CHOROIDAL AND RETINAL ABNORMALITIES IN CUSHING SYNDROME
Correlation with the Cortisol Level
JIANAN DUAN, MD,* SIKUI SHEN, MD,; CHUNYAN LEI, MD,* SHENG GAO, MD,* TIANCONG CHANG, MD,* YUN ZHANG, MD,* MEIXIA ZHANG, MD*
Purpose: To investigate the structure and blood flow of the retina and choroid in Cushing syndrome and their relationship with cortisol levels.
Methods: A consecutive series of patients with Cushing syndrome with adrenocortical carcinoma were included in this study. Cortisol levels gradually returned to normal after adrenalectomy. Optical coherence tomography and optical coherence tomography angiography were used to assess patients with Cushing syndrome before and after the surgery for retina and choroid. Correlation analysis was performed between cortisol level and fundus changes.
Results: Compared with normal cortisol levels, patients with Cushing syndrome had significantly lower central macular thickness with increased cortisol level (220.82 + 16.59 pm and 223.68 ± 15.78 pm, P = 0.019). However, the central choroidal thickness was higher with increased cortisol level (255.18 ± 105.89 um and 205.94 ± 87.04 pm, P < 0.001). The choriocapillaris flow area was higher with increased cortisol level (2.05 ± 0.14 mm2 and 2.00 ± 0.13 mm2, P = 0.02). The change of choriocapillaris flow area was correlated with the score of Huaxi Emotional-distress Index and 24-hour urine-free cortisol (24h-UFC).
Conclusion: The increased cortisol level was correlated with lesser central macular thickness and thicker central choroidal thickness. The decrease of choriocapillaris flow area was correlated with 24h-UFC, indicating the effect of increased cortisol level on choroidal vessels.
RETINA 44:861-867, 2024
C entral serous chorioretinopathy (CSC) is the most common reason for vision loss in working-age men.1 It is characterized by serous detachment of the neurosensory retina and dilation of choroidal vessels.
From the *Department of Ophthalmology and Research Labora- tory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China; and }Department of Urology, West China Hospital, Sichuan University, Chengdu, China.
Supported by the Sichuan Provincial Science and Technology Support Project (no. 2022YFQ0070) and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC21025), and the Science and Technology Planning Project of Sichuan Province (key research and development project - 2020YFS0257).
None of the authors has any financial/conflicting interests to disclose.
J. Duan and S. Shen authors contributed equally to this work. Reprint requests: Meixia Zhang, MD, Department of Ophthal- mology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; e- mail: zhangmeixia@scu.edu.cn
Lately, CSC was classified as a pachychoroid spec- trum disease.2 However, the precise pathophysiology of CSC remains unknown. Several risk factors have been reported, including steroid usage, sleeping distur- bance, psychopharmacologic medication use, and Type A behavior.1,3 Glucocorticoid exposure is the strongest risk factor for CSC.4
Cushing syndrome (CS) refers to the constellation of clinical signs and symptoms resulting from chronic exposure to the elevated cortisol level, due to pituitary or adrenal gland adenoma.5,6 Tumor resection is the major treatment approach to CS, and the serum corti- sol level gradually return to normal levels after the surgery.6,7
Until now, the correlation between cortisol levels and choroidal/retinal abnormalities has not been established. It was found that central choroidal
thickness (CCT) was significantly higher in patients with CS than in healthy controls, and about one-fifth of patients with CS developed macular degeneration.8 The latest cross-sectional study showed that the increase of CCT was correlated with 24-hour urine- free cortisol (24h-UFC).9 To date, advances in optical coherence tomography (OCT) have enabled better visualization of the retina and choroid.10 The enhanced depth imaging mode of OCT can scan up to 800 pm, which can clearly display choroid and choroidal- scleral interface.10 Images of blood flow of the retina and choroid could be noninvasively obtained by OCT angiography (OCTA).11 So far, there has been no research about the changes of choroidal and retinal blood flow in patients with CS using OCTA. Keto- conazole, as one of the treatment options for CS, can block the synthesis of cortisol. It has been used as one treatment option for patients with CSC, which helped to improve vision and promote the structural recovery of the fundus.12 This indicated that cortisol levels played an important role in the pathogenesis of CSC.
