Association between visual function and the integrity of residual ellipsoid zone in resolved central serous chorioretinopathy

ABSTRACT Central serous chorioretinopathy (CSC) usually resolves spontaneously; however, in some patients, it can be chronic and visual impairment remains even after resolution of the serous

retinal detachment. The impaired photoreceptor cells often present with disrupted ellipsoid zone (EZ) on optical coherence tomography (OCT). In this study, the integrity of EZ was

quantified by calculating the index of residual EZ, identified on binarized OCT images from 25 eyes of 23 patients with resolved CSC. To estimate residual EZ, integrity of residual EZ with

the central horizontal line on the fovea (rEZc) and average integrity of residual EZ within 3 × 3-mm macular area (rEZave) were investigated. The interrater reliability of the method was

assessed using the intraclass correlation coefficient (ICC). The relationship between LogMAR VA and age, central retinal thickness, central choroidal thickness, rEZc, and rEZave were

evaluated using the linear mixed model. Retinal sensitivity was measured with the MP-3 microperimeter and similar analyses were iterated for mean retinal sensitivity (MS). ICC values were

0.938 with rEZc and 0.979 with rEZave. rEZc was significantly related to LogMAR VA (p = 0.039). rEZave was significantly related to MS (p < 0.001). These results suggested potential

usefulness of residual EZ to predict visual function in resolved CSC. SIMILAR CONTENT BEING VIEWED BY OTHERS LONGITUDINAL CHANGES IN THE GANGLION CELL COMPLEX THICKNESS IN ACUTE CENTRAL

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SEROUS CHORIORETINOPATHY Article Open access 11 July 2024 INTRODUCTION Central serous chorioretinopathy (CSC) is an eye disease with serous retinal detachment (SRD) induced by leakage

through the retinal pigment epithelium (RPE) into the subretinal space, causing decreased visual acuity (VA)1,2,3. Although CSC usually resolves spontaneously, or after either retinal

photocoagulation or photodynamic therapy, some symptoms may persist after the resolution of SRD, such as decreased retinal sensitivity (RS) and VA and metamorphopsia4,5,6,7. The ellipsoid

zone (EZ), formerly known as the inner/outer segment of photoreceptors (IS/OS), refers to the second hyper-reflective band on an optical coherence tomography (OCT) image (Fig. 1)8,9. The

development of OCT imaging technology has enabled us to precisely identify the EZ line10,11,12,13. Previous reports have indicated that the integrity of EZ was associated with visual

outcomes in various retinal diseases14,15,16,17,18, such as cone dystrophy19, achromatopia20, and age-related macular degeneration (AMD)8,9. Recent studies revealed that the association of

the integrity of EZ with VA and RS in resolved CSC is notable5,21,22. However, in these reports, the integrity of EZ was assessed only qualitatively, but not quantitatively. In the current

study, to quantify the residual EZ in patients with resolved CSC, we applied the binarization technique to the OCT images. As a result, the integrity of EZ was successfully measured

quantitatively in all eyes. Consequently, quantitative assessment of EZ with the proposed method had a high interrater reliability and a significant structure-function relationship. The

quantitative method using binarization technique would be useful to predict visual function in macular diseases. RESULTS PATIENT DEMOGRAPHICS The demographic data is given in Table 1. The

mean age of the patients was 56.9 years (standard deviation, SD: 11.8, range: 33–80). The mean retinal sensitivity (MS) was 25.2 ± 3.30 [18.4–29.6] dB. Central retinal thickness (CRT) and

central choroidal thickness (CChT) were 194 ± 49.5 [112–298] μm, 330 ± 95.5 [169–513] μm, respectively. rEZc was 0.785 ± 0.230 [0.0846–1]. rEZave was 0.759 ± 0.239 [0.240–0.992]. The numbers

of eyes showing rEZc of <0.4, 0.4 to 0.7, and >0.7 were 1, 8, 16 eyes, respectively. Univariate analysis showed a significant correlation between LogMAR VA and MS (p < 0.01, linear

mixed model). THE INTERRATER AGREEMENT The intraclass correlation coefficient (ICC) of residual EZ with the central horizontal line on the fovea (rEZc) was 0.938 [95% confidence interval

(CI): 0.916–0.945, p < 0.001) (Fig. 2(a))] whereas that of average integrity of residual EZ within 3 × 3-mm macular area (rEZave) was 0.979 [(95% CI: 0.936–0.987, p < 0.001) (Fig. 

