Acute (attack) primary angle-closure (APAC) is an important

Transcription

1 Glaucoma Choroidal Thickness in Fellow Eyes of Patients with Acute Primary Angle-Closure Measured by Enhanced Depth Imaging Spectral-Domain Optical Coherence Tomography Minwen Zhou, 1,2 Wei Wang, 1,2 Xiaoyan Ding, 1 Wenbin Huang, 1 Shida Chen, 1 Alan M. Laties, 3 and Xiulan Zhang 1 PURPOSE. We evaluated choroidal thickness in the fellow eyes of patients with acute primary angle-closure (APAC) and compared findings to those of normal controls. METHODS. The study group comprised 44 fellow eyes defined as primary angle-closure suspect (PACS) of 44 subjects who had experienced APAC and 43 eyes of 43 healthy volunteers. Using enhanced depth imaging optical coherence tomography (EDI- OCT), the peripapillary and macular choroidal thickness of the PACS eyes and the control eyes were measured and compared at each location or segment. Pearson correlation analysis and a multivariable regression model were used to evaluate the relationships between choroidal thickness and related factors. RESULTS. At all the macular locations, the choroidal thickness was thickest at the subfovea. The PACS eyes had a thicker choroid than the control eyes at all macular locations (all P < 0.05), and it still was significantly thicker after controlling for age, axial length, and sex, except at 3 mm superior from the fovea (P ¼ 0.124). Multivariable linear regression analysis showed that the subfoveal choroidal thickness was significantly thicker in association with the PACS diagnosis, and thinner in association with older subjects and longer axial length eyes. There were no statistically significant differences in the choroidal thickness between the groups at any peripapillary location or segment (P > 0.05). CONCLUSIONS. PACS eyes that had a fellow eye experience of APAC had a thicker macular choroid than the control eyes. The potential role of a thicker choroid as a risk factor for APAC must be investigated further. (Invest Ophthalmol Vis Sci. 2013; 54: ) DOI: /iovs From the 1 Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, People s Republic of China; and the 3 Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania. 2 These authors contributed equally to the work presented here and should therefore be regarded as equivalent authors. Supported by the National Natural Science Foundation of China ( ) and the Fundamental Research Funds of State Key Laboratory of Ophthalmology (2011C02). The authors alone are responsible for the content and writing of the paper. Submitted for publication October 5, 2012; revised December 4, 2013; accepted December 26, Disclosure: M. Zhou, None;W. Wang, None;X. Ding, None; W. Huang, None;S. Chen, None;A.M. Laties, None;X. Zhang, None Corresponding author: Xiulan Zhang, Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, China ; zhangxl2@mail.sysu.edu.cn. Acute (attack) primary angle-closure (APAC) is an important cause of blindness in East Asian people. 1,2 A previous study revealed that middle-aged Chinese women, especially those older than 60 years, are predisposed to APAC. 3 The disease usually also has been found to be responsible for bilateral glaucoma blindness. 4 APAC is a sudden increase in intraocular pressure (IOP) in individuals who are predisposed anatomically to this condition by having a shallow anterior chamber, shorter axial length, small corneal diameter and radius of curvature, increased lens thickness, and an anterior lens iris diaphragm. 5 According to a new theory, choroidal expansion also may have an important role in APAC. 6 Despite extensive clinicopathologic descriptions of the anatomy of eyeball changes in APAC, to our knowledge there have been virtually no similar analyses of corresponding in vivo choroidal morphologic changes. Researchers first attempted to find a method to measure choroidal thickness in the early 1970s. They found that human choroidal thickness could be measured accurately in vivo using ultrasound; however, this method lacked reproducibility due to its inability to track the same point across multiple sample captures. 7 The recent development of enhanced depth imaging (EDI) has made choroidal examination with spectral-domain optical coherence tomography (SD-OCT) possible The EDI-OCT is based on a longer wavelength light source, and allows higher penetration at the RPE. EDI-OCT provides images of the full-thickness choroid, thereby enabling the choroidal thickness to be determined. The thickness normally is represented by the distance between the RPE and the chorioscleral interface. 16 When an eye suffers an APAC attack, because of the extent of media opacity, we cannot obtain an image using EDI-OCT. However, as the fellow eyes have a similar anatomic structure, it is possible to detect the choroidal characteristics in APAC patients by examining the fellow eyes. Our study focused on the fellow eyes, defined as primary angle-closure suspect (PACS), and of APAC eyes, and examined the choroidal structure around the optic disk and macula using EDI-OCT. The data were compared to those of controls obtained from the same source. SUBJECTS AND METHODS Subjects and Enrollment Criteria This prospective, comparative study was approved by the Ethical Review Committee of Zhongshan Ophthalmic Center and adhered to the provisions of the Declaration of Helsinki for research involving human subjects. Written informed consent was obtained from all the participants involved in the study. All subjects were from a Chinese Han population. Investigative Ophthalmology & Visual Science, March 2013, Vol. 54, No. 3 Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc. 1971