Methods
This prospective clinical study included 34 eyes of 17 patients with CS at the Department of Urology, West China Hospital, Sichuan University, between June 2019 and January 2021. The study protocol was approved by the ethics committee of West China Hospital of Sichuan University (Approval No. 2019- 1131). Written informed consent was obtained from all participants.
Subjects
We included patients with CS due to unilateral adrenal adenoma, who were underwent adrenalec- tomy. The exclusion criteria were listed as follows:
1. Refractive error exceeding ± 6.00 diopters or axial length more than 26.50 mm.
2. Other fundus diseases included glaucoma, diabetic retinopathy, retinal artery/vein occlusion, and age- related macular degeneration.
3. 3History of intraocular surgery, intravitreal injec- tions of steroids and/or antivascular endothelial growth factor (vascular endothelial growth factor) agents, and/or laser treatment.
4. A poor OCTA image quality (quality score < 6).
The cortisol level of patients with CS was evaluated by an urologist after the adrenalectomy. Depending on individual conditions, recovery time might be differ- ent. Clinical evaluation for fundus was performed again when their serum cortisol level was normal.
Ophthalmic Examination
All patients underwent comprehensive ophthalmic examination, including best-corrected visual acuity, slit- lamp examination, intraocular pressure (TX-20, Canon, Tokyo, Japan), axial length (IOL Master Advanced Technology, Carl Zeiss, Meditec, Dublin, CA), OCT (SPECTRALIS, Heidelberg Engineering, Heidelberg), and OCTA (RTVue-XR Avanti; Optovue Inc., Fre- mont, CA). The OCT measurements of the retina and choroid were taken by horizontal/vertical scans (ART 100 frames, enhanced depth imaging mode, High Speed) and radial macular scans (ART nine frames, enhanced depth imaging mode, High Speed). Central macular thickness was measured automatically. The CCT was defined as the distance between the retinal pigment epithelium and the scleral-choroidal interface beneath the foveal center. It was measured manually using the caliper of the Eye Explorer software by two experienced ophthalmologists. The EDI-OCT images of the choroid were converted to binary images using Im- ageJ software (ImageJ 1.52a, Wayne Rasband, National Institutes of Health), and the luminal and interstitial areas of the choroid were calculated. The luminal area, which presented a black signal, was defined as the ves- sel area in the choroid. The vessel density of retinal superficial capillary plexus and retinal deep capillary plexus and choriocapillaris flow area (CCFA) were measured automatically by OCTA. All participants underwent OCT and OCTA in the afternoon to avoid diurnal variations. EDI-OCT and OCTA with follow-up mode were used to evaluate the retina and choroid after the cortisol level returned to normal between 1 month and 6 months.
Endocrinological Evaluation and Systemic Parameters
Serum cortisol at 8 AM and midnight, 24h-UFC, and adrenocorticotropic hormone were measured before and after the adrenalectomy in all patients. The above endocrinological evaluation was performed within 1 day of the eye examination. The psychological survey was performed using the Huaxi Emotional-distress Index (HEI).13 Body mass index, computed tomogra- phy area of adenoma, and blood sugar were included as systemic parameters. We analyzed the relationship between systemic parameters/cortisol level and fundus change in patients with CS.
Statistical Analysis
Statistical analysis was performed using SPSS (IBM, statistics 24.0). Comparisons between the groups were performed with two independent samples
t tests, analysis of variance, and two independent sam- ples nonparametric tests where appropriate. Analysis of covariance was conducted to reduce the influences from confounding factors, such as the axial length. The Pearson correlation test was used to analyze the correlation between variables. The difference was con- sidered statistically significant if the P value <0.05.