2(b))]. RELATIONSHIP BETWEEN OCT PARAMETERS AND VISUAL FUNCTION With univariate analysis, rEZc, rEZave, and CRT were significantly correlated to LogMAR VA, (linear mixed model, p = 0.0125, p

 = 0.0322, and p = 0.0180, respectively) whereas CChT was not significantly correlated to LogMAR VA (Table 2). As a result of Akaike information criterion, second order, (AICc) model

selection, rEZc and CRT were selected as the best explanatory variables for LogMAR VA (AICc = −17.6, Table 2); LogMAR VA = 0.535–0.284 x rEZc (Standard error (SE) = 0.129, p = 0.0386) −

0.00125 × CRT (SE = 0.000616, p = 0.0555). Excluding the variable of rEZc resulted in a significant decrease of the log-likelihood compared to the optimal model (p = 0.0258, ANOVA). Among

rEZave, rEZ1mm, CRT and CCT, AICc model selection resulted in selecting rEZ1mm as the best explanatory variable for LogMAR VA (AICc = −23.4). LogMAR VA = 0.337–0.366 × rEZ1mm (SE = 0.0891, p

 < 0.001, Fig. 3(a)). Univariate analysis also indicated that rEZc, rEZave and macular volume (MV) were significantly correlated to MS (linear mixed model, p < 0.01, respectively),

whereas CChT was not significantly correlated with MS (Table 3). As a result of AICc model selection, age and rEZave were selected as explanatory variables for MS (AICc = 116, Table 3); MS

(dB) = 21.2–0.0721 × age (SE = 0.0347, p = 0.0497) + 10.7 × rEZave (SE = 1.71, p < 0.001). Excluding the variable of rEZave resulted in a significant decrease of the log-likelihood

compared to the optimal model (p < 0.01, ANOVA, Fig. 3(b)). DISCUSSION In this study, we quantified the integrity of residual EZ in patients with resolved CSC and analysed the

relationship between the quantified EZ integrity and visual function. Based on AICc model selection, rEZc and CRT were selected as the best explanatory variables for LogMAR VA, and age and

rEZave were designated for MS. The usefulness of the assessment of residual EZ has been increasingly reported in recent reports especially of eyes with retinitis pigmentosa (RP). Hood and

associates suggested that the point where EZ disappears provides a structural marker for visual field (VF)23. Birch _et al_. measured the width of the EZ and suggested its potential

usefulness as surrogate for the deterioration of VF24. Smith _et al_. reported that EZ width and RS are correlated25. Later, Hariri _et al_. obtained en-face OCT images and assessed the

residual EZ area, expecting that their method could be used for monitoring the EZ changes of patients with advanced RP26. In RP, the peripheral retina is predominantly and diffusely involved

such that the damage in the visual function starts at the periphery gradually expanding to the central area with progression of the disease. This implies that the assessment of the residual

EZ area is an appropriate approach when monitoring the progression of RP27. In contrast, CSC usually occurs in the macular area with the decrease of cone density. A previous report has

suggested that the disappearance of the normal cone mosaic was coincident with the disruption of EZ28. Therefore, the integrity of EZ in the macula, not the EZ area, would be more predictive

of visual function in resolved CSC. In corroboration, our results suggested that the integrity of residual EZ was significantly related to both LogMAR VA and RS measured with the MP-3

microperimeter. The correlation between the integrity of EZ and visual function has been investigated in resolved CSC in previous studies. Ojima _et al_. reported that areas with defective