2 1972 Zhou et al. IOVS, March 2013, Vol. 54, No. 3 All enrolled glaucoma patients had experienced an attack of APAC in one eye that lasted 1 to 10 days before presenting to the clinic, and the fellow eye was confirmed as PACS. The APAC was defined according to the following criteria: (1) the presence of at least two of the following symptoms 17 : ocular or periocular pain, nausea and/or vomiting, or an antecedent history of intermittent blurring of vision with halos; (2) IOP of at least 22 mm Hg (as measured by Goldmann applanation tonometry) and the presence of at least three of the following signs: conjunctival injection, corneal epithelial edema, a middilated unreactive pupil, and shallow anterior chamber; and (3) an occluded angle in the affected eye verified by gonioscopy. PACS is defined as a pigmented trabecular meshwork in the eye not visible for 1808 under static gonioscopy (Goldmann) and IOP lower than 21 mm Hg, without peripheral anterior synechiae or glaucomatous neuropathy. 18 All eyes underwent an ultrasound biomicroscopy (UBM) examination to confirm the existence of a narrow-angle pupillary block component. Patients with any of the following criteria were excluded: secondary acute attack because of lens subluxation, uveitis, iris neovascularization, trauma, tumor, or any obvious cataract leading to an intumescent lens; diabetes or systemic hypertension; a history of intraocular surgery; and inability to tolerate gonioscopy or UBM examination. Other exclusion criteria for the PACS and control groups included high myopia or hyperopia (greater than þ6 or 6 diopters [D] of the spherical equivalent refractive error); any retinal or RPE detachment; any retinal abnormalities, such as choroidal neovascularization, asymptomatic pigment epithelial detachment, or whitish myopic atrophy; clinically relevant opacities of the optic media; and lowquality images due to unstable fixation or a severe cataract. As APAC eyes suffer from corneal edema, pupil dilation, and media opacity to some extent, only PACS eyes scheduled for peripheral iridectomy that underwent EDI-OCT choroidal scans at the glaucoma department of the Zhongshan Ophthalmic Center were recruited for this study prospectively and consecutively between October 2011 and July To limit any potential change of the choroidal structure by antiglaucomatous eye drops, no medications, especially pilocarpine to constrict the pupil, were administered to the PACS eyes that underwent the EDI-OCT examination. We enrolled 43 eyes of 43 agematched healthy volunteers with no ophthalmic symptoms. The normal controls did not have any pathology other than mild-tomoderate cataracts. For the comparisons of the choroidal thickness between the normal controls and the PACS patients, one eye of the normal controls was chosen randomly for inclusion in the study. Examination All eyes of all the subjects underwent a thorough ophthalmic evaluation, including slit-lamp biomicroscopy, IOP measurement (applanation tonometry), gonioscopy, fundus examination, UBM, and B-scanning. They also underwent a refractive error examination with an autorefractometer (KR-8900 version 1.07; Topcon Corporation, Tokyo, Japan) and axial length measurements with partial optical coherence interferometry (IOLMaster; Carl Zeiss Meditec, La Jolla, CA). The central anterior chamber depth (ACD), distance from the posterior corneal surface to the anterior crystalline lens surface, lens thickness (LT), distance from the anterior to the posterior lens surface, vitreous chamber depth (VCD), and distance from the posterior lens surface to the inner limiting membrane were measured by A-mode ultrasonography (CINESCAN; Quantel Medical, Clermont-Ferrand, France). Demographic data, such as age, sex, and blood pressure, were collected for both groups. A single experienced ophthalmologist masked to the clinical diagnosis of the patient performed the EDI-OCT examinations in the morning, always around 10 AM. Choroid imaging was performed using the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) device (Fig. 1). Choroid imaging was averaged for 100 scans using the device s automatic averaging and eye-tracking features. To measure the thickness of the macula and peripapillary choroid, horizontal and vertical sections going directly through the center of the fovea and optic disk were selected (Figs. 1A D). A 3608, 3.4 mm diameter peripapillary circle scan also was performed using the standard protocol for the assessment of choroidal thickness (Fig. 1E). 