Result
Seventeen patients with CS due to unilaterally adrenocortical carcinoma were included in this study. The mean age was 37.3 ± 12.8 years, and 14 of them were female. Seven eyes of four patients with CS (16%) presented abnormal fundus, including serous retinal detachment (two eyes of one patient) and dis- connection of ellipsoid/interdigitation zone (five eyes of three patients).
Structural Changes of Retina and Choroid
The retinal thickness was measured in patients with CS before and after the surgery. The preoperative central macular thickness in patients with CS (220.82 ± 16.59 pm) was significantly lower than the post- operative central macular thickness (223.68 ± 15.78 um, P = 0.019; Figure 1). Meanwhile, the retinal thickness of the macular area, paramacular area, tem- poral side of the macula, nasal side of the macula, and submacular side of the macula were significantly high- er after surgery than before surgery.
The volume and thickness of the choroid decreased significantly in patients with CS after the surgery (Figure 2). The CCT before surgery was 255.18 ± 105.89 um, which is higher than that after surgery (205.94 ± 87.04 um, P < 0.001; Figure 3). Before surgery, the average area of the luminal to choroidal was 3,143.54 ± 601.84 pm2, which is significantly higher than that after adrenalectomy (2,811.59 ± 553.60 pm2, P < 0.001; Figure 3).
The Blood Flow Change of Retina and Choroid
The blood flow change of retina before and after the surgery is shown in Figure 4. There was no significant
difference in the superficial vessel density (47.79% ± 3.49% and 47.27% ± 2.60%, P= 0.108) and the deep vessel density (52.25% ± 2.99% and 52.73% ± 1.94%, P = 0.681) between high cortisol level and normal cortisol level.
The preoperative CCFA was 2.05 ± 0.14 mm2, which was higher than the postoperative CCFA (2.00 ± 0.13 mm2, P = 0.02; Figure 5).
Correlation Analysis
Correlation analysis of potential correlation factors with fundus structural changes before and after surgery in patients with CS is summarized in Table 1.
Pearson correlation analysis indicated that central macular thickness was correlated with body mass index and blood sugar. Superficial vessel density of retina was correlated with body mass index and tumor size on computed tomography, while deep vessel density was not correlated with any systemic factors.
However, CCT was not correlated with the cortisol level. The vessel density of choriocapillaris was corre- lated with the score of HEI, blood sugar, and 24h-UFC. The CCFA was correlated with the score of HEI.
Discussion
This study aimed to investigate the relationship between cortisol level and fundus change. To the best of our knowledge, this is the first prospective self- control clinical study on the relationship between the serum cortisol level and fundus abnormalities, and OCTA was first used to evaluate the blood flow density of the fundus in patients with CS.
In this study, the choroidal thickness was signifi- cantly decreased with normal cortisol levels after the surgery in patients with CS, compared with high cortisol levels before the surgery. Images of EDI- OCT were binarized and analyzed using ImageJ.14-16 The total choroid volume and vascular lumen area were significantly decreased after the surgery. Our result was in line with the findings of Abalem et al.8 They found choroidal thickness was significantly increased in active patients with CS, compared with healthy controls.8 It was reported that the increased
*
260
*
Thickness (um)
240-
220-
A
200
CMT
Fovea
*
330
Preoperation
*
Postoperation
Thickness (um)
320
*
310
B
300
Whole Parafovea
T
S
N
I
A
B
C
D
secretion of glucocorticoid caused the dilation of cho- roidal blood vessels. Compared with the healthy con- trol group, the choroid was significantly thicker in patients with CS, especially in the adrenocorticotropic
*
400
*
40
350
CCT (um)
300
Mean Ratio (%)
39
38
250
37
200
150
36
Preoperation
Postoperation
35
Preoperation
Postoperation
A
B
*
*
40000
60000
Luminal (um2)
35000
Total (um2)
55000
30000
50000
25000
45000
20000
40000
Preoperation
Postoperation
Preoperation
Postoperation
C
D
hormone-dependent CS group.17 It was still contro- versial about the effect of corticosteroids on choroidal thickness. Eymard et al4 reported that there was no significant difference in choroidal thickness between the CS group and the healthy control group, and the change of choroid thickness was independent of the cortisol level in urine and saliva. In anatomical struc- ture, the choroid comprised blood vessels, including the choriocapillary layer and large vascular layer (Haller’s and Sattler’s layers).10 Patients with CS had elevated glucocorticoids due to adrenocortical carci- noma, and cortisol levels gradually returned to normal after adrenalectomy. Increased choroidal thickness in patients with CS before the surgery may reflect that high cortisol levels caused the dilation of choroidal blood vessels. In our correlation analysis, choroidal thickness was not associated with cortisol levels. The previous studies showed that the increase of choroidal thickness in patients with CS was significantly corre- lated with their 24h-UFC.9 Exploring the relationship between glucocorticoid levels and fundus changes was challenging.