EZ tend to have decreased RS measured using MP-1 microperimeter29. Matsumoto and associates reported that resolved CSC eyes with worse VA had discontinuity of EZ more frequently than those

with better VA21. Chung _et al_. divided resolved CSC eyes into two groups, those with intact EZ and those with disruptive EZ. The RS and retinal thickness of the disruptive EZ group were

significantly lower than those of the intact EZ group5. Hence, the integrity of EZ appears to be a critical factor for visual function in resolved CSC. However, in all these reports, the

integrity of EZ was assessed only qualitatively, not quantitatively. In these reports, the integrity of EZ was determined as continuous/discontinuous or intact/damaged; but in some cases of

resolved CSC, it is difficult to judge if EZ is discontinuous or damaged just by the impression of the examiner alone. Actually, in the current study, out of 25 eyes, rEZc of 8 eyes ranged

from 0.40 to 0.69, which means that EZ was moderately damaged. Our results suggested that quantitative assessment of EZ by applying the binarization technique enabled the identification of

EZ in all eyes with a sufficient reliability as suggested by the high reproducibility and the tight structure-function relationship. Therefore, the integrity of EZ should be quantified for

precise investigation of the visual function. In this study, we have proposed a novel method for the quantification of EZ in the macula, using binarized images. The quantified index was

determined to have statistically significant correlation with VA and MS. Hariris’ quantification method of preserved EZ area with en-face OCT images for RP showed an extremely high ICC of

0.996 (95% CI, 0.995–0.997; p < 0.001)26. In this study, we quantified the integrity of EZ using spectral domain OCT (SD-OCT); however, the ICC values were similarly high (0.94: rEZc and

0.98: rEZave). In this study, the optimal model suggested that rEZc and VA are associated, suggesting that VA reflects retinal function in the fovea. Consistent with the relationship between

rEZc and VA, the integrity of EZ within 1mm of the macula was correlated with LogMAR VA more strongly than that within 3 mm of the macula. On the contrary, rEZave was related to MS which

indicates that MS reflects retinal function in a wider area around the fovea. We have recently reported that VA was significantly related to the RS within 2 degrees of the fovea measured by

the MP-3 microperimeter, but not the RS obtained from wider retinal area in chronic CSC patients30. Our current results are in accordance of the previous report. In resolved CSC, even after

VA recovers to normal, some patients continue to experience symptoms, such as metamorphopsia and loss of contrast sensitivity31. Even after the recovery of VA, RS measured using MP-1

microperimeter was reported as decreased in resolved CSC compared with that of the control eyes32. With the automatic tracking system for the retina, the MP-3 microperimeter can project

target lights directly to the retina, rather than to the screen, and as a result, they stimulate an intended identical retinal location, even when there is an eye movement. Recently, we have

demonstrated the merit of such an approach in eyes with glaucoma; the measured RS had better structure-function relationship than a perimetry without the automatic retinal tracking

system33. Therefore, in this study, we used the MP-3 microperimeter and as a result, the RS measured using the MP-3 microperimeter was significantly correlated to the integrity of EZ. Many

of the other macular diseases, such as cone dystrophy, age-related macular degeneration, and Stargardt disease, are associated with greater decrease in VA and/or central visual sensitivity

loss. Consequently, the fixation status becomes poor during VF measurement and also VF measurement can be inaccurate, without the automatic retinal tracking system34. The VF measured using

the MP-3 microperimeter can be considered reliable even with poor fixation, and would be of further interest to investigate the relationship between the integrity of EZ and RS measured with

the MP-3 microperimeter in these diseases. Our result of the multivariate regression analysis indicated that age was negatively correlated with RS, like the previous reports. Ismail _et al_.

