally, 1 mm nasal to the fovea and 1 mm temporal to fovea by Enhanced depth imaging OCT (Cirrus HD-OCT 5000, Carl Zeiss Meditec Inc., Dublin, CA). The mean posterior CT was calculated from the data thus obtained [Figure 2].
Figure 2: Original image: EDI-OCT with Manual Measurement of CT: Horizontal red lines indicating distance from centre of fovea; Vertical red lines indicating choroidal thickness. CT: Choroidal thickness, EDI-OCT: Enhanced depth imaging optical coherence tomography
The data collected were analyzed using the Statistical Package for the Social Sciences Version 20 (IBM SPSS statistics [IBM corp. Armonk, NY, USA released 2011]) software for doing frequency analysis, percentage calculation, and calculating mean and standard deviation. The test of significance was the Chi-square test and Fischer's exact test. The power of the study was 90% and P < 0.05 was considered statistically significant. All necessary statistical methods were applied at the time of analysis.
Results
In the present study, both cases and controls had an equal number of study participants distributed in all the groups. Males 46 (92%) outnumbered females four (8%). We tested the association of AST measured by ASOCT in cases with that in controls (P = 0.09); AST in cases measured by ASOCT with that measured by UBM (P = 0.001), and CT measured by OCT in cases with that in controls (P = 0.002) [Table 1].
Table 1: Association of anterior scleral thickness and choroidal thickness in cases versus controls
The mean CT among cases and controls was 443.56 ± 63.148 μm and 373.88 ± 53.741 μm, respectively. Unpaired t-test showed a significant difference (P = 0.000) between them. The mean AST among cases and controls was 703.86 ± 71.326 μm and 667.54 ± 56.816 μm, respectively. Unpaired t-test showed a significant difference (P = 0.006) between them.
We found a weak positive correlation (r = 0.11) between CT and AST measured by ASOCT, but it was not statistically significant (P = 0.43). When compared with cases, controls had a weaker positive correlation (r = 0.077) between CT and AST measured by ASOCT, but it was not statistically significant as well (P = 0.596) [Table 2]. Pearson correlation found a very weak negative correlation (r = −0.07) between CT by OCT and AST measured by UBM and was not statistically significant (P = 0.62). A positive correlation (r = 0.431) was found between AST measured by ASOCT and UBM and it was statistically significant (P = 0.000) [Table 2].
Table 2: Correlation between choroidal thickness and anterior scleral thickness in cases and controls
Discussion
Various studies have hypothesized that CSCR is related to choroidal vascular pathology. A multitude of risk factors of CSCR are supposed to affect the choroidal vascular network using stasis, ischemia or inflammation, leading to choroidal hyperpermeability, further damage to RPE and subsequent accumulation of Sub-Retinal Fluid (SRF).[12,13,14]
Increased CT in patients of CSCR in the affected eye as well as in the fellow eye in unilateral cases is a well-known fact.[2,3,13] There is a report of exudative macular detachment in the absence of choroidal detachment in a nanophthalmic eye. The patient improved after partial-thickness sclerectomy.[4] This raised the possibility that increased scleral thickness, leading to compromised transscleral outflow may be a cause of increased choroidal fluid accumulation, which eventually leads to the development of CSCR.
However, it was unknown whether the scleral thickness in a patient with CSCR is greater than in normal individuals until the recent retrospective study by Imanaga et al. and pilot study by Lee et al.[10,11] Both these studies compared the choroidal and scleral thickness of a CSCR patient with that of age- and gender-matched controls, and found an association [Table 3].