19 The resultant images were viewed and measured with Heidelberg Eye Explorer software (version ; Heidelberg Engineering). Keratometry readings and the most recent refraction were entered into the software program to estimate optical magnification and, therefore, to allow for more accurate comparisons across individuals. The choroid was measured from the outer portion of the hyper-reflective line corresponding to the RPE to the inner surface of the sclera. Measurements were taken of the subfoveal choroid, and at 1 and 3 mm superiorly, inferiorly, temporally, and nasally to the fovea. The choroid was measured by two independent graders who were blinded to the diagnosis. If the thickness difference measurements of the two examiners exceeded 15% of the mean of the two values, there was open adjudication with the senior author and then averaged for analysis. We also measured peripapillary choroidal thicknesses in the superior, inferior, nasal, and temporal quadrants. Two measurements were made in each of the four quadrants at 1 mm intervals along the line of the RPE. For example, the first measurement was made close to the optic nerve at 1 mm distal to the beginning of the RPE, and the second measurement was taken at 2 mm away from the beginning of the RPE. A peripapillary circle scan was performed, and the choroidal thickness was delineated manually using the Heidelberg Eye Explorer software (Heidelberg Engineering) as the area of visible choroidal vasculature between the epithelial border of the outer retinal pigment and the inner scleral wall (Fig. 1E). Statistical Analyses The data were processed and analyzed statistically using SPSS for Windows XP (Version 13.0; SPSS, Chicago, IL). All values are presented as mean 6 SD. Categorical covariates were assessed individually with Fisher s exact test. For comparison between the two different groups, an independent sample t-test was used to evaluate differences in the average. Pearson correlation analysis was performed to evaluate the relationships between the subfoveal choroidal thickness, and age, sex, diastolic blood pressure, systolic blood pressure, diastolic ocular perfusion pressure, systolic ocular perfusion pressure, mean ocular perfusion pressure, axial length, IOP at imaging, ACD, LT, and VCD in each group. The multivariable regression model was fitted with the PACS diagnosis, age, sex, and axial length variables. For adjusted age, sex, and axial length factors, multivariate linear regression analyses of the choroidal thickness were used. For all tests, P < 0.05 was considered to be significant. RESULTS Patients Demographic Data We included in this study 44 PACS patients (44 eyes) who fulfilled the inclusion criteria, in addition to a normal control group containing 43 subjects (43 eyes). The mean ages of the PACS patients and the normal control individuals were (mean 6 SD) and years, respectively. The mean spherical equivalent was D in the PACS group and D in the control group. The mean axial lengths were and mm, respectively. All data are summarized in Table 1. There were no significant differences in sex, mean age, diastolic blood pressure, systolic blood pressure, diastolic ocular perfusion pressure, systolic ocular perfusion pressure, mean ocular perfusion pressure, and IOP at imaging between the two groups, whereas the axial length, ACD, LT, VCD, and the spherical equivalent between two groups were significantly different (P < 0.05). Table 2 shows the mean axial length, ACD, LT, and VCD between the

3 IOVS, March 2013, Vol. 54, No. 3 Choroidal Thickness in PACS Eyes 1973 FIGURE 1. EDI-OCT scans showing the macula and the peripapillary choroidal thickness of the same subject. (A) Image of macular choroidal thickness from a horizontal scan. Left, nasal; right, temporal. EDI-OCT image shows SFCT, T1 mm, N1 mm, T3 mm, and N3 mm, with choroidal thickness of 268, 264, 239, 143, and 156 lm, respectively. (B) Image of macular choroidal thickness from a vertical scan. Left, inferior; right, superior. EDI-OCT image shows SFCT, S1 mm, I1 mm, S3 mm, and I3 mm, with choroidal thickness of 263, 263, 269, 233, and 223 lm, respectively. (C) Image of peripapillary choroidal thickness from a vertical scan. Left, inferior; right, superior. EDI-OCT image shows S1 mm, I1 mm, S2 mm, and I2 mm, with choroidal thickness of 173, 125, 197, and 120 lm, respectively. (D) Image of peripapillary choroidal thickness from a horizontal scan. Left, nasal; right, temporal. EDI-OCT image shows T1 mm, N1 mm, T2 mm, and N2 mm, with choroidal thickness of 153, 207, 190, and 244 lm, respectively. (E) Image of peripapillary choroidal thickness from 3608 peripapillary circle scans. Following this scan, the choroidal thickness was delineated manually using Heidelberg Eye Explorer software as the area of visible choroidal vasculature between the outer retinal pigment epithelial border and the inner scleral wall. SFCT, subfoveal choroidal thickness; S, superior; I, inferior; N, nasal; T, temporal.