divided 50 healthy subjects into four age groups and investigated the influence of age on macular sensitivity. They demonstrated a linear decline in RS with increasing age35. Gella and

associates prospectively investigated the RS in the central 20 degrees of the macula of 144 healthy volunteers aged from 25 to 69 years, and the linear regression analysis revealed a 0.04 

dB/year decline in MS36. Even in healthy eyes, the decrease in RS is one of the natural age-related changes. There are previous reports that have suggested a reduction of subfoveal choroidal

thickness after spontaneous resolution in acute CSC43. In this study, on the contrary, CChT was not related to LogMAR VA and MS. This study has several limitations. Firstly, the study

design was retrospective, and the number of enrolled eyes was less. Secondly, the EZ lines on OCT images were manually identified by examiners. If the image recognition technology, such as

deep learning, is exploited to automatically identify the EZ, our method can be more accurate and established. Although this approach usually requires a much large number of samples, future

studies should be conducted. Additionally, in the present study, residual EZ was investigated only in CSC, and hence the residual EZ was easily identified, because of the relatively

maintained retinal structure. Further studies are needed to examine the usefulness of the current quantification of residual EZ in other retinal diseases, such as cone dystrophy, age-related

macular degeneration, and Stargardt disease, in which the outer retinal structure is severely deteriorated. In conclusion, the quantification of residual EZ had a high interrater

reliability and the obtained value was closely related to visual function in patients with resolved CSC. METHODS This study was a retrospective observational case series and was conducted at

The University of Tokyo, School of Medicine, Tokyo, Japan. Institutional Review Board (IRB) approval was obtained from the University of Tokyo Hospital. All data were fully anonymized

before we accessed them. Written informed consent was not required by the IRB but participants who did not grant authorization to use their medical records for the research were excluded

from analyses. This study was performed according to the tenets of the Declaration of Helsinki. We examined, consecutively, 25 eyes of 23 patients (15 males and 8 females) with resolved CSC

at the retina clinic at The University of Tokyo Hospital. All patients underwent comprehensive ophthalmic examination including refractive error evaluation, best-corrected visual acuity

(BCVA), intraocular pressure, anterior segment examination, and fundus biomicroscopy with pupil dilation. OCT, fluorescein angiography, and indocyanine green angiography were also performed

to diagnose patients as having CSC. Eyes with other macular diseases such as choroidal neovascularization, AMD, and intraocular inflammation were excluded. The BCVA was measured with a

Landolt chart and converted LogMAR VA for the analyses. Retinal sensitivity was assessed using the MP-3 microperimeter (Nidek Co. ltd., Japan). The automatic tracking system of the MP-3

microperimeter for fundus movements allows accurate measurement of RS in various ocular diseases33,37. The MP-3 measurement was performed with 4–2 full-threshold staircase strategy using the

standard Goldmann III stimulus size, similar to previous studies33,38. Twenty-five measurement points were located within central 12 degrees of the macular area (Fig. 4). The MP3

microperimetry measurement was conducted centered at fovea. In addition, it was very carefully monitored that visual field grid was well centered at fovea throughout the MP3 microperimetry

measurements in all eyes. Only reliable VFs with the following criteria were used for analyses: a fixation loss rate < 20% and a false-positive rate < 15% following our previous

report30. We calculated the average of the thresholds of 25 measurement points (mean sensitivity: MS). Simultaneously we obtained SD-OCT images using the Spectralis OCT (Heidelberg

Engineering, Germany). For each eye, 13 line scans within 3 × 3-mm area of the macula were obtained. First, the original OCT image was viewed on the ImageJ software (U.S. National Institute

of Health, MD). The images were then binarized using the Niblack method. Followingly, EZ within 3 mm square area of the fovea was manually traced by two graders (AF and YA) on the binarized

image, referring to the original OCT image (Fig. 4). Once we traced EZ, the rate of white area on the traced line was automatically calculated, which we regarded as the integrity of residual