Until now, OCTA has not been used to assess choroidal blood flow changes in patients with CS. We found significantly greater CCFA in CS preoperation than postoperation, through the built-in software of OCTA. Based on these results, we believed that high cortisol levels were involved in the choroidal vasodi- lation and hyperperfusion. Ozsoylu et al18 also claimed that glucocorticoids could lead to choroidal vascular insufficiency. In our univariate analysis, CCFA was correlated with the score of HEI. As we know, the score of HEI was correlated with type A personality and anxiety, which was a well-established risk factor for CSC, indicating that type A personality and anxiety might be associated with CSC through raising the cortisol level.1
Preoperation
Postoperation
60
60
55
SCP (%)
DCP (%)
55
50
45
50
40
Superficial_whole
Superficial_ParaFovea
Superficial_T
Superficial_S
Superficial_N
Superficial_
45
Deep_whole
Deep_ParaFovea
Deep_T
Deep_S
Deep_N
Deep_
B
A
In this study, we found that the retinal thickness was significantly increased in patients with CS after the surgery, especially in the macular area. It is well known that the choroid provide nutrition for the outer layer of the retina. The high cortisol level leads to choroidal vasodilation and choroidal hyperperfusion, resulting in the retinal cells having enough oxygen. Relative hypoxia of the retina after surgery might lead to the increase of retinal thickness. There was no difference in the vessel density of the retina before and after the surgery. Univariate analysis indicated that retinal thickness was correlated with the diagnosis time of CS, the maximum cross-sectional area of the adrenal tumor, and 24h-UFC. As we know, the cortisol level was correlated with diagnosis time of CS, the maximum cross-sectional area of the adrenal tumor, and 24h-UFC, consisting with the retinal thickness change. Therefore, we believe that the changes in retinal thickness are caused by inadequate vascular perfusion in choroid after the surgery.
In our study, CSC-like changes were found in seven eyes of 4 patients with CS (16%), including serous retinal detachment, and disconnection of ellipsoid/ interdigitation zone. Brinks et al19 also discovered that CSC-like fundus changes were found in 27.3% of patients with CS. Another study found that 18.18% of patients with CS developed macular disease, which was higher than the healthy population of the same age.8 It was proved that the increase in glucocorticoid levels was related to the occurrence of CSC.20 Large sample size was required for more precise epidemio- logical data. The high cortisol level might induce cho- roidal vasodilation and hyperperfusion, leading to retinal pigment epithelium decompensation. The serous retinal detachment and subretinal fluid accumu- lation was caused by the disfunction of retinal pigment epithelium. The occurrence of CSC-like changes in this study might relate to the changes in choroid vas-
culature with high cortisol levels.21 Therefore, we con- sidered that cortisol might play an important role in the physiopathology of CSC. Arndt et al22 claimed that glucocorticoids might cause fundus disease by affect- ing ion transport in retinal pigment epithelium cells. Hyperperfusion of choroid and destruction of pigment epithelium barrier were two potential mechanisms of CSC.9 In this study, abnormalities in fundus structure were restored after the functional adrenal tumors were removed. Therefore, early surgical intervention is rec- ommended for patients with CS due to adrenal gland neoplasms. We also suggested that patients with CS with visual symptoms should be treated in time to avoid permanent vision loss.