4 1974 Zhou et al. IOVS, March 2013, Vol. 54, No. 3 TABLE 1. Clinical Characteristics in Study Subjects PACS Normal Control Overall P N patients (N eyes) 44 (44) 43 (43) 87 (87) Mean age (SD), y (9.24) (8.99) (9.16) 0.861* Sex, male/female 11/33 17/26 28/ IOP at imaging (SD), mm Hg (4.06) (3.50) (3.75) 0.630* Spherical equivalent (SD), D 0.94 (1.07) 0.43 (1.11) 0.71 (1.11) 0.034* Axial length (SD), mm (0.88) (0.72) (0.93) <0.001* ACD (SD), mm 2.11 (0.28) 2.94 (0.40) 2.43 (0.53) <0.001* LT (SD), mm 5.30 (0.38) 4.70 (0.41) 5.06 (0.49) <0.001* VCD (SD), mm (0.69) (0.60) (0.73) <0.001* DBP (SD), mm Hg (10.05) (14.47) (12.39) 0.515* SBP (SD), mm Hg (17.52) (25.25) (21.73) 0.253* Diastolic OPP (SD), mm Hg (14.36) (15.18) (14.74) 0.435* Systolic OPP (SD), mm Hg (19.47) (23.79) (21.80) 0.195* Mean OPP (SD), mm Hg (10.38) (16.82) (13.94) 0.327* Data are expressed as the mean 6 SD. DBP, diastolic blood pressure; SBP, systolic blood pressure; OPP, ocular perfusion pressure. * Independent sample t-test. Fisher s exact test. Calculated as the differential pressure between Diastolic or Systolic Blood Pressure and IOP. Calculated as the differential pressure between mean BP and IOP ðmean BP ¼ DBP þ 1=3 3½SBP DBPŠÞ. APAC and PACS eyes. There were no significant differences in the mean axial length, ACD, LT, and VCD between the PACS and APAC eyes. Peripapillary Choroidal Thickness Measurements with Line Scans Table 3 compares the mean peripapillary choroidal thickness in both groups at all locations. There was a similar trend, with the inferior quadrant exhibiting the thinnest peripapillary choroidal thickness among all four quadrants in both groups. The thickness of the peripapillary choroid generally increased, moving distally from the optic disc. At each location, the mean peripapillary choroidal thickness of the PACS group was thinner than that of the normal control group. However, none of the locations demonstrated significant differences between the groups (all P > 0.05). Peripapillary Choroidal Thickness Measurements with 3608 Circle Scans Table 4 shows the different average peripapillary segment choroidal thicknesses in both groups with circle scans. Compared to the normal control group, there were no statistically significant differences in choroidal thickness between the groups in any peripapillary segment (all P > 0.05). Macular Choroidal Thickness Measurements The mean subfoveal choroidal thickness was lm in the PACS group and lm in the normal control group, with a statistically significant difference (P < 0.05). In the horizontal section, both groups showed comparable trends; they were noted to be thinnest nasally, thicker in the subfoveal region, and then thinner again temporally. In the vertical section, the choroids of both groups were thinnest inferiorly, thicker in the subfoveal region, and then thinner again superiorly. At all locations, the choroid was thinnest nasally and generally decreased, moving distally from the subfovea. The subfoveal choroidal thickness, and the thickness in the nasal, temporal, superior, and inferior quadrants 1 and 3 mm from the fovea of both groups are shown in Table 5. The comparison of the choroidal thickness between these two groups showed that the eyes of the PACS patients were significantly thicker than those of the normal control individuals at all locations (all P < 0.05; Figs. 2, 3). Pearson Correlation Analysis The results of the Pearson correlation analysis of the subfoveal choroidal thickness are shown in Table 6. Age and axial length were related significantly with the subfoveal choroidal thickness in the PACS and normal control groups. The spherical equivalent factor was related significantly to the subfoveal choroidal thickness in the normal control group and all subjects, but not in the PACS group. The subfoveal choroidal thickness was not correlated with the IOP at imaging or the LT, but it was correlated significantly with the VCD in the PACS group and all subjects, and with the ACD in all subjects. None of the following variables was associated significantly with the subfoveal choroidal thickness: diastolic blood pressure, systolic blood pressure, diastolic ocular perfusion pressure, systolic ocular perfusion pressure, and mean ocular perfusion pressure. Stepwise Multiple Regression Analysis We performed stepwise analysis to determine factors associated most with the subfoveal choroidal thickness. The model included the PACS diagnosis, age, sex, and axial length factor. A PACS diagnosis (PACS subjects had a subfoveal choroidal thickness that was, on average, lm thicker than that of the normal controls) and age were associated most commonly with the subfoveal macular choroidal thickness (P ¼ 0.001), followed by axial length (P ¼ 0.006), and sex (P ¼ 0.04). Table 7 shows the results of the multiple regression analysis. TABLE 2. Clinical Characteristics in PACS and APAC Eyes PACS APAC P Axial length (SD), mm (0.88) (0.78) ACD (SD), mm 2.11 (0.28) 2.17 (0.25) LT (SD), mm 5.30 (0.38) 5.31 (0.41) VCD (SD), mm (0.69) (0.69) Data are expressed as the mean 6 SD.