Table 3: Comparison of similar recently published studies
There are many previous studies for the measurement of scleral thickness by various techniques in vivo[8,9,15,16,17] and ex vivo.[18,19] Our measurements are most consistent with the measurements done by Buckhurst et al.[9] CT in patients with CSCR was found to be higher in comparison to age- and gender-matched controls and it is associated with the disease process, which is consistent with the various previous studies in this regard.[2,3]
Our results revealed that CT and AST showed poor positive correlation and changes in one parameter did not reflect reliable changes in the other. Therefore, we were unable to substantiate the hypothesis proposed by Venkatesh et al. that "increased scleral thickness, leading to compromised transscleral outflow may be a cause of increased choroidal fluid accumulation, which eventually leads to the development of CSCR."[4] Our results do not indicate a relationship between CT and scleral thickness. Contradictory to this, recent studies by Imanaga et al. and Lee et al. established a statistically significant correlation.[10,11] Our study has the advantage of the largest sample size, performed in Indian-origin subjects where a maximum number of cases of CSCR are reported.
We also measured the AST using UBM and compared it with AST measured by ASOCT in cases of CSCR. This is the first study to compare the two modalities of measurement. Many of the cases 39 (78%) were found to have an AST in the range of 600–700 μm by UBM as opposed to >700 μm in most cases 28 (56%) when measured by ASOCT. It is thus apparent that measurements done by UBM are lower as compared to those done by ASOCT. AST measured by UBM was lower with a mean difference of 46.44, which was statistically significant (P = 0.001). We also found a significant (P = 0.000) positive correlation (r = 0.431) between AST measured by ASOCT and that by UBM [Table 2]. We noticed that the outer and inner scleral borders were better demarcated in images obtained by ASOCT as compared to that of UBM. However, the separation of episcleral tissue from scleral tissue was better in images obtained by UBM vis a vis ASOCT. Hence, our measurements in ASOCT include the episcleral tissue and measurements in UBM exclude the episcleral tissue [Figure 1]. This is a limitation of our study regarding the comparison of measurements done by ASOCT and UBM. Further, manual measurement with a digital caliper could be better controlled to the optimum level of accuracy in ASOCT rather than UBM. Hence, it was concluded that the measurement of AST by UBM is not in agreement with that of ASOCT. It is recommended that further studies to validate AST measured by UBM and ASOCT should be done by excluding episcleral tissue from the measurement using ASOCT. The lesser time needed for the test, better control of the manual measuring caliper, and noncontact nature of the test makes ASOCT superior to UBM in the measurement of AST. The second limitation of our study was that the measurements were done by a single individual which creates the possibility of bias. Hence, it is recommended that further studies should be done for this with blinding of the person who is performing the measurements. The persons doing the measurements by UBM and by ASOCT should be different. Furthermore, it is apparent that the measurement of AST by these two techniques may yield different results and may not be comparable across studies. The third limitation was the inclusion of all types of CSCR cases. The fourth limitation was manual measurements.
Conclusions
We have contributed to a knowledge gap in the topic by presenting data regarding scleral thickness in controls versus patients with CSCR. Our results have shown that scleral thickness is not significantly different between cases and controls. We have also shown that there is little correlation between choroidal and scleral thickness. In addition, we have demonstrated that there is a difference in measurements of scleral thickness by ASOCT and UBM and suggested that ASOCT may be the better modality for the measurement of scleral thickness and that the measurements cannot be used interchangeably.
We hypothesize that thick sclera in some way causes choroidal congestion which may be the underlying mechanism in CSCR. It is tempting to suggest that this may be due to vortex vein compression; however, we were unable to measure scleral thickness at the area of the vortex vein exit site. Furthermore, CSCR occurs at the posterior pole, which is the site with a thick choroid and has larger caliber vessels further suggesting that it is due to more localized causes. Further studies are required to validate these possibilities. Although we have considered AST to represent an overall increase in scleral thickness, it is possible that this speculation is wrong and there is a significant increase in posterior scleral thickness in patients with CSCR while AST is not affected. Hence, we recommend future studies with measurements of posterior scleral thickness near the pathology.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
Dr. Vinod Kumar for the interesting discussion that started this chain of thought.
Dr. Asha Bullappa for the support and guidance in statistical analysis.
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