EZ (rEZ index). External limiting membrane (ELM) and RPE were identifiable even in cases with continuous disruption of EZ. In those cases, we estimated where EZ should have existed on OCT

images from the location of ELM and RPE. For each eye, we calculated three indices for residual EZ, which are rEZc, rEZave and rEZ1mm. rEZc stands for the white index of the single

horizontal line scan on the fovea. rEZave indicates the average of white indices of 13 line scans within 3 × 3-mm area of the macula. rEZ1mm stands for the average of white indices of 5 line

scans within 1mm area of the fovea. Using the enhanced depth imaging mode, we measured CRT, MV, and CChT. To assess the accuracy (interrater agreement) of our current method, we calculated

the ICC of rEZ indices. After evaluating reproducibility, the values obtained by the two examiners were averaged for the subsequent statistical analyses. We evaluated the relationship

between LogMAR VA and five variables of age, rEZc, rEZave, CRT, and CChT, using the linear mixed model whereby eyes were nested within a patient, since two eyes of a patient were included in

the current study. We also investigated the relationship between MS and age, rEZc, rEZave, MV, and CChT. Additionally, using the corrected AICc model selection from all of 25 models, we

investigated which of rEZc and rEZave was responsible for VA and MS, respectively. The AIC is the common statistical measure with which optimal variables can be determined without having an

over-fit problem, unlike the coefficient of determination39. AICc gives an accurate estimation even when the sample size is small40. It is recommended to use model selection methods, instead

of multivariate regression, to improve the model fit by removing redundant variables, because the degrees of freedom decrease as the number of variables increases41,42. The log-likelihood

values of a paired models were compared using the ANOVA. Similar analysis was conducted for MS, instead of LogMAR VA. All statistical analyses were performed using the R statistical

programming language (R version 3.4.3; The Foundation for Statistical Computing, Austria). DATA AVAILABILITY The datasets generated and analysed during the current study are available from

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(1973). MATH  Google Scholar  Download references ACKNOWLEDGEMENTS We would like to thank Asako Ogawa and Motoshi Yamamoto for assistance with technical issues and data analysis. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Department of Ophthalmology, The University of Tokyo Hospital, Tokyo, Japan Asahi Fujita, Yurika Aoyama, Saori Tsuneyoshi, Aya Sugiura, Keiko Azuma, 

Kimiko Asano-Shimizu, Hirotsugu Soga, Yohei Hashimoto, Ryo Asaoka, Tatsuya Inoue & Ryo Obata Authors * Asahi Fujita View author publications You can also search for this author inPubMed 

Google Scholar * Yurika Aoyama View author publications You can also search for this author inPubMed Google Scholar * Saori Tsuneyoshi View author publications You can also search for this

author inPubMed Google Scholar * Aya Sugiura View author publications You can also search for this author inPubMed Google Scholar * Keiko Azuma View author publications You can also search

for this author inPubMed Google Scholar * Kimiko Asano-Shimizu View author publications You can also search for this author inPubMed Google Scholar * Hirotsugu Soga View author publications

You can also search for this author inPubMed Google Scholar * Yohei Hashimoto View author publications You can also search for this author inPubMed Google Scholar * Ryo Asaoka View author

publications You can also search for this author inPubMed Google Scholar * Tatsuya Inoue View author publications You can also search for this author inPubMed Google Scholar * Ryo Obata View

author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS R.O. and T.I. designed this study; A.F., Y.A., S.T., K.A., K.A.S. and A.S. collected the data;

Y.H., R.A., H.S., K.A., T.I. and R.O. analysed the data; A.F., T.I. and R.A. drafted the article. All authors reviewed the manuscript. CORRESPONDING AUTHOR Correspondence to Tatsuya Inoue.

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Fujita, A., Aoyama, Y., Tsuneyoshi, S. _et al._ Association between visual function and the integrity of residual ellipsoid zone in

resolved central serous chorioretinopathy. _Sci Rep_ 9, 12433 (2019). https://doi.org/10.1038/s41598-019-48825-7 Download citation * Received: 10 April 2019 * Accepted: 12 August 2019 *

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