5 IOVS, March 2013, Vol. 54, No. 3 Choroidal Thickness in PACS Eyes 1975 TABLE 3. Average Choroidal Thickness and 95% Confidence Interval (CI) at Different Locations in Peripapillary with Line Scans Location, mm from optic disc PACS Normal Control 95% CI, lm Mean, lm SD, lm Mean, lm SD, lm Mean Difference, lm* Lower Bound Upper Bound P Superior 1 mm Superior 2 mm Inferior 1 mm Inferior 2 mm Nasal 1 mm Nasal 2 mm Temporal 1 mm Temporal 2 mm Data are expressed as the mean 6 SD. * Normal group as reference. TABLE 4. Average Choroidal Thickness and 95% CI at Different Segments with 3608 Peripapillary Circle Scans Sector PACS Normal Control 95% CI, lm Mean, lm SD, lm Mean, lm SD, lm Mean Difference, lm* Lower Bound Upper Bound P Superior Superotemporal Superonasal Inferior Inferotemporal Inferonasal Temporal Nasal Data are expressed as the mean 6 SD. * Normal group as reference. TABLE 5. Average Choroidal Thickness and 95% CI at Different Locations in Macula Location (mm from fovea) PACS Normal Control 95% CI, lm Mean, lm SD, lm Mean, lm SD, lm Mean Difference, lm* Lower Bound Upper Bound P SFCT <0.001 Superior 1 mm <0.001 Superior 3 mm Inferior 1 mm <0.001 Inferior 3 mm <0.001 Nasal 1 mm <0.001 Nasal 3 mm <0.001 Temporal 1 mm <0.001 Temporal 3 mm <0.001 SFCT, subfoveal choroidal thickness. * Normal group as reference. Adjusted for Age, Sex, and Axial Length The IOP at imaging, spherical equivalent, ACD, LT, VCD, diastolic blood pressure, systolic blood pressure, diastolic ocular perfusion pressure, systolic ocular perfusion pressure, and mean ocular perfusion pressure were not included in the stepwise multiple regression. Thus, the multivariate linear regression only included the PACS diagnosis, age, sex, and axial length. When multivariate linear regression analysis was used to control for compounding factors of age, sex, and axial length, the differences in the choroidal thickness at all locations still remained statistically significant (P < 0.05, Table 8), except at 3 mm superior from the fovea (P ¼ 0.124). DISCUSSION Several studies have examined the choroidal thickness in glaucoma. Of the reported studies, Yin et al. were among the first to report an association between choroidal thinning and glaucoma 20 ; these researchers found that eyes with primary open angle glaucoma (POAG) had the thinnest global and peripapillary choroid, whereas normal controls had the thickest choroid. Mwanza et al. measured 38 normal subjects, 20 normal tension glaucoma (NTG) subjects, and 56 POAG subjects with EDI-OCT, and conducted a comparison among the groups. 21 They did not detect any relationship between the choroidal thickness and glaucoma. Similarly, another study

6 1976 Zhou et al. IOVS, March 2013, Vol. 54, No. 3 FIGURE 2. The average subfoveal choroidal thickness, and 1 mm, 3 mm nasal, temporal to the fovea between the two groups. Mean 6 SD. FIGURE 3. The average subfoveal choroidal thickness, and 1 mm, 3 mm superior, inferior to the fovea between the two groups. Mean 6 SD. found no difference in choroidal thickness between glaucoma and other retinopathies. 22 To the best of our knowledge, there have been no previous studies regarding choroidal thickness in PACS or APAC patients by means of any imaging modalities. As is well known, APAC eyes have a particular characteristic anatomic structure, which includes a shallow anterior chamber and a shorter axial length. Fellow eyes, defined as PACS of patients presenting with APAC, are at risk of suffering a similar attack because of the similar anatomic structure in both eyes. 23 In our study, the spherical equivalent, axial length, ACD, LT, and VCD of PACS eyes were comparable to the APAC eyes. These findings confirmed once again that APAC eyes have a similar anatomic structure to that of the fellow eyes. APAC always has been thought to represent mixed possible mechanisms. In addition to relative pupillary block, forward movement of the lens, and a thicker lens, Quigley et al. hypothesized that choroidal expansion may have a key role in APAC. 6 This conjecture is based on the theory that choroidal expansion leads to forward lens movement and decreases the volume of the anterior chamber, thereby increasing the absolute IOP. However, it has not yet been determined how frequently and how actively choroidal expansion contributes to APAC attacks due to the lack of an accurate measurement systems for this parameter. Recently, a new method of obtaining EDI-OCT has been developed that makes it possible to evaluate the cross-sectional structure and thickness of the choroid. 