This was a prospective and self-controlled analysis, which maximized eliminating the interference of confounding factors. Besides, OCT and OCTA were first used in evaluating the structural and functional changes of the fundus in patients with CS. However,
2.4
*
CCFA(mm2)
2.2
2.0
1.8
1.6
Preoperation
Postoperation
| Characteristic | Correlation Coefficient of CMT | P | Correlation Coefficient of CCT | P | Correlation Coefficient of SCP | P | Correlation Coefficient of DCP | P | Correlation Coefficient of CCFA | P |
|---|---|---|---|---|---|---|---|---|---|---|
| AL | -0.019 | 0.918 | -0.244 | 0.179 | 0.153 | 0.404 | 0.008 | 0.965 | 0.047 | 0.799 |
| Age | -0.190 | 0.282 | -0.219 | 0.214 | 0.205 | 0.246 | -0.047 | 0.794 | 0.028 | 0.874 |
| Summarized | 0.046 | 0.796 | -0.258 | 0.140 | -0.318 | 0.067 | -0.300 | 0.084 | 0.009 | 0.962 |
| duration of disease | ||||||||||
| BMI | 0.382 | 0.026* | -0.150 | 0.399 | -0.391 | 0.022* | -0.098 | 0.582 | 0.194 | 0.272 |
| Score of HEI | -0.269 | 0.151 | 0.188 | 0.319 | 0.114 | 0.548 | 0.109 | 0.568 | 0.416 | 0.022* |
| Tumor size | -0.153 | 0.421 | -0.136 | 0.474 | 0.379 | 0.039* | -0.219 | 0.245 | 0.135 | 0.478 |
| on CT | ||||||||||
| Blood sugar | -0.615 | <0.001* | 0.011 | 0.952 | 0.286 | 0.125 | -0.090 | 0.637 | 0.306 | 0.100 |
| COR 8 AM | -0.071 | 0.689 | 0.202 | 0.251 | 0.247 | 0.159 | -0.045 | 0.803 | -0.021 | 0.970 |
| COR | -0.125 | 0.511 | -0.044 | 0.816 | 0.354 | 0.055 | -0.006 | 0.974 | 0.135 | 0.478 |
| midnight | ||||||||||
| 24h-UFC | -0.051 | 0.789 | -0.044 | 0.816 | 0.242 | 0.197 | 0.114 | 0.550 | 0.325 | 0.080 |
| ACTH | 0.129 | 0.467 | 0.201 | 0.286 | 0.093 | 0.600 | 0.253 | 0.148 | -0.181 | 0.745 |
*, statistically significant.
ACTH, adrenocorticotropic hormone; CMT, central macular thickness.
our study still has some limitations. First, our sample size of patients with CS was small, due to low morbidity rates of adrenal gland neoplasms. Second, long-term follow-up was lacking in our study. Long- term follow-up can be conducted to observe the recovery of choroidal vasodilatation and insufficiency of vascular perfusion and further clarify the effect of adrenal hormones on the fundus.
In conclusion, the choroidal thickness and blood flow were significantly affected by cortisol levels. The high cortisol level was correlated with lesser central macular thickness and thicker CCT, and the decrease of CCFA was correlated with 24h-UFC. The high cortisol level could be relieved by laparoscopic adrenalectomy for the treatment of CS. Besides, it indicated the importance of normal cortisol levels in maintaining the structure and blood flow density of fundus.
Key words: central serous chorioretinopathy, cho- roid, Cushing syndrome, glucocorticoid, retina.
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