9,12 15,24,25 This might help us to understand better the choroidal morphology of APAC eyes. In our prospective, comparative study, we measured the peripapillary and macular choroidal thickness in PACS and normal eyes. The macular choroidal thickness exhibited similar regularity in both groups. The subfoveal location was the thickest, and the nasal region was the thinnest. The thickness of the choroid generally decreased, moving distally from the fovea. This trend is similar to that reported previously The average subfoveal choroidal thickness of the normal control group in this study was lm. This is comparable to our previous research group finding, where Ding et al. found that the subfoveal choroidal thickness among healthy Chinese subjects aged 60 to 70 years was lm. 28 Compared to the normal eyes, the results of this study revealed that the choroidal thickness was increased significantly in the PACS eyes. More importantly, the multiple regression analysis in our present study showed that a PACS diagnosis was the factor associated most with the subfoveal macular choroidal thickness and that the subfoveal choroidal thickness of the PACS eyes was, on average, lm thicker than in the normal controls. Previous studies have shown that the mean choroidal thickness within the macula has a negative correlation with axial length, spherical equivalent, and age We found similar results, with the univariable analysis showing that age and axial length were related significantly with the subfoveal choroidal thickness in all the subjects in the two groups. In the multiple regression model, age and axial length still were associated significantly with the subfoveal choroidal thickness in all subjects. Thus, we investigated whether the thicker choroid might be due to the shorter axial length and the age of the PACS eyes. Surprisingly, after adjusting for the axial length, age, and sex by multivariate linear regression analysis, the average macular choroidal thickness of the PACS group still was significantly thicker than that of the normal control group. This indicates that the increased choroidal thickness in the fellow eyes of the APAC patients was independent of potential compounding factors: age, axial length, and sex. Thus, we concluded that the macular choroid in PACS patients is thicker than in normal subjects. However, given that factors other than age, sex, axial length, and the spherical equivalent likely affect the choroidal thickness, this conclusion should be viewed with caution. A thicker choroid might be added to the list of characteristics of the anatomic structure of PACS. However, we should be conscious that the anatomy of eyeball changes in PACS eyes mainly involved the ocular anterior segment. We measured the choroid in the posterior 6 mm of the eye. It is possible that other areas of the choroid might have different thicknesses. Our study also was unable to show changes in the peripheral choroid or to measure the thickness of the peripheral choroid because of the limitation of the present EDI-OCT. Confirmation of increased peripheral choroid thickness might support the idea that a thicker choroid is part of the characteristic anatomic structure of PACS. Irrespective of the aforementioned issues, the finding of a thicker macular choroid in PACS eyes is novel and to our knowledge has not been reported previously. We cannot explain the reason for the thicker choroid compared to the normal controls, and it is not known whether the thicker choroid is genetic, or is a cause or effect of choroidal expansion in primary angle closure-glaucoma or APAC patients.

7 IOVS, March 2013, Vol. 54, No. 3 Choroidal Thickness in PACS Eyes 1977 TABLE 6. Pearson Correlation Were Calculated for Variation in Subfoveal Choroidal Thickness PACS Normal All Factors r P r P r P Age, y <0.001 IOP at imaging, mm Hg Spherical equivalent, D <0.001 Axial length, mm < <0.001 ACD, mm LT, mm VCD, mm <0.001 DBP, mm Hg SBP, mm Hg Diastolic OPP, mm Hg Systolic OPP, mm Hg Mean OPP, mm Hg TABLE 7. Subfoveal Macular Choroidal Thickness and Stepwise Model Multivariable Associations Factors Beta (95% CI) P PACS, vs. normal (23.34, 92.42) Age, y 2.90 ( 4.56, 1.25) Sex, male vs. female (1.52, 64.90) Axial length, mm ( 44.22, 7.63) We also measured the peripapillary choroidal thickness with 3608 circle scans and line scans. In most studies that have used EDI-OCT, choroidal thickness is a representative value obtained at one or several different measurement points. 32,33 However, measurement of a few sampling points tends to be influenced by focal thickening or thinning of the choroid. Thus, in addition to line scans, we also applied the 3608 circle scan method to measure the average thickness of the peripapillary choroid at different segments. Both scan methods showed similar results, and the findings were in accordance with those of previous studies. 9,19 However, in comparison with the normal control group, there was no statistically significant difference in the choroidal thickness between the groups at any peripapillary segment or peripapillary location. While the choroidal thicknesses of the peripapillary area were comparable between the two groups, the macular choroidal thickness was increased in the fellow eyes of the APAC subjects. This raises the question of why different locations yielded different results. We speculate that the optic cup is the last part of the globe to close and that this region may contribute to a thinner choroid in ocular development. Due to the relatively thin choroid and compact tissue in this region, peripapillary choroid has little space to expand. It should be noted that our study has a few limitations. First, the measurements of the choroidal thickness were performed manually, and automated software will be required for a more objective evaluation. Second, the sample size was limited; further long-term studies with larger samples may provide more accurate outcome prediction. Although our APAC eyes were similar to the fellow eyes in terms of their anatomic structures, the choroidal thickness of the fellow eyes may not represent those of the APAC eyes. Further study is expected to reveal a relationship between choroidal thickness changes in APAC eyes. If this is indeed the case, the potential role of a thicker choroid as a risk factor for APAC and as a marker for diagnosing the disease must be investigated further. Lastly, in our study, we did not find additional evidence supporting the theory of choroidal expansion. Further research is required to shed light on this issue. CONCLUSIONS In conclusion, in a specific Chinese population, PACS eyes that had a fellow APAC eye experience having a thicker macular choroid than control eyes. Whether the thicker choroid is a risk factor for APAC must be investigated further. TABLE 8. Multivariate Linear Regression Analysis of Choroidal Thickness at Different Locations (Adjusted for Age, Sex, and Axial Length) Location Mean Difference, lm* (PACS-Normal) Lower Bound 95% CI Upper Bound P SFCT Superior 1 mm Superior 3 mm Inferior 1 mm Inferior 3 mm <0.001 Nasal 1 mm Nasal 3 mm <0.001 Temporal 1 mm Temporal 3 mm <0.001 * Normal group as reference.

8 1978 Zhou et al. IOVS, March 2013, Vol. 54, No. 3 References 1. Aung T, Friedman DS, Chew PT, et al. Long-term outcomes in asians after acute primary angle closure. Ophthalmology. 2004;111: Sawada A, Aoyama A, Yamamoto T, Takatsuka N. Long-term therapeutic outcome of acute primary angle closure in Japanese. Jpn J Ophthalmol. 2007;51: Seah SK, Foster PJ, Chew PT, et al. Incidence of acute primary angle-closure glaucoma in Singapore. An island-wide survey. Arch Ophthalmol. 1997;115: Foster PJ, Oen FT, Machin D, et al. The prevalence of glaucoma in Chinese residents of Singapore: a cross-sectional population survey of the Tanjong Pagar district. Arch Ophthalmol. 2000; 118: Lowe RF. Aetiology of the anatomical basis for primary angleclosure glaucoma. Biometrical comparisons between normal eyes and eyes with primary angle-closure glaucoma. Br J Ophthalmol. 1970;54: Quigley HA, Friedman DS, Congdon NG. Possible mechanisms of primary angle-closure and malignant glaucoma. J Glaucoma. 2003;12: Coleman DJ, Lizzi FL. In vivo choroidal thickness measurement. Am J Ophthalmol. 1979;88: Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol. 2009;147: Ho J, Branchini L, Regatieri C, Krishnan C, Fujimoto JG, Duker JS. Analysis of normal peripapillary choroidal thickness via spectral domain optical coherence tomography. Ophthalmology. 2011;118: Regatieri CV, Branchini L, Fujimoto JG, Duker JS. Choroidal imaging using spectral-domain optical coherence tomography. Retina. 2012;32: Regatieri CV, Branchini L, Carmody J, Fujimoto JG, Duker JS. Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina. 2012;32: Branchini L, Regatieri CV, Flores-Moreno I, Baumann B, Fujimoto JG, Duker JS. Reproducibility of choroidal thickness measurements across three spectral domain optical coherence tomography systems. Ophthalmology. 2012;119: Reibaldi M, Boscia F, Avitabile T, et al. Enhanced depth imaging optical coherence tomography of the choroid in idiopathic macular hole: a cross-sectional prospective study. Am J Ophthalmol. 2011;151: Wang NK, Lai CC, Chu HY, et al. Classification of early dry-type myopic maculopathy with macular choroidal thickness. Am J Ophthalmol. 2012;153: , 677.e1 677.e Maruko I, Iida T, Sugano Y, Ojima A, Ogasawara M, Spaide RF. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology. 2010;117: Usui S, Ikuno Y, Akiba M, et al. Circadian changes in subfoveal choroidal thickness and the relationship with circulatory factors in healthy subjects. Invest Ophthalmol Vis Sci. 2012; 53: Ang LP, Aung T, Chew PT. Acute primary angle closure in an Asian population: long-term outcome of the fellow eye after prophylactic laser peripheral iridotomy. Ophthalmology. 2000;107: Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol. 2002;86: Ehrlich JR, Peterson J, Parlitsis G, Kay KY, Kiss S, Radcliffe NM. Peripapillary choroidal thickness in glaucoma measured with optical coherence tomography. Exp Eye Res. 2011;92: Yin ZQ, Vaegan, Millar TJ, Beaumont P, Sarks S. Widespread choroidal insufficiency in primary open-angle glaucoma. J Glaucoma. 1997;6: Mwanza JC, Hochberg JT, Banitt MR, Feuer WJ, Budenz DL. Lack of association between glaucoma and macular choroidal thickness measured with enhanced depth-imaging optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52: McCourt EA, Cadena BC, Barnett CJ, Ciardella AP, Mandava N, Kahook MY. Measurement of subfoveal choroidal thickness using spectral domain optical coherence tomography. Ophthalmic Surg Lasers Imaging. 2010;41(Suppl):S28 S Edwards RS. Behaviour of the fellow eye in acute angle-closure glaucoma. Br J Ophthalmol. 1982;66: Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness after ranibizumab therapy for neovascular age-related macular degeneration: 12-month results. Ophthalmology. 2012;119: Aoyagi R, Hayashi T, Masai A, et al. Subfoveal choroidal thickness in multiple evanescent white dot syndrome. Clin Exp Optom. 2012;95: Manjunath V, Goren J, Fujimoto JG, Duker JS. Analysis of choroidal thickness in age-related macular degeneration using spectral-domain optical coherence tomography. Am J Ophthalmol. 2011;152: Manjunath V, Taha M, Fujimoto JG, Duker JS. Choroidal thickness in normal eyes measured using Cirrus HD optical coherence tomography. Am J Ophthalmol. 2010;150: Ding X, Li J, Zeng J, et al. Choroidal thickness in healthy Chinese subjects. Invest Ophthalmol Vis Sci. 2011;52: Ouyang Y, Heussen FM, Mokwa N, et al. Spatial distribution of posterior pole choroidal thickness by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52: Hirata M, Tsujikawa A, Matsumoto A, et al. Macular choroidal thickness and volume in normal subjects measured by sweptsource optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52: Maul EA, Friedman DS, Chang DS, et al. Choroidal thickness measured by spectral domain optical coherence tomography: factors affecting thickness in glaucoma patients. Ophthalmology. 2011;118: Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina. 2009;29: Maruko I, Iida T, Sugano Y, Saito M, Sekiryu T. Subfoveal retinal and choroidal thickness after verteporfin photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